Drugs of anaesthesia and cancer
Letterio B. Santamaria, Daniela Schifilliti, Domenico La Torre,
Department of Neurosciences, Psychiatric and Anesthesiological Sciences, University of Messina,
Via C.Valeria, Messina, Italy
Accepted 16 March 2009
Anaesthesia represents one of the most important medical advances in history, and, nowadays,
can widely be considered safe, thanks to the discovery of new drugs and the adoption of
modern technologies. Nevertheless, anaesthetic practices still represent cause for concern
regarding the consequences they produce. Various anaesthetics are frequently used
without knowing their effects on specific diseases: despite having been reported that
invasion or metastasis of cancer cells easily occurs during surgical procedures, numerous
anaesthetics are used for cancer resection even if their effect on the behaviour of cancer cells
Guidelines for a proper use of anaesthetics in cancer surgery are not available, therefore,
the aim of the present review is to survey available up-to-date information on the effects of
the most used drugs in anaesthesia (volatile and intravenous anaesthetics, nitrous oxide,
opioids, local anaesthetics and neuromuscular blocking drugs) in correlation to cancer. This
kind of knowledge could be a basic valuable support to improve anaesthesia performance
and patient safety.
ª 2009 Elsevier Ltd. All rights reserved.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64
Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64
Drugs of anaesthesia and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .65
* Corresponding author. Tel.: þ39 090 2212774; fax: þ39 090 2212821.
E-mail address: email@example.com (V. Fodale).
0960-7404/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/suronc
Surgical Oncology (2010) 19, 63e81
‘‘Volatile anaesthetic agents’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
‘‘Intravenous anaesthetic agents’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
‘‘Nitrous oxide’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
‘‘Opioids’’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Neuromuscular blocking drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Regional anaesthesia and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Discussion and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76
Cell Lines cited in the text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77
List of abbreviations used in the text . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .81
Described as a group of diseases characterized by an
abnormal growth of cells which tend to proliferate in an
uncontrolled way and, in some cases, to spread, often
resulting in death, cancer represents one of the most
common causes of mortality in many countries around the
world. The need for reliable risk calculation factors and
prognostic criteria for tumours has been widely recognized,
and many authors have attempted to define parameters to
identify different factors involved in tumour genesis.
Cancer is often treated by chemotherapy, immunotherapy,
radiation and surgery. Anaesthesia has an important role in
almost all of the above procedures, particularly during
surgery. At present, many anaesthetic agents are used,
during cancer resection surgery, for example, without
knowing their effects on cancer, mutagenic potential,
impaired metastatic capability, and growth of pre-existing
tumour cells [1,2]. In spite of all of this, to date, few papers
have been published specifically addressing a possible
correlation between anaesthetic drugs and cancers, and
the results are often confused and disputed. A compre-
hensive paper on interaction between anaesthetics and
cancer is, therefore, timely.
In the staging of carcinogenesis, two phenomena have
been proposed. One is malignant transformation, which is
the result of a multi-step process in which cells acquire
mutations of genes that activate protoncogenes or negate
theactionof tumour suppresser
phenomenon in carcinogenesis is immortalization . First
applied to cancer cells, the term immortalization describes
the ability of cells to reproduce indefinitely: they escape
from the normal limitation on growth of a finite number of
division cycles (Hayflick limit).
Recently, it has been suggested that anaesthetic drugs
can induce biomolecular change involved in different
physiological and pathophysiological cellular functions,
such as proliferation, angiogenesis and apoptosis [1,2,4].
These findings support the hypothesis that, by virtue of
some still unknown mechanisms, anaesthesia regime may
influence physiological cellular and/or molecular process,
and that this is one possible explanation for their potential
involvement in tumour development. Nevertheless, the
possible role of anaesthetic drugs in cancer development
and progression is still unclear.
The aim of the present review is to survey available up-
to-date information on the effects of anaesthetic agents on
cancer cells, in order to provide a useful means to decrease
the risk of unwelcome events and to increase anaesthesia
performance, patient safety and, in the future, maybe
outcome. Moreover, this paper may be considered as
a possible background for future studies designed to clarify
the complex interactions between anaesthetic drugs and
The evidence-based practice approach aims at incorpo-
rating the best available research evidence in clinical
decision-making. It is a source of structured information
that includes the following steps: asking answerable ques-
tions, accessing the best information, appraising informa-
tion for validity and relevance, and applying information in
We formulated the following question: What are the
effects on cancer of anaesthesia?
The structured question was used as a starting point for
deriving search terms, as well as inclusion criteria for
retrieving articles. More specifically, the name of each
anaesthetic drug in combination with terms such as cancer
tumour has been used.
Owing to the medical nature of the question, the search
was confined to three databases: The Cochrane Library,
MedLine accessed through PubMed, and CINAHL.
Over one hundred and fifty articles e published from
1980 to 2008, and including studies in vitro, in animals and
humans e were considered.
In the literature reviewed, there is evidence to support
the fact that, by virtue of some still unknown mecha-
nisms, anaesthesia regime may influence physiological
cellular and/or molecular process involved in tumour
development. Nevertheless, the possible role of anaes-
thetic drugs in cancer development and progression is still
64L.B. Santamaria et al.
Drugs of anaesthesia and cancer
‘‘Volatile anaesthetic agents’’
Used alone, or as part of a balanced anaesthesia, volatile
anaesthetics have been the most usually given drugs in
between these drugs and cancer has been investigated
[1,5], especially due to the suspect of inducing tumours,
spontaneous abortions, and congenital anomalies, above all
in chronicallyexposed anaesthetic
hypotheses, however, were not verified from the first
animal and epidemiological studies on effects of chronic
exposure to subanaesthetic concentrations of volatile
anaesthetic agents [6e8].
Halothane is a volatile anaesthetic which, even if
replaced in many clinical practices by sevoflurane as it
causes hepatocellular injury with a high mortality rate, is
still widely employed in many countries and in several third
world regions . Halothane effects on cancer cells have
also been extensively investigated. In 1986, Katzav et al.
demonstrated how halothane, used during excision of Lewis
lung carcinoma (3LL) tumour, decreases natural killer (NK)
cell activity accelerating postsurgical metastasis growth of
mouse tumours . In 1994, Waxler et al., instead,
investigated the effects of this volatile agent on tissue
proteinase inhibitor content and tumour behaviour in lungs
of mice. They demonstrated how the stimulation of
proteinase inhibitory activity by halothane in oxygen may
be responsible for the inhibition of tumour cell prolifera-
tion, resulting in smaller tumour nodules and with no effect
on the incidence of colonization . In more recent years,
in their study in vitro on halothane, sevoflurane and iso-
flurane, Kvolik et al. have observed how, in the clinical
setting, halothane has an antitumour potency which is
higher in comparison to isoflurane . In particular, growth
suppression in cells exposed to halothane was enhanced in
laryngeal carcinoma cells (HEp-2) (growth was reduced to
67.7% of the control amount), colon carcinoma cells (Caco-
2) (to 76.3%), and poorly differentiated cells from lymph
node metastasis of colon carcinoma (SW620) (to 80.9%),
while it was minimal in normal fibroblasts (WI-38) (to
89.4%). Moreover, in Caco-2 cells treated by halothane,
a decrease in deoxyribonucleic acid (DNA) synthesis (52.4%,
p Z0.001), and protein synthesis (19.2%, pZ 0.004) was
recorded. In HEp-2 cells, DNA and RNA syntheses were
decreased to 72.5% and 79.9%, whereas protein synthesis
was 14% of controls. In SW620 cells, protein synthesis after
4 h was 24.4%, while a DNA fragmentation was observed in
Caco-2 cells and pancreatic carcinoma cells (MIA PaCa-2)
. Also, the activity of NK cells was affected by halothane.
Although its effect does not reach statistical significance,
this drug, similarly to other anaesthetics (ketamine, thio-
pental), has been seen to reduce the number of circulating
NK cells per millimetre of blood in rats, increasing lung
metastases or MADB106 lung tumour retention (a selected
variant cell line obtained from a pulmonary metastasis of
a mammary adenocarcinoma e MADB100 e chemically
induced in the inbred Fischer-344 rat) [4,12]. Nevertheless,
the additionof spinalblock
for decades. Interaction
anaesthesia markedly attenuates (by 70%) the promotion of
metastasis by surgery . The effects of halothane on lung
carcinoma cells A 549 have also been evaluated by
Valtcheva et al., demonstrating that sub toxic halothane
concentrations of 0.6 vol.% inhibit surfactant production;
concentrations in the range of 0.8e1.4 vol.% induce
membrane damage, and concentrations equal to and higher
than 1.4 vol.% cell death of approximately 50% of the cells
. In rat glioma C6 cells, halothane inhibits the capaci-
tive calcium ions (Ca2þ) influx with a 50% inhibitory
concentration (IC50) of 1.9 vol.% , and, as demon-
strated by other studies, halothane, at clinically relevant
concentrations, inhibits Ca(2þ)-ATPase (PMCA) pumping
activity in a dose-dependent manner in cells of neural
origin (rat C6 glioma cells, B104 rat neuroblastoma, PC12
rat pheochromocytoma) . The effects of halothane
based anaesthesia on Kþ and carbachol stimulated [3H]
noradrenaline release and associated increases in intra-
cellular Ca2þ in a cultured human neuroblastoma cell line,
SH-SY5Y, were investigated by Atcheson et al. . The
findings demonstrate how halothane produces a dose-
dependent reduction in Kþ evoked release of [3H]
noradrenaline, with significant inhibition (17%) occurring
from 1.26 atm%, a dose-dependent reduction in Kþ evoked
increases (measured at the peak) in intracellular Ca2þ with
significant inhibition (29%) occurring from 0.88 atm% .
In these kinds of cells, moreover, clinically relevant doses
of halothane enhance basal and carbachol-stimulated
second messenger inositol (1,4,5) triphosphate (Ins(1,4,
5)P3) formation . Basal and carbachol evoked release,
instead, are not affected similarly to Kþ plateau and basal
and carbachol evoked increases in intracellular Ca2þ .
Finally, reversible suppression for activity of Hypoxia-
inducible factor 1 (HIF-1), a central component in the
hypoxic response pathway, has been observed by Tatsuya
et al., in their study carried out using a cell line derived
from a human hepatocellular carcinoma, Hep3B, and
halothane, in a range of clinically relevant doses .
Isoflurane is an older inhalational anaesthetic, but is
still widely used in clinical practice. Similar to sevoflurane,
it modifies tumour cell growth in a time-dependent
manner. Nevertheless, the inhibitory effect is absent or
minimal in comparison to that recorded for other inhaled
anaesthetics . While isoflurane does not cause biologi-
cally important differences in tumour growth for either
Caco-2 or MIA PaCa-2 cells, it shows an inhibitory effect
after 6 h of exposure in normal fibroblasts WI-38. On Hep-2
cell lines, instead, it determines a slight increase in the
growth of treated cells, while only a mild increase after 2 h
of exposure, and changes lower than 5% are induced in
metabolic activity, respectively, of MIA-Paca-2 and SW620
cells . Moreover, according to the study in vitro by
Mitsuhata et al., isoflurane e in the same way as sevo-
flurane e is capable of altering the release of cytokines by
NK and NK-like cells in response to tumour cells . Unlike
sevoflurane, instead, isoflurane seems to induce apoptosis
rarely , even if it has been reported how clinically
apoptosis, alter amyloid precursor protein (APP) process-
ing, and increase amyloid beta protein (Abeta) production
in a human neuroglioma cell line [20,21]. Numerous other
studies have been carried out on the interaction between
Drugs of anaesthesia and cancer65
this anaesthetic agent and cancer. Isoflurane seems to
induce cytotoxicity in rat PC12 pheochromocytoma cells
and primary cortical neurons, which may be related to its
ability to decrease the ratio of apoptotic/antiapoptotic
proteins Bcl-2/Bax, promoting apoptosis . The effect of
this anaesthetic oncalcitonin
(CGRP), instead, was investigated by Kuroda et al., in their
study on pithed rats and human neuroblastoma cells. The
results suggest that isoflurane inhibits CGRP-induced
vasodilatation at the site between the CGRP receptor and
adenylate cyclase activation, involving Gs protein .
Moreover, isoflurane enhances the expression and activity
of glutamate transporter type 3 in C6 glioma cells . In
particular, it increases the expression and activity of
excitatory amino acid transporter type 3 (EAAT3) by
stabilizing EAAT3 mRNA and proteins via protein kinase
C- and phosphatidylinositol 3 kinase-independent pathways
. Finally, it reported how xenon and isoflurane affect
lipodolsaccharide (LPD)-induced activation of the nuclear
transcription factor kB (NF-kB) in different ways . While
xenon increases, isoflurane inhibits the activation of NF-kB,
highlighting a possible molecular mechanism for the
Summary of the most important effects of anaesthetic drugs on cancer in human studies.
Anesthetics Effects Reference
Isoflurane During open cholecystectomy, a TIVA with propofol and remifentanil
suppresses the inflammatory response caused by surgery to a greater extent
than a balanced inhalation technique using isoflurane: TNF-alpha, IL-6, IL-
10 e measured at the end of anaesthesia and surgery e are significantly
higher when isoflurane is used.
Propofol During an open cholecystectomy a TIVA using propofol and remifentanil
seems to suppress the inflammatory response caused by surgery to a greater
extent than a balanced inhalation technique using isoflurane: the plasma
levels of TNF-alpha, interleukin IL-6 and interleukin IL-10 e measured at
the end of anaesthesia and surgery e are significantly lower in the propofol/
remifentanil group than in the group treated with isoflurane.
A randomised controlled clinical trial have demonstrated how, in the
critically, ill single doses of this anaesthetic agent may interfere with
cortisol synthesis, for at least 24 h.
The use of flow-dose ketamine e especially in women e may be beneficial
for post-operative pain management after oral maxillofacial surgery,
reducing the risk of cancer metastasis caused by suppressing NK cell
Exposure to clinically-used concentrations of halothane and nitrous oxide
does not interfere with the natural killer lymphocyte response in patients
with benign and malignant breast disease.
The administration of nitrous oxide to cancer-bearing patients, but not to
those undergoing orthopaedic surgery, produces major changes in amino
acid metabolism, and consideration should be given to the avoidance of
exposure of cancer patients to nitrous oxide.
Nitrous Oxide 
Opioids FentanylLarge dose fentanyl administration is more effective in suppression of
immunity function than small-doses.
Used in combination with propofol, it seems to suppress the inflammatory
response caused by surgery.
In ASA I-II patients undergoing simple abdominal hysterectomy,
remifentanil-based anaesthesia, in combination with adequate analgesia,
affects the natural killer cell count and increases neutrophils.
TIVA with propofol and a minimal dose of sufentanil or a moderate dose
midazolam-sufentanil affects the pro-inflammatory cytokine response to
surgical stimulation before starting cardiopulmonary bypass, but it does not
modify the pro-inflammatory cytokine response to ischemia-reperfusion or
TIVA with propofol, sufentanil and atracurium does not affect IL-1beta, IL-
4, IL-6, TNF-alpha and INF-gamma release in ASAI-II patients, undergoing
elective laparoscopic or open cholecystectomy.
When administered in analgesic doses after surgery in cancer patients, does
not affect NK cell activity that is, instead, significantly enhanced by
Humoral and cellular immunity is, in part, modulated by morphine-derived
metabolites at the early phase of morphine therapy, in patients with
advanced cancer who required morphine for pain relief.
66 L.B. Santamaria et al.
Table 1 (continued)
Tramadol Tramadol shows analgesic activity comparable to that of morphine, but
induces improvement in postoperative immunosuppression suggesting how
it may be preferred for the treatment of postoperative pain in cancer
The administration of this opioid before and after laparatomy seems to
prevent surgery-induced NK activity suppression blocking the enhancement
of lung metastases.
The effects of these drugs on cancer have been poorly investigated: the few
existing studies have principally analyzed the influence of some of these
agents on the proliferation of normal human cells and their
pharmacokinetic and neuromuscular effects in patients with liver disease.
Summary of the most important effects of anaesthetic drugs on cancer in animal studies.
Halothane Reduces NK cell activity accelerating postsurgical metastases growth of mouse
The stimulation of proteinase inhibitory activity by halothane in oxygen may
be responsible for inhibition of tumour cell proliferation.
Reduces the number of NK cells per millimetre of blood, while it increases
MADB106 lung tumour retention or lung metastases.
The addition of spinal block to general halothane anaesthesia attenuates (by
70%) the promotion of metastases by surgery.
Sevoflurane The addition of spinal block to sevoflurane based anaesthesia attenuates the
suppression of tumouricidal function of liver mononuclear cells, reducing the
promotion of tumour metastases.
Propofol It does not alter NK activity or increase MADB106 lung tumour retention or lung
The administration of this agent prevents oxidative stress, NF-kB activation
and inducible nitric oxide synthase (iNOS) overexpression in liver rats.
Therefore, propofol treatment might block the production of noxious
mediators involved in the development of halothane-induced injury.
Reduces the activity of NK cells and increases lung tumour retention and lung
metastases more than 2.5 fold (effect markedly reduced when pre-treated
with b-adrenergic antagonist e nadodol e or chronic small doses of an
immunostimulator is executed).
Presents anti-inflammatory action in various immune cells (macrophage,
peripheral leucocytes) stimulated with LPS in vitro and in vivo.
Thiopental inhibits immune responses.
Single dose of thiopental (37e42 mg/kg) e sufficient to achieve anaesthesia
induction e increases the growth rate of a 3-methylcholanthrene-induced
syngeneic murine fibrosarcoma in C57B1/6 mice with significant alterations in
Thiopental reduces NK activity significantly and increases MADB106 lung
tumour retention or lung metastases: effect absent during excision of 3LL
tumour, and aggravated by the presence of hypothermia during thiopental-
This agent, in low concentrations, is not responsible for the reportedly higher
than average incidence of reticuloendothelial malignancies in operating room
During excision of the 3LL tumour in rats, the use of N2O has no effect on NK
cell activity, avoiding postsurgical growth acceleration of metastases.
(continued on next page)
Drugs of anaesthesia and cancer67
Table 2 (continued)
The use of this anaesthetic shortly before or during methotrexate
administration e used in chemotherapeutic protocols for treatment of
malignancies e should be avoided as it increases cytotoxic effects of
methotrexate on proliferating cells with unexpected myelosuppression and
Combining the anticobalamin activity of N2O with an anti-folate seems to be
a promising chemotherapeutic approach with significant anti-leukaemic
Opioids Fentanyl Determines a consistent decrease of bone pain symptoms and tumour growth-
induced bone destruction, showing clear antinociceptive properties, as well as
reduction in cancer cell-induced bone lesions.
Used with intermediate doses, it suppresses NKCC, and increases MADB106
lung tumour retention in a correlated manner augmenting the risk of tumour
NKCC returns to control values in patients treated with small-dose fentanyl,
whereas NKCC remains significantly suppressed after large-dose fentanyl
Fentanyl does not prevent immunosuppression induced by surgery
Summary of the most important effects of anaesthetic drugs on cancer for studies ‘‘in vitro’’.
AnestheticsEffects Cell LineReference
Halothane Halothane has a higher antitumour potency than
sevoflurane and isoflurane: growth suppression enhances
in Hep-2, Caco-2 and SW620 cells, while it is minimal
in WI-38 cells.
The effects of halothane on lung carcinoma cells A 549
have also been evaluated demonstrating that sub toxic
halothane concentrations of 0.6 vol.% inhibits surfactant
production; concentrations in the range 0.8-1.4 vol.%
induce membrane damage and concentrations ? 1.4
vol.%ecell death of approximately 50% of the cells.
In rat glioma C6 cells it inhibits the capacitative Ca2þ
influx with an IC50 of 1.9 %vol.
Halothane, at clinically relevant concentrations, inhibits
PMCA pumping in a dose-dependent manner in cells of
neural origin (rat C6 glioma cells, B104 rat
neuroblastoma, PC12 rat pheochromocytoma)
Produces a dose-dependent reduction in Kþ evoked
release of [3H]noradrenaline with significant inhibition,
and a dose-dependent reduction in Kþ evoked increases
in intracellular Ca2þ with significant inhibition.
Reversible suppression for activity of HIF-1 has been
observed in a cell line derived from a human
hepatocellular carcinoma, Hep3B, treated with
halothane in a range of clinically relevant doses.
Modifies tumour cell growth in a time dependent manner
with inhibitory effect absent or minimal in comparison to
other inhaled anaesthetics: in Caco-2 and MIA PaCa-2
cells it does not produce biologically important
differences; in WI-38 cells shows an inhibitory effect
after 6h of exposure; in Hep-2 cells a slight increase in
growth of treated cells; in MIA Paca-2 and SW620 cells
induces changes <5% in metabolic activity after 2h of
C6, B104, PC12
68L.B. Santamaria et al.
Table 3 (continued)
AnestheticsEffects Cell LineReference
Isoflurane seems to induce apoptosis rarely, even if
clinically relevant concentration of isoflurane induces
apoptosis, alters APP processing, and increases Abeta
production in human neuroglioma cells.
Induces cytotoxicity in rat PC12 pheochromocytoma cells
and primary cortical neurons.
Isoflurane enhances the expression and activity of
glutamate transporter type 3 in C6 glioma cells.
Isoflurane inhibits activation of the NF-kB.
Modifies tumour cell growth in a time dependent
manner: in both Caco-2 and SW620 cells the growth of
treated cells is significantly reduced after 6h of exposure
to sevoflurane. In Hep-2 cells, instead, sevoflurane
favours cell growth in the first 2h, and then reduces it in
a significant manner, while MIA PaCa-2 and WI-38 cells
did not show marked growth alterations.
Capable of altering the release of cytokines by NK and
NK-like cells in response to tumour cells, significantly
inhibiting the release of IL-1beta, TNF-alpha, but not
Apoptosis can be detected in cells exposed to
Sevoflurane does not induce cytotoxicity in either PC12
cells or primary cortical neurons.
 SevofluraneHep-2, Caco-2,
Propofol Clinically relevant concentrations of propofol inhibit the
invasion of human cancer cells: in particular, it prevents
pulmonary metastasis of cancer cells by inhibiting
invasion activity rather than by inhibiting growth.
Propofol-based conjugates (propofol-DHA, propofol-EPA)
may be useful for the treatment of breast cancer
inhibiting cell adhesion and migration, and inducing
The activation of GABA-A receptor by propofol increases
the migration of MDA-MB-468 cells.
Propofol does not affect the production of nitric oxide or
Inhibits the carbachol evoked release without affecting
the associated increase in [Ca2þ]I, suggesting that
etomidate may exert additional effects at either the
muscarinic receptor or the secretory machinery in SH-
SY5Y human neuroblastoma cells.
Etomidate seems not to affect the number of migrating
Reduces the activity of NK cells and increases lung
tumour retention and lung metastases more than 2.5
fold (effect markedly reduced when pre-treated with
b.adrenergic antagonist e nadodol e or chronic small
doses of an immunostimulator is executed).
Clinically achievable concentrations of ketamine may
suppress some inflammatory responses of both
astrocytes and microglia cells treated with LPS: it
inhibits LPS-induced PGE2 production in astrocytes and
reduces LPS-stimulated production of TNG-alpha in
astrocytes, microglia and in glial cells.
Ketamine in subnarcotic doses exerts a selective effect
on tumour cells.
(continued on next page)
Drugs of anaesthesia and cancer69
Table 3 (continued)
Anesthetics Effects Cell LineReference
It may have a valuable effect on amelioration of early
apoptosis in astrocytoma cells.
In concentrations used during routine anaesthesia, it
inhibits tumour-cell killing in a dose-related manner.
Thiopental reduces NK activity significantly and
increases MADB106 lung tumour retention or lung
metastases: effect absent during excision of 3LL tumour,
and aggravated by the presence of hypothermia during
Thiopental inhibits both the production of TNF-alpha and
In SH-SY5Y cells, thiopental inhibits both Kþ- and
carbachol-evoked release, causes noncompetitive
inhibition of Kþ-stimulated Ca2þ influx, inhibits
carbachol-stimulated increased intracellular Ca2þ
concentrations in the presence and absence of
extracellular Ca2þ, and has no effect on carbachol-
stimulated inositol (1,4,5)-triphosphate formation.
N2O alone or in combination with methionine or
methotrexate might be of value for cancer treatment,
thanks to synergistic effect on depletion of functional
folate, reducing cellular proliferation that significantly
affects leukaemic growth.
During excision of the 3LL tumour in rats, the use of N2O
has no effect on NK cells activity, avoiding postsurgical
growth acceleration of metastases.
Nitrous oxide seems to suppress carbachol-stimulated
increases in cytosolic free calcium.
N2O has no effect on TNF-alpha induced E-selectin
expression while it decreases TNF-alpha-induced
transcriptional activity of NF-kB, highlighting
a protective effect of anaesthetic on TNF-alpha-induced
endothelial cell damage.
OpioidsRemifentanil It has no significant effect on neutrophil respiratory
burst even in higher concentrations.
Kuraishi, during his study in mice and using B16-BL6
melanoma cells, showed that administration of
morphine suppresses tumour growth and
In MCF-7, MDA-MB231 and HT-29 cells it has been
suggested that morphine, alone or in combination with
naxolone, may reduce the growth of certain tumours,
apparently in part through activation of p53
Morphine also shows higher cytotoxic activity against
three human tumour cell lines: lung carcinoma A549,
mammary gland carcinoma MCF7, promyelocytic
leukemia HL-60 highlighting how it might provide a new
strategy for the treatment and prevention of cancer.
Atracurium and cisatracurium, but not mivacurium,
inhibit proliferation of human cell lines.
LidocaineAt the level of tissue concentration under topical or local
administration, lidocaine has a direct inhibitory effect
on the activity of epidermal growth factor receptor
(EGFR), which is a potential target for antiproliferation
in cancer cells.
70 L.B. Santamaria et al.
different effects on monocyte tumour necrosis factor-alpha
(TNF-alpha) and Interleukin-6 (IL-6) production . In
accordance with these results, Ke et al., have also
demonstrated how, during open cholecystectomy, a total
intravenous anaesthesia using propofol and remifentanil
suppresses the inflammatory response caused by surgery to
a greater extent than a balanced inhalation technique
using isoflurane. The plasma levels of TNF-alpha, inter-
leukin IL-6 and interleukin IL-10 e measured at the end of
anaesthesia and surgery e are significantly higher when
this anaesthetic agent is used .
Sevoflurane is currently considered the inhalational
agent of choice in anaesthesia. Its effects on Caco-2, Hep-
2, MIA PaCa-2, SW-620 and WI-38 cells were investigated by
Kvolilk et al., simulating, in vitro, a clinical setting, where
anaesthesia for cancer surgery usually takes a few hours
. The findings demonstrate how sevoflurane, similar to
other inhaled anaesthetics, such as isoflurane and halo-
thane, modifies tumour cell growth in a time-dependent
manner . In both Caco-2 and SW620 cells, for example,
the growth of treated cells is significantly reduced after 6 h
of exposure to sevoflurane. In HEP-2 cells, instead, sevo-
flurane favours cell growth in the first 2 h, and then reduces
it in a significant manner, while MIA PaCa-2 and WI-38 cells
did not show marked growth alterations . This inhala-
tional anaesthetic is also capable of altering the release of
cytokines by NK and NK-like cells in response to tumour
cells, significantly inhibiting the release of interleukin-1
beta (IL-1 beta) and TNF-alpha, but not that of interleukin-
2 (IL-2) .
In other words, sevoflurane expresses a marked inhibi-
tory effect in most cell lines, which could represent
a fundamental advantage when used in cancer surgery.
Moreover, according to what Wada et al. found in their
study on mice, the addition of spinal block to sevoflurane
based anaesthesia accompanying surgery attenuates the
suppression of tumoricidal function of liver mononuclear
cells, presumably by preserving the T helper 1/T helper 2
(Th1/Th2) cytokine balance, thereby reducing the promo-
tion of tumour metastasis .
In the context of the study described above, Kvolik and
other authors demonstrated, nevertheless, how apoptosis
can be detected in cells exposed to sevoflurane , while
Wei et al., in their study on rats, showed how this volatile
anaesthetic does not induce cytotoxicity in either PC12
cells or primary cortical neurons, leaving the Bcl-2/Bax
ratio unchanged .
Desflurane, a recently introduced volatile anaesthetic
drug, has a low blood/gas solubility coefficient that allows
rapid changes in anaesthesia depth . It is generally used
in anaesthesia to facilitate rapid emergence. A faster
recovery following desflurane, in fact, may be desirable
especially after long surgical procedures, enabling the
patient’s full cooperation and facilitating early diagnosis of
any potential neurological deficit . The effects of this
drug on cancer have been poorly treated in literature.
‘‘Intravenous anaesthetic agents’’
Intravenous anaesthesia is a technique extensively admin-
istered in both surgical operations for cancer treatment and
in the intensive care setting after surgery . This use has
focused the interest of research, for potential effects of
the intravenous agents, on neoplastic tissue.
Propofol, a phenolic derivative, which is structurally
unrelated to other sedative hypnotic agents, is an intra-
venous agent largely used for the induction of general
anaesthesia in adult and paediatric patients older than 3
years of age; maintenance of general anaesthesia in adults,
and children older than 2 months of age; and intensive care
unit sedation for intubated,
adults. Its pharmacokinetic profile is characterized by
a rapid onset and short duration of action that, together
with its stress control and amnesic properties, makes it an
ideal hypnotic recommended during surgical procedures.
Different studies carried out have demonstrated how
clinically relevant concentrations of propofol inhibit the
invasion of human cancer cells by modulating Rho A . In
particular, it has been observed that in mice, a propofol
infusion of 40 mg/kg per day, for 4 weeks, prevents pulmo-
nary metastasis of cancer cells by inhibiting the invasion
activity of cancer cells rather than by inhibiting their growth
. It should be emphasised that this animal model is not
clinically relevant in terms of dosage and length of time
administration. Nevertheless, these results confirm the
study by Kushida et al., who found that this anaesthetic
. Unlike other anaesthetics, propofol does not alter NK
activity or increase MADB106 lung tumour retention or lung
metastases . The synthesis, purification, characterization
Table 3 (continued)
AnestheticsEffectsCell Line Reference
Might be an ideal infiltration anesthetic for surgical
Unlike the reported inhibiting effects of local
anaesthetics on purified protein kinase C isoforms, no
such modulation is found in intact neuroblastoma cells
for ropivocaine, lidocaine and bupivacaine.
It shows little effect on nitrite production (160% of control
values) and only at the highest concentration (3.3 mM,
corresponding to 890 microg/mL or 0.089% w/v).
It has growth-inhibitory effects in MCF-7 breast cancer
cells, causing mitotic arrest.
Drugs of anaesthesia and cancer71
and evaluation of two novel anticancer conjugates, propo-
fol-docosahexaenoate (propofol-DHA) and propofol-eicosa-
pentaenoate (propofol-EPA), are all described by Siddiqui
et al. In particular, they demonstrate how these propofol
based conjugates may be useful for the treatment of breast
cancer. Although they are no longer considered anaes-
thetics, and therefore cannot be used as general anaes-
thesia, the propofol-DHA or propofol-EPA conjugates
significantly inhibit cell adhesion (15e30%) and migration
(about 50%) and induced apoptosis (about 40%) in breast
cancer cells . Different findings, instead, have been
observed for MDA-MB-468 breast carcinoma cells that
respond to non-volatile anaesthetics, such as propofol, with
an increased migration. The activation of GABA-A receptors
by propofol determines, in fact, that the migration of MDA-
MB-468cells (64.4 ?7%)
85.0 ?5.0% [32,33]. Moreover, while several studies of the
effects of propofol on cytokine release from lipopolysac-
charide (LPS) stimulated immune cells have produced con-
augmentation, Shibakawa et al. have investigated the
effects of this drug on the inflammatory responses of native
glial cells highlighting how propofol does not affect the
production of nitric oxide or tumour necrosis factor-alpha
(TNF-alpha), which play key roles in acute and chronic
neurodegenerative processes . Nevertheless, during an
propofol and remifentanil seems to suppress the inflamma-
tory response caused by surgery to a greater extent than
a balanced inhalation technique using isoflurane: the
plasma levels of TNF-alpha, interleukin IL-6 and interleukin
significantly lower in the propofol/remifentanil group than
in the group treated with isoflurane . Finally, propofol
presents a high potential as an efficient antioxidant in clin-
ical anaesthesia: the administration of this agent prevents
oxidative stress, NF-kB activation and inducible nitric oxide
synthase (iNOS) overexpression in liver rats receiving halo-
thane . Therefore, the propofol treatment might block
the production of noxious mediators involved in the devel-
opment of halothane-induced injury .
Etomidate is a short acting intravenous anaesthetic
agent used for the induction of general anaesthesia and for
sedation in short procedures. The effects of this intrave-
nous anaesthetic induction agent on Kþ and carbachol
evoked [3H] noradrenaline ([3H]NA) release and [Ca2þ]i
have been examined by Sikand et al. in their study in vitro
in SH-SY5Y human neuroblastoma cells . In particular,
experimental results have demonstrated how it inhibits the
carbachol evoked release without affecting the associated
increase in [Ca2þ]i, suggesting that etomidate may exert
additional effects at either the muscarinic receptor or the
secretory machinery in these cells . The effects of
single doses of etomidate on adrenocortical function,
instead, have been investigated by Absalom et al., in
a randomised controlled clinical trial demonstrating how, in
the critically ill, single doses of this anaesthetic agent may
interfere with cortisol synthesis for at least 24 h . In
fact, the use of intravenous anaesthetic, etomidate, for
prolonged sedation has been associated with low levels of
plasma cortisoland increased
as etomidateinhibits adrenal
suggested that, when used, treating selected patients with
corticosteroids should be considered . In recent years,
instead, Garib et al. have investigated, in vitro, the direct
influence of etomidate on migration of breast carcinoma
cells MDA-MB-468 . While both treatment with propofol
and treatment with lidocaine produce an increase of the
percentage of migrating cells, as well as the velocity, eto-
midate does not seem to affect the number of migrating
cells . In other words, it does not support cancer
progression by suppressing the activity of immune cells.
Ketamine is a general dissociative anaesthetic whose
effects on cancer have been well investigated. The effects
of anaesthesia, with this anaesthetic agent, on lung tumour
retention, number and activity of NK cells, and metastases
of MADB106 were described by Melamed et al. . The
results show how ketamine, similarly to other analyzed
anaesthetics, except propofol, reduces the activity of
circulating NK cells and increases lung tumour retention
and lung metastases more than 2.5-fold in all experiments.
This effect is markedly reduced when pre-treatment with
b-adrenergic antagonist (nadodol) or chronic small doses of
acid) is executed . These results confirm research
previously performed by Katzav et al., who found that the
use of ketamine during excision of Lewis lung carcinoma
(3LL) tumour produces an NK cell activity decrease which,
moreover, was reversed following treatment with poly-
inosinic-polycytidylic acid (poly I:C), an NK cell potentiator
. Nevertheless, despite these findings, the use of low-
dose ketamine (0.5 mg/kg) e especially in women e was
suggested as being beneficial for postoperative pain
management after oral maxillofacial surgery, reducing the
risk of cancer metastasis caused by suppressing natural
killer (NK) cell activity . The effects of this drug on
inflammatory responses have also been analyzed: while
several studies show how ketamine presents anti-inflam-
matory action in various immune cells e such as macro-
phage and peripheral leucocytes e stimulated with LPS in
vitro and in vivo [39e41], Shibakawa et al., have demon-
strated that clinically achievable concentrations of ket-
amine may suppress some of the inflammatory responses of
both astrocytes and microglia cells treated with LPS
without causing significant changes in nitric oxide release.
In particular, this anaesthetic agent inhibits LPS-induced
prostaglandin E(2) (PGE2) production in astrocytes, and
reduces LPS-stimulated production of TNF-alpha in astro-
cytes, microglia and in glial cells [34,42]. Other authors,
instead, have investigated the influence of ketamine on
hydration processes of tumoural and normal glandular cells,
and on the binding of labelled ouabain with tissues in order
to reveal changes in the number of active NaeK-ATPase
molecules on the cell membrane [43,44]. They have
demonstrated, in vitro, how hydration of tumoural and
normal cells diminished in 1-h incubation in a solution
comparable to anaesthetics, and sub-anaesthetic, concen-
trations of ketamine, proving that the content of water in
the tumoural cells increases and that ketamine in sub-
narcotic doses exerts a selective effect on tumoural cells
[43,44]. In tumour-bearing mice, the xylazine plus ketamine
(Xy/Ke) anaesthesia reduces tumour uptake ratios through
inhibition of insulin release in mice kept fasting 4 h . In
astroglioma cells, ketamine reduces cell shrinkage and
72 L.B. Santamaria et al.
increases granularity during the early period, and amelio-
rates cell swelling during the late reperfusion period, sug-
gesting that it may have a valuable effect on amelioration of
early and late apoptosis in astrocytoma cells, even though
the exact mechanism remains to be verified .
Sodium thiopental, better known as thiopental, is
a barbiturate anaesthetic agent. Several reports have
demonstrated that thiopental inhibits immune responses
[47e49]. Duncan et al. showed how thiopental, in concen-
trations used during routine anaesthesia, inhibits tumour-
cell killing in a dose-related manner . In particular,
analyzing, in vitro e by incubating 51Cr-labelled YAAC-1
tumour cells obtained from the peritoneal cavities of
syngeneic A/JAX white mice, with immune leukocytes from
the peritoneal cavities of allogeneic C57/black mice e the
effects of this drug on the ability of leukocytes to kill
tumour cells, the authors observed how inhibition of cyto-
toxicity ranged from 8.6% at 2.8 ? 10(?5 M thiopental) to
38.1% at 8.5 ?10?5M thiopental . Similarly, in 1983,
Lovett et al. highlighted how a single dose of thiopental
(37e42 mg/kg) e sufficient to achieve anaesthesia induc-
tion in mice e increased the growth rate of a 3-methyl-
cholanthrene-induced syngeneic murine fibrosarcoma in
C57B1/6 mice with significant alterations in cell-mediated
immunity . In accordance with these results, Melamed
et al. confirmed how thiopental, similar to other anaes-
thetic agents, significantly reduces group NK activity and
increases MADB106 lung tumour retention or lung metas-
tases . On the one hand, this effect is absent during
excision of the 3LL tumour , but on the other it can be
further aggravated by the presence of hypothermia during
thiopental-based anaesthesia. While normothermic anaes-
thesia reduces natural killer cell activity to 39 ?6.2% of
control levels, hypothermia reduces it to 15 ? 6.6%,
increasing tumour retention to 250% of control levels, and
the number of metastases from 1.1 ? /0.4 to 4.7 ?/1.2,
placing patients with metastasizing tumours or dormant
viral infections at greater risk for complications . The
inhibition effect of thiopental, however, also regards
tumour necrosis factor-alpha and nuclear factor kappa B.
Thiopental, in fact, inhibits both the production of TNF-
alpha and NF-kB activation induced by LPS in human glioma
cells A-172 : inhibition of NF-kB which, as Loop et al.
have demonstrated, is due to the suppression of IkB kinase
activity and depends, at least in part, on the barbiturate
molecule. In particular, inhibition of NF-kB binding activity
by thiopental is not due to GABA receptor stimulation and
does not involve direct targeting of activated NF-kB .
The results, rather, indicate that thiopental suppresses the
NF-kB activating signalling cascade by altering IkB kinase
activity, and that the thio-group at the C2 position within
the barbiturate molecule plays a key role in mediating this
effect . The effects of this intravenous anaesthetic on
potassium Kþ and carbachol-evoked [3H] noradrenaline
release from a human neuroblastoma cell line, SH-SY5Y,
have also been investigated: thiopental inhibits both Kþ-
and carbachol-evoked release with IC50 values respec-
tively, of 116? 15 mM and 169? 39 mM; it causes noncom-
petitive inhibition of Kþ-stimulated Ca2þ influx, with IC50
values of 127? 7 mM and 121 ? 10 mM; inhibits carbachol-
stimulated increased intracellular Ca2þ concentrations in
the presence and absence of extracellular Ca2þ, and has no
effect on carbachol-stimulated inositol (1,4,5)-triphos-
phate formation .
Nitrous oxide (N2O) is a weak anaesthetic agent and for this
reason it is usually not used alone in general anaesthesia,
but in combination with more powerful volatile anaesthetic
drugs, such as sevoflurane, desflurane, isoflurane or halo-
thane. Its effects on cancer were, and are, subject of
numerous studies. Similarly to many other inhalation
anaesthetics, also N2O was suspected of inducing tumours or
congenital anomalies in chronically exposed anaesthetic
staff. At the end of the 1970s, Coate et al. investigated the
effects of prolonged exposure to low-concentration combi-
nations of halothane and nitrous oxide on tumour incidence,
especially with regard to the reticuloendothelial system, in
rats . The results did not lend support to the hypothesis
that these anaesthetic agents, in low concentrations, are
responsible for the reportedly higher than average inci-
personnel.Successively, thestudy ofKano etal.showed
how N2O alone, or in combination with methionine or
methotrexate, might be of value for cancer treatment,
thanks to synergistic effects on depletion of functional
folate that these drugs have demonstrated . Nitrous
oxide, in fact, inactivates the vitamin B12-dependent
enzymemethionine synthetasewithsubsequent impairment
of folate metabolism and a reduction of cellular prolifera-
tion which, increased by mean cycloleucine, significantly
affects leukemic growth [57e59]. Moreover, Katzav et al.
showed how the use of N2O e during excision of Lewis lung
carcinoma (3LL) tumour in rats e has no effect on NK cell
activity, avoiding, hence, the acceleration of postsurgical
growth of metastases . Similarly, Griffith et al. found
that exposure to clinically used concentrations of halothane
and nitrous oxide does not interfere with the natural killer
lymphocyte response in patients with benign and malignant
breast diseases . A few years later, however, Ermens’
clinical observations in patients treated for breast carci-
noma or childhood cancer showed how the use of this
anaesthetic, shortly before or during methotrexate admin-
istration e used in several chemotherapeutic protocols for
the treatment of malignancies e should be avoided as it
increases cytotoxic effects of methotrexate on proliferating
cells with unexpected myelosuppression and mucosal
damage . The same authors suggested how combining
the anticobalamin activity of N2O with an anti-folate seems
to be a promising chemotherapeutic approach with signifi-
cant anti-leukemic potential . For example, the reduc-
tion of leukemic proliferation by N2O retards leukemic
infiltration ofthebone marrowcompartment .However,
the findings of a randomized controlled clinical trial
demonstrated that the administration of nitrous oxide to
cancer-bearing patients, but not to those undergoing
orthopaedic surgery, produces major changes in amino acid
metabolism, and consideration should be given to the
avoidance of exposure of cancer patients to nitrous oxide
. While the administration of nitrous oxide (60e150 min)
not affect blood L-methionine, in patients requiring resec-
tion of tumours, blood L-methionine concentration was
Drugs of anaesthesia and cancer73
significantly lower and the blood amino acid pattern was
significantly affected after the administration of N2O (120e
310 min) compared with values after the induction of
anaesthesia and before surgery . The effect of different
insufflations of gases, nitrous oxide included, on the
implantation of a tumour cell suspension, following laparo-
scopic surgery, in an established small animal model
suggests how the development of metastases in port sites
after laparoscopy may be influenced, in part, by the choice
of insufflation gas used to create the pneumoperitoneum:
while helium is associated with reduced rate of metastases,
no significant differences exist between air, carbon dioxide
(CO2), and N2O [65e67]. Also, the effects of this anaesthetic
agent on Cytosolic-free calcium mobilization and membrane
potential in the human neuroblastoma cell line, SK-N-SH,
have been widely analyzed. In particular, nitrous oxide
seems to suppress carbachol-stimulated increases in cyto-
solic free calcium (Cytosolic-free calcium) e that plays
fundamental roles in the initiation and regulation of many
neuronal processes e by enhancing Naþ/Caþþ exchange
activity . Recently, finally, the impact of different
anaesthetics e such as nitrous oxide e on TNF-alpha-
induced endothelial cell adhesion molecule expression has
been investigated. In particular, the findings suggest that
N2O, similarly to other analyzed agents, has no effect on
TNF-alpha induced E-selectin expression, while there is
decreased TNF-alpha-induced transcriptional activity of NF-
kB, highlighting a protective effect of anaesthetic on TNF-
alpha-induced endothelial cell damage .
Opioids represent an important cornerstone in treating
various types of pain, at all stages of cancer. The rela-
tionships between postoperative pain and metastasis e
already widely demonstrated in rats e determine that pain
management is a critical factor in preventing surgery-
induced decreases in host resistance against metastasis,
and moreover, becomes a priority in postoperative care
. In addition to their therapeutic efficacy, opioids can
however produce several well-known adverse events, and,
as recently reported, can interfere with immune responses
. An adequate knowledge of their effects with regard to
cancer, hence, becomes important in order to avoid
metastatic diffusion following surgery.
Fentanyl is an opioid anaesthetic agent with an anal-
gesic potency about 80 times that of morphine. Similarly to
some lesser degree morphines, it seems to have potential
benefits in the treatment and development of bone cancer
pain. In a murine model of bone cancer pain, repeated
administration of equianalgesic doses of fentanyl (0.16 mg/
kgs.c. once a day) and morphine (20 mg/kg s.c. once a day)
e initiated at day 1 (prophylactic treatment) or at day 7
(curative treatment) after tumour cell inoculation in the
femoral cavity e determines a consistent decrease of bone
pain symptoms and tumour growth-induced bone destruc-
tion, suggesting how treatments based on these anaes-
thetic agents show clear antinociceptive properties, as well
as reductions in cancer cell-induced bone lesions [72,73].
Shavit et al. investigated the effects of different doses of
fentanyl, administered at different time points relative to
tumour inoculation, on natural killer cell cytotoxicity
(NKCC) and on experimental tumour metastasis, demon-
strating how, when used with intermediate doses, fentanyl
suppresses NKCC and increases MADB106 lung tumour
retention in a correlated manner, increasing the risk of
tumour metastasis . Moreover, also large-dose fentanyl
administration is more effective in suppression of immunity
function than small-doses, as shown by Li et al., analyzing
the effects of different doses of this anaesthetic on T-
lymphocyte subpopulations and natural killer cells during
esophageal cancer surgery under general anaesthesia .
Nevertheless, the two types of anaesthesia (with small-
dose or large-dose fentanyl) show impressive differences in
the rate of recovery of NKCC suppression. On the second
postoperative day, NKCC returned to control values in
patients treated with small-dose fentanyl administration,
whereas NKCC remains significantly suppressed after large-
dose fentanyl administration, indicating how the latter
approach causes prolonged suppression of NK cell function,
and might have a long-term impact on the overall outcome,
especially in cancer patients [76,77]. In general, hence,
similarly to many other opioids employed in clinical prac-
tice, fentanyl does not prevent immunosuppression induced
by surgery [71,77,78]. The effects of this anaesthetic agent
on [3H] noradrenaline in SH-SY5Y human neuroblastoma
cells have also been widely investigated, demonstrating
how fentanyl produces a significant, concentration-depen-
dent inhibition of [3H] noradrenaline release .
Remifentanil, an ultra short acting opioid, is recom-
mended as an ideal analgesic agent during neurosurgical
procedures. It allows perfect titration of the analgesic
effects to varying noxious stimulation intensities, along with
rapid recovery and early assessment of postoperative
neurological function [80,81]. While most studies in litera-
ture have widely investigated the effects of this agent on
extubation time, recovery and cerebral hemodynamics
during procedures, such as non-emergency intracranial
surgery or craniotomy for brain tumour resection [82e84],
little is still known about the effects of remifentanil on
cancer.Nevertheless, the few studies onthis argument show
how, used in combination with propofol in a total intrave-
nous anaesthesia, remifentanil seems to suppress the
than isoflurane used with a balanced inhalation technique
. Also, the effects on cellular immune response, a key
element for perioperative tumour surveillance, have been
investigated, demonstrating how in ASA IeII patients
undergoing simple abdominal hysterectomy, remifentanil-
based anaesthesia, in combination with adequate analgesia,
reduces the counts of natural killer cells that are involved in
tumour surveillance and destruction, and determines an
increase of neutrophils . Nevertheless, in their study
executed in vitro, Jaeger et al. have found that this
anaesthetic agent has no significant effect on neutrophil
respiratory burst, even in concentrations higher than those
encountered during in vivo conditions .
Sufentanil is a synthetic opioid analgesic agent,
approximately 5e10 times more potent than fentanyl. It is
used in operations and critical care sites, where pain relief
is required for a short period of time. Moreover, as
demonstrated by De Leon-Casasola and Lema , sufen-
tanil seems more effective than morphine when adminis-
tered intraspinally in opioid-tolerant patients. Results
74 L.B. Santamaria et al.
suggest that sufentanil should be considered an effective
alternative therapy for postoperative pain control in
chronic opioid users, using high doses of oral opioids before
surgical intervention . The effects of this drug on
cancer have been poorly treated in literature. Most studies
carried out regard the use of sufentanil in cancer pain
management or surgery and were directed to evaluating
incidence on time to extubation , neurological recovery
time , intracranial pressure , and cost issues .
However, the effects of this anaesthetic agent on plasma
levels of TNF-alpha, IL-6 and interleukin 8 (IL-8) were
examined by El Azab et al., in their analysis on patients
undergoing cardiac surgery with cardiopulmonary bypass
. In particular, they have demonstrated that while total
intravenous anaesthesia with propofol and minimal dose
sufentanil, or with a moderate dose of midazolam-sufen-
tanil, affects the pro-inflammatory cytokine response to
bypass, it does not modify the pro-inflammatory cytokine
response to ischemiaereperfusion or extracorporeal circu-
lation , confirming that total intravenous anaesthesia
(TIVA) with propofol, sufentanil and atracurium does not
seem to have a significant effect on IL-1beta, IL-4, IL-6,
TNF-alpha and interferon-gamma (IFN-gamma) release in
forty adult patients, ASA I-II, undergoing elective laparo-
scopic or open cholecystectomy .
Morphine, worldwide, is given by several different
routes, such as, oral, rectal, subcutaneous, intravenous,
epidural or intrathecal, for the relief of cancer related pain
[93e97]. The effects of this drug on tumour growth and
metastasis have been investigated. Simon and Arbo
demonstrated that in rats, the use of morphine produces an
increase in metastatic growth . On the contrary, Yeager
and Colacchio demonstrated in vivo, that injections of
morphine may decrease the growth of tumour cells that
gain access to the circulation during a surgical procedure
. Similarly, Kuraishi, during his study in mice, and using
B16-BL6 melanoma cells, showed that administration of
morphine suppresses tumour growth and metastasis .
These results were also confirmed by Sasamura et al. in
. Sacerdote et al. have demonstrated that morphine,
when administered in analgesic doses after surgery in
cancer patients, does not affect NK cell activity, which,
instead, is significantly enhanced by tramadol administra-
tion . In particular, they suggest that tramadol should
be used in place of morphine for the treatment of post-
operative pain. The inhibitory effect of morphine on
experimental lung metastasis and invasion of colon 26-L5
cells, instead, has been investigated by Harimaya et al.
demonstrating that this analgesic drug inhibited the adhe-
sive and invasive properties of tumour cells by different
inhibitory mechanisms involving the mediation of an opioid
receptor . In MCF-7, MDA-MB231 and HT-29 cells it has
been suggested that morphine, alone or in combination
with naxolone, may reduce the growth of certain tumours,
possibly in part through activation of p53 phosphorylation
. Morphine also shows higher cytotoxic activity against
three human tumour cell lines: lung carcinoma A549,
mammary gland carcinoma MCF7, and promyelocytic
leukaemia HL-60, highlighting how it might provide a new
strategy for the treatment and prevention of cancer
[105,106]. Nevertheless, in recent years it has been shown
promotes tumour growth, and a DNA vaccine may be
a useful approach in treating severe immunosuppressive
reaction and preventing tumourigenesis after long-term
morphine treatment . Moreover, in a murine model of
bone cancer, sustained morphine treatment increases pain,
osteolysis, bone loss, and spontaneous fracture, as well as
markers of neuronal damage in DRG cells and expression of
pro-inflammatory cytokines . Finally, the effects of
morphine and its metabolites, such as morphine-3-glucu-
ronide (M-3-G) and morphine-6-glucuronide (M-6-G) on
immune function in advanced cancer patients, have been
analyzed by Hashiguchi et al. , demonstrating that
part of humoral and cellular immunity is modulated by
morphine-derived metabolites at the early phase of
morphine therapy, in patients with advanced cancer who
required morphine for pain relief .
Alfentanil, a fentanyl derivative, is a potent analgesic
characterized by a quick onset time, short duration of
action, low toxicity and short elimination time. Mainly used
intraoperatively, it is also adopted postoperatively for pain
relief: used intravenously after abdominal operations, it is
approximately ten times more effective than morphine
. Little is known about alfentanil in relation to cancer.
The effect of this drug on cancer has been poorly investi-
gated in literature. Oxycodone is a semi-synthetic opioid
agonist used in controlling cancer pain . In particular,
the clinical efficacy of CR oxycodone in cancer-pain control
appears at least the same as morphine, with a similar safety
profile . Hydromorphone is a semi-synthetic deriva-
tive of morphine, and is more potent, more soluble and has
a comparable side-effect profile . Nowadays, it is
often used in the management of cancer-related pain.
There is a lack of information about alfentanil, hydro-
morphon or oxycodone in relation to cancer development.
Tramadol is a centrally acting analgesic drug which,
often used for treating moderate to severe pain, appears to
be a good choice for the treatment of pain in patients
where immunosuppression is particularly contraindicated
. In particular, when administered after surgery in
cancer patients, tramadol shows analgesic activity compa-
rable to that of morphine, but induces an improvement in
postoperative immunosuppression, suggesting how it may
be preferred for the treatment of postoperative pain with
these patients . Moreover, the administration of this
opioid, before and after laparatomy, seems to prevent
surgery-induced NK activity suppression blocking the
enhancement of lung metastasis .
long-term dose-dependentmorphine treatment
Neuromuscular blocking drugs
Neuromuscular blocking drugs (NMBDs) are given as part of
general anaesthesia. Although NMBDs provide no anaes-
thesia or analgesia, they eliminate spontaneous breathing
and promote mechanical ventilation. The effects of these
drugs on cancer have been poorly investigated: the few
existing studies have principally analyzed the influence of
some of these agents on the proliferation of normal human
cells and their pharmacokinetics, and neuromuscular
effects in patients with liver disease [116,117]. In partic-
ular, in their study executed in vitro on hepatoma HepG2
cells and human umbilical vein endothelial cells, Amann
Drugs of anaesthesia and cancer75
et al. have demonstrated that atracurium and cis-
atracurium inhibit proliferation of human cell lines, but not
mivacurium, and that this effect is alleviated by gluta-
thione and N-acetylcysteine, as well as by the carboxyl,
Regional anaesthesia and cancer
In vitro data and in vivo animal studies suggest that three
factors associated with cancer surgery impair cellular
[118,119]: stress response to tissue injury, general anaes-
thesia, and opioid analgesia. Regional analgesia, instead,
seems a valuable solution capable of decreasing this risk,
reducing the neuroendocrine stress response to surgical
tissue injury, eliminating or decreasing the need for general
anaesthesia, and minimizing opioid requirement .
Results also confirmed the association between regional
anaesthetic techniques at primary cancer surgery and
reduced incidence of metastatic disease . Similarly,
Groetelaers and colleagues, in their follow-up study after
five years, show how axillary recurrence is significantly
reduced (only 0.8% encountered) after sentinel lymph node
biopsy under local anaesthesia for breast cancer .
Kumar et al. have investigated the use of spinal anaesthesia
with a micro-catheter as a primary method of anaesthesia
for colorectal cancer surgery, and other major abdominal
surgery in high-risk patients for whom general anaesthesia
would be associated with higher morbidity and mortality
. However regional anaesthesia based on para-
vertebral blocks (PVB) can be successfully performed for
breast cancer surgery in the majority of patients, signifi-
cantly reducing nausea, vomiting, pain and other side-
effects . Hashimoto and colleagues demonstrated that
epidural anaesthesia blocks the effect of stress induced by
major surgery (such as gastrectomy) on fluctuation of
peripheral lymphocyte subpopulations, which may be
associated with immunity suppression .
Lidocaine is a common, local anaesthetic and antiar-
rhythmic drug that can also be used for controlling pain in
cancer patients. In agreement with what was reported
recently by Sharma et al., a single IV infusion of lidocaine
provided a significantly greater magnitude and duration of
pain relief in opioid-refractory patients with cancer pain
. Similarly, intravenous lidocaine may be an effective
alternative to opioids in the treatment of refractory
malignant pain in the paediatric patient with terminal
cancer . At the level of tissue concentration under
topical or local administration, lidocaine has a direct
inhibitory effect on the activity of epidermal growth factor
receptor (EGFR), which is a potential target for anti-
proliferation in cancer cells . In particular, in a human
tongue cancer cell line, CAL27, concentrations of lidocaine
400 mM and 4000 mM show an antiproliferative effect e
respectively, with and without cytotoxicity e suggesting
that the inhibition of epidermal growth factor (EGF)-stim-
ulated EGFR activity is one of the basic mechanisms of the
antiproliferative effect of this drug. Moreover, lidocaine, at
concentrations used in surgical operations (5e20 mM),
seems able to effectively inhibit the invasive ability of
human cancer (HT1080, HOS, and RPMI-7951) cells modu-
lating ectodomain shedding of heparin-binding epidermal
riskof cancer recurrence
growth factor-like growth factor (HB-EGF), demonstrating
that it might be an ideal infiltration anaesthetic for surgical
cancer operations .
Ropivacaine is a local anaesthetic drug which, devel-
oped after bupivacaine, is usually adopted for infiltration,
nerve block, epidural and intrathecal anaesthesia in adults,
and children over 12 years. The effects of this anaesthetic
agent on protein kinase C function in vitro were examined
in both mouse Neuro-2a neuroblastoma cells and muscarine
M1-receptormediated phosphoinositide breakdown in
human SK-N-MC neuroblastoma cells . In particular,
the study demonstrated that unlike the reported inhibiting
effects of local anaesthetics on purified protein kinase C
isoforms, no such modulation is found in intact neuroblas-
toma cells for ropivacaine, lidocaine and bupivacaine .
The effect of this local anaesthetic agent on the energy
metabolism of Ehrlich ascites tumour cells has been inves-
tigated by Di Padova et al., suggesting how it impairs
energy metabolism of Ehrlich ascites tumour cells by
affecting primarily, mitochondrial metabolism . Ropi-
vacaine, at all concentrations tested, stimulated aerobic
lactate production, and this increase, in addition to the
inhibition of respiration, was also due to an activation of
mitochondrial ATPase . Also, the effects of ropiva-
caine on the expression of calcium-independent nitric oxide
synthase (NOS2) have been examined in immunostimulated
rat C6 glioma cells . Unlike bupivacaine and high dose
lidocaine, it shows little effect on nitrite production (160%
of control values) and only at the highest concentration
(3.3 mM, corresponding to 890 mg/mL or 0.089% w/v) .
Procaine is a local anaesthetic drug, first synthesized in
1989, used less frequently today. As demonstrated by Vil-
lar-Garea and colleagues in their 2003 study, procaine is
a DNA-demethylating agent that has growth-inhibitory
effects in MCF-7 breast cancer cells, causing mitotic arrest
. The synthesis of procaine, together with that of
cisplatin, represents the basis of Cis-diaminechloro-[2-
platinum (II) monohydrochloride monohydrate (DPR). This
new platinum triamine complex seems to be an antitumour
agent able to trigger apoptosis, endowed with a peculiar
mechanism of action and a special selective activity against
two tumours, namely neuroblastoma and small cell lung
cancer (SCLC), which are still characterized by a low inci-
dence of long-term survivors . Moreover, when simul-
taneously administered with standard anticancer agents
DPR, it appears to promote cytokilling .
Discussion and conclusion
Anaesthetic drugs, acting on intracellular pathways, are
able to trigger biomolecular cascades involved in different
physiological and pathophysiological cellular functions,
such as proliferation, angiogenesis and apoptosis [1,2,4].
Therefore, drugs of anaesthesia, probably interacting with
functional modules such as molecular complexes, signalling
networks, and whole organelles, often regulate cellular
processes that may result in genetic dysfunction. Finally,
genetic disorders, with different gene expression, may
explain a possible role of anaesthetic drugs in cancers, but
the findings present in the current literature are very
confusing, and it is difficult to draw any firm conclusions. In
76L.B. Santamaria et al.
fact, there seems to be a potential, strong correlation
between volatile anaesthetic drugs and cell survival. In
particular, inhaled anaesthetics such as isoflurane and
halothane, modify tumour cell growth in a time dependent
manner , whereas Huafeng Wei et al. suggest that iso-
flurane and sevoflurane differentially affect cell survival
. Moreover, isoflurane but not sevoflurane, induces
cytotoxicity with different mechanisms. Finally, there is
weak evidence that volatile anaesthetic agents mediate
cellular and systemic homeostatic responses to reduced O2
availability in mammals, including erythropoiesis, angio-
genesis, and glycolysis . Some authors suggest a possible
role of barbiturates in apoptosis and therefore in tumour
development and progression [53,135].
The role of anaesthesia and immune response is also
significant. There is evidence that an anaesthetic regime is
able to induce an immunosuppressive state in humans,
resulting in an ineffective immune response, and therefore
may contribute to genetic disorders, thereby playing a role
in tumour genesis. It has been observed that propofol, an
intravenous agent, inhibits the invasion activity of different
cancer cells [2,4]. Moreover, this anaesthetic agent seems
to have a beneficial effect on antitumour immunity, at least
in mice . Similar to volatile agents, intravenous drugs
seem to have some apoptotic functions. Finally, the role of
anaesthetic drugs as a molecular delivery system, such as
that proposed by Siddiqui et al., is a very interesting, but
still weak, proposal. These authors described the synthesis,
purification, characterization and evaluation of two novel
anticancer conjugates, propofol-docosahexaenoate (pro-
EPA), showing how these propofol-based conjugates may be
useful for the treatment of breast cancer .
There are many interpretations for these surprisingly
varied available data. The first is that the most of these
results are related to studies performed in vitro: therefore,
at present, they should be viewed as hypothesis generation.
These anaesthetic mechanisms in modulating tumour
behaviour should be tested systematically in animal models
and also in clinical studies, where different anaesthesia
techniques are performed and many anaesthetic drugs co-
administered . In fact, the relative weakness of the
findings specifically addressing these issues is mainly due to
the lack of clinical studies. Moreover, in experiments, some
authors use anaesthetic drugs in a wide range of clinically
relevant doses. On other hand, the argument cannot be
simply ignored, as the care staff is today still unable to
understand the importance of the problem and give
answers to the patients’ and families’ questions. There is
the suspicion that several anaesthetics are used for cancer
resection, even if clinical effects on the behaviour of
cancer cells are unclear, despite having been reported that
invasion, or metastasis of cancer cells easily occurs during
surgical procedures, and that, in general, there is evidence
supporting the fact that, by virtue of some still unknown
mechanisms, anaesthesia regime may influence physiolog-
ical cellular and/or molecular process involved in tumour
development, finally raising the question if, at all, it should
be considered socially acceptable and safe. This kind of
knowledge could therefore be a basic valuable support to
improve anaesthesia performance and patient safety.
Cell Lines cited in the text
Conflict of interest statement
Role of the funding source
Support was provided solely from departmental sources.
 Kvolik S, Glavas-Obrovac L, Bares V, Karner I. Effects of
inhalation anaesthetics halothane, sevoflurane, and iso-
flurane on human cell lines. Life Sci 2005;77:2369e83.
 Mammoto T, Mukai M, Mammoto A, Yamanaka Y, Hayashi Y,
Mashimo T, et al. Intravenous anaesthetic, propofol inhibits
invasion of cancer cells. Cancer Lett 2002;184:165e70.
 Tatsuya I, Tsunehisa N, Kazuhiko F, Gregg LS, Kiichi H.
Reversible inhibition of hypoxia-inducible factor 1 activation
by exposure of hypoxic cells to the volatile anesthetic halo-
thane. FEBS Lett 2001;509:225e9.
 Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-
Eliyahu S. Suppression of natuarl killer cell activity and
promotion of tumour metastasis by ketamine, thiopental,
and halothane, but not by propofol: mediating mecha-
nisms and prophylactic measures. Anesth Analg 2003;97:
 Van de Louw A, Plaud B, Debaene B. Use of sevoflurane for
surgery of phaeochromocytoma. Ann Fr Anesth Reanim 1998;
Drugs of anaesthesia and cancer77
 ASA ad hoc Committee on Effects of Trace Anaesthetics on
the Operating Room Personnel. Occupational disease among
operating room personnel: a national study. Anesthesiology
 Mazze RI, Fujinaga M, Rice SA, Harris SB, Baden JM. Repro-
ductive and teratogenic effects of nitrous oxide, halothane,
isoflurane, and enflurane in SpragueeDawley rats. Anesthe-
 Eger II EI, White AE, Brown CL, Biava CG, Corbett TH,
Stevens WC. A test of the carcinogenicity of enflurane, iso-
flurane, halothane, methoxyflurane and nitrous oxide in
mice. Anaesth Analg 1978;57:678e94.
 Brasil LJ, San-Miguel B, Kretzmann NA, Gomes Do Amaral JL,
Zettler CG, Marroni N, et al. Halothane induces oxidative
stress and NF-kB activation in rat liver: protective effect of
propofol. Toxicology 2007;227:53e61.
 Katzav S, Shapiro J, Segal S, Feldman M. General anesthesia
during excision of a mouse tumor accelerates postsurgical
growth of metastases by suppression of natural killer cell
activity. Isr J Med Sci 1986;22:339e45.
 Waxler B, Zhang X, Wezeman FH. Anesthetic agents modify
tissue proteinase inhibitor content and tumor behaviour. J
Lab Clin Med 1994;123:53e8.
 Page GG, Ben-Eliyahu S. Increased surgery-induced metastasis
and suppressed natural killer cell activity during pro-
estrus/estrusin rats. Breast Cancer ResTreat1997;45:159e67.
 Bar-Yosef S, Melamed R, Page GG, Shakhar G, Shakhar K,
Ben-Eliyahu S. Attenuation of the tumor-promoting effect of
surgery by spinal blockade in rats. Anesthesiology 2001;94:
 Valtcheva R, Stephanova E, Jordanova A, Pankov R,
Altankov G, Lalchev Z. Effect of halothane on lung carcinoma
cells A 549. Chem Biol Interact 2003;146:191e200.
 Tas PW, Roewer N. The volatile anesthetic enflurane acti-
vates capacitative Ca2þ channels in rat glioma C6 cells.
Toxicol Lett 1998;100-101:265e9.
 Singh G, Janicki PK, Horn JL, Janson VE, Franks JJ. Inhibition
of plasma membrane Ca(2þ)-ATPase pump activity in
cultured C6 glioma cells by halothane and xenon. Life Sci
 Atcheson R, Bjornstrom K, Hirst RA, Rowbotham DJ,
Lambert DG. Effect of halothane on Kþ and carbachol
stimulated [3H]noradrenaline release and increased [Ca2þ]
in SH-SY5Y human neuroblastoma cells. Br J Anaesth 1997;
 Smart D, Smith G, Lambert DG. Halothane and isoflurane
enhance basal and carbachol-stimulated inositol(1,4,5)-
triphosphate formation in SH-SY5Y human neuroblastoma
cells. Biochem Pharmacol 1994;47:939e45.
 Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of
volatile anaesthetics on cytokine release in human periph-
eral blood mononuclear cells. Int J Immunopharmacol 1995;
 Xie Z, Dong Y, Maeda U, Moir RD, Xia W, Culley DJ, et al. The
inhalation anesthetic isoflurane induces a vicious cycle of
apoptosis and amyloid beta-protein accumulation. J Neurosci
 Xie Z, Dong Y, Maeda U, Alfille P, Culley DJ, Crosby G, et al.
The common inhalation
apoptosis and increases amyloid beta protein levels. Anes-
 Wei H, Kang B, Wei W, Liang G, Meng QC, Li Y, et al. Iso-
flurane and sevoflurane affect cell survival and BCL-2/BAX
ratio differently. Brain Res 2005;1037:139e47.
 Kuroda M, Yoshikawa D, Nishikawa K, Saito S, Goto F. Volatile
anesthetics inhibit calcitonin gene-related peptide receptor-
mediated responses in pithed rats and human neuroblastoma
cells. J Pharmacol Exp Ther 2004;311:1016e22.
 Huang Y, Zuo Z. Isoflurane enhances the expression and
activity of glutamate transporter type 3 in C6 glioma cells.
 De Rossi LW, Brueckmann M, Rex S, Barderschneider M,
Buhre W, Rossaint R. Xenon and isoflurane differentially
nuclear transcription factor KB and production of tumor
necrosis factor-a and interleukin-6 in monocytes. Anesth
 Ke JJ, Zhan J, Feng XB, Wu Y, Rao Y, Wang YL. A comparison
of the effect of total intravenous anaesthesia with propofol
and remifentanil and inhalational anaesthesia with isoflurane
on the release of pro- and anti-inflammatory cytokines in
patients undergoing open cholecystectomy. Anaesth Inten-
sive Care 2008;36:74e8.
 Wada H, Seki S, Takahashi T, Kawarabayashi N, Higuchi H,
Habu Y, et al. Combined spinal and general anaesthesia
attenuates liver metastasis by preserving TH1/TH2 cytokine
balance. Anesthesiology 2007;106:499e506.
 Bedforth NM, Girling KJ, Skinner HJ, Mahajan RP. Effects of
desflurane on cerebral autoregulation. Br J Anaesth 2001;87:
 Boisson-Bertrand D, Laxenaire MC, Mertes PM. Recovery after
prolonged anaesthesia for acoustic neuroma surgery: des-
flurane versus isoflurane. Anaesth Intensive Care 2006;34:
 Kushida A, Inada T, Shingu K. Enhancement of antitumor
immunity after propofol treatment in mice. Immuno-
pharmacol Immunotoxicol 2007;29:477e86.
 Siddiqui RA, Zerouga M, Wu M, Castillo A, Harvey K,
Zaloga GP, et al. Anticancer properties of propofol-docosa-
cancer cells. Breast Cancer Res 2005;7:645e54.
 Garib V, Lang K, Niggemann B, Za ¨nker KS, Brandt L,
Dittmar T. Propofol-induced calcium signalling and actin
reorganization within breast carcinoma cells. Eur J Anaes-
 Garib V, Niggemann B, Za ¨nker KS, Brandt L, Kubens BS.
Influence of non-volatile anesthetics on the migration
behavior of the human breast cancer cell line MDA-MB-468.
Acta Anaesthesiol Scand 2002;46:836e44.
 Saito Shibakawa Y, Sasaki Y, Goshima Y, Echigo N, Kamiya Y,
Kurahashi K, et al. Effects of ketamine and propofol on
inflammatory responses of primary glial cell cultures stimu-
lated with lipopolysaccharide. Br J Anaesth 2005;95:803e10.
 Sikand KS, Hirota K, Smith G, Lambert DG. Etomidate inhibits
[3H]noradrenaline release from SH-SY5Y human neuroblas-
toma cells. Neurosci Lett 1997;236:87e90.
 Absalom A, Pledger D, Kong A. Adrenocortical function in
critically ill patients 24 h after a single dose of etomidate.
 Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D.
Inhibition of adrenal steroidogenesis by the anesthetic eto-
midate. N Engl J Med 1984;310:1415e21.
 Bentley MW, Stas JM, Johnson JM, Viet BC, Garrett N. Effects
of preincisional ketamine treatment on natural killer cell
activity and postoperative pain management after oral
maxillofacial surgery. AANA J 2005;73:427e36.
 Chang Y, Chen TL, Sheu JR, Chen RM. Suppressive effects of
ketamine on macrophage functions. Toxicol Appl Pharmacol
 Takenaka I, Ogata M, Koga K, Matsumoto T, Shigematsu A.
Ketamine suppresses endotoxin-induced tumor necrosis factor
alpha production in mice. Anesthesiology 1994;80:402e8.
 Kawasaki T, Ogata M, Kawasaki C, Ogata J, Inoue Y,
Shigematsu A. Ketamine suppresses proinflammatory cyto-
kine production in human whole blood in vitro. Anesth Analg
78 L.B. Santamaria et al.
 Wang E, Guo QL, Hu S, Wang YJ. Effects of intravenous
anesthetics on LPS-induced production of tumour necrosis
factor-alpha from primary cultures of rat glial cells in
vitro. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2007;32:
 Danielian AA, Mirakian MM, Aı ˇrapetian SN. The dehydration
action of ketamine on tumorous and normal glandular breast
tissues in vitro. Eksp Klin Farmakol 1999;62:51e4.
 Danielian AA, Mirakian MM, Aı ˇrapetian SN. The dehydrating
action of ketamine on malignant breast tumors. Vopr Onkol
 Lee KH, Ko BH, Paik JY, Jung KH, Choe YS, Choi Y, et al.
Effects of anesthetic agents and fasting duration on 18F-FDG
biodistribution and insulin levels in tumor-bearing mice. J
Nucl Med 2005;46:1531e6.
 Choi SJ, Kim MH, Lim SW, Gwak MS. Effect of ketamine on
apoptosis by energy deprivation in astroglioma cells using
flow cytometry system. J Korean Med Sci 2005;20:113e20.
 Lundy J, Lovett 3rd EJ, Conran P. Pulmonary metastases,
a potential biologic consequence of anesthetic-induced
immunosuppression by thiopental. Surgery 1977;82:254e6.
 Lovett 3rd EJ, Varani J, Lundy J. Suppressor cells and
increased primary tumor growth rate induced by thiopental.
J Surg Oncol 1983;22:26e32.
 Lovett 3rd EJ, Alderman J, Munster E, Lundy J. Suppressive
effects of thiopental and halothane on specific arms of the
immune response. J Surg Oncol 1980;15:327e34.
 Duncan PG, Cullen BF, Ray-Keil L. Thiopental inhibition of
tumor immunity. Anesthesiology 1977;46:97e101.
 Ben-Eliyahu S, Shakhar G, Rosenne E, Levinson Y, Beilin B.
Hypothermia in barbiturate-anesthetized rats suppresses
natural killer cell activity and compromises resistance to
tumor metastasis: a role for adrenergic mechanisms. Anes-
 chiyama T, Nishikawa M, Lipton JM, Matsubara T, Takashi H,
Furukawa S. Thiopental inhibits NF-kappaB activation in
human glioma cells and experimental brain inflammation.
Brain Res 2001;911:56e61.
 Loop T, Humar M, Pischke S, Hoetzel A, SchmidtR Pahl HL,
et al. Thiopental inhibits tumor necrosis factor a-induced
activation of nuclear factor kB through suppression of IkB
kinase activity. Anesthesiology 2003;99:360e7.
 Lambert DG, Willets JM, Atcheson R, Frost C, Smart D,
Rowbotham DJ, et al. Effects of propofol and thiopentone on
potassium- and carbachol-evoked [3H]noradrenaline release
and increased [Ca2þ]i from SH-SY5Y human neuroblastoma
cells. Biochem Pharmacol 1996;51:1613e21.
 Coate WB, Ulland BM, Lewis TR. Chronic exposure to low
concentrations of halothane-nitrous oxide: lack of carcino-
genic effect in the rat. Anesthesiology 1979;50:306e9.
 Kano Y, Sakamoto S, Sakuraya K, Kubota T, Hida K, Suda K,
et al. Effect of nitrous oxide on human bone marrow cells and
its synergistic effect with methionine and methotrexate on
functional folate deficiency. Cancer Res 1981;41:4698e701.
 Kroes AC, Ermens AA, Lindemans J, Abels J. Effects of 5-
fluorouracil treatment of rat leukemia with concomitant
inactivation of cobalamin. Anticancer Res 1986;6:737e42.
 Kroes AC, Lindemans J, Abels J. Synergistic growth inhibiting
effect of nitrous oxide and cycloleucine in experimental rat
leukaemia. Br J Cancer 1984;50:793e800.
 Kroes AC, Lindemans J, Hagenbeek A, Abels J. Nitrous oxide
reduces growth of experimental rat leukemia. Leuk Res 1984;
 Griffith CD, Kamath MB. Effect of halothane and nitrous
oxide anaesthesia on natural killer lymphocytes from
patients with benign and malignant breast disease. Br J
 Ermens AA, Schoester M, Spijkers LJ, Lindemans J, Abels J.
Toxicity of methotrexate in rats preexposed to nitrous oxide.
Cancer Res 1989;49:6337e41.
 Abels J, Kroes AC, Ermens AA, van Kapel J, Schoester M,
Spijkers LJ, et al. Anti-leukemic potential of methyl-cobal-
amin inactivation by nitrous oxide. Am J Hematol 1990;34(2):
 Ermens AA, Vink N, Schoester M, van Lom K, Lindemans J,
Abels J. Nitrous oxide selectively reduces the proliferation of
the malignant cells in experimental rat leukaemia. Cancer
 Crespo ML, Gime ´nez A, Bas T, Garcı ´a C, Puertes IR, Vin ˜a JR.
Effect of nitrous oxide and propofol on amino acid metabo-
lism in neoplasic patients. Nutr Cancer 1997;27:80e3.
 Hopkins MP, von Gruenigen V, Haller NA, Holda S. The effect
of various insufflation gases on tumor implantation in an
animal model. Am J Obstet Gynecol 2002;187:994e6.
 Neuhaus SJ, Ellis T, Rofe AM, Pike GK, Jamieson GG,
Watson DI. Tumor implantation following laparoscopy
using different insufflation gases. Surg Endosc 1998;12:
 Neuhaus SJ, Watson DI, Ellis T, Rowland R, Rofe AM, Pike GK,
et al. Wound metastasis after laparoscopy with different
insufflation gases. Surgery 1998;123:579e83.
 Resendes MC, Kalogeros GC, Dixon SJ, Philp RB. Nitrous oxide
enhances Naþ/Caþþ exchange in the neuroblastoma cell
line SK-N-SH. J Pharmacol Exp Ther 1997;280:795e801.
 Weber NC, Kandler J, Schlack W, Grueber Y, Fra ¨dorf J,
Preckel B. Intermitted pharmacologic pretreatment by
xenon, isoflurane, nitrous oxide, and the opioid morphine
prevents tumor necrosis factor alpha-induced adhesion
molecule expression in human umbilical vein endothelial
cells. Anesthesiology 2008;108:199e207.
 Page GG, Blakely WP, Ben-Eliyahu S. Evidence that post-
operative pain is a mediator of the tumor-promoting effects
of surgery in rats. Pain 2001;90:191e9.
 Sacerdote P. Opioids and the immune system. Palliat Med
 El Mouedden M, Meert TF. The impact of the opioids fentanyl
and morphine on nociception and bone destruction in
a murine model of bone cancer pain. Pharmacol Biochem
 El Mouedden M, Meert TF. Pharmacological evaluation of
opioid and non-opioid analgesics in a murine bone cancer
model ofpain. Pharmacol
 Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B. Effects of fentanyl
on natural killer cell activity and on resistance to tumor
metastasis in rats.Dose
 Li W, Tang HZ, Jiang YB, Xu MX. Influence of different doses
of fentanyl on T-lymphocyte subpopulations and natural
killer cells of patients with esophageal tumor during pre-
operation and postoperation. Ai Zheng 2003;22:634e6.
 Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, et al.
Effects of anesthesia based on large versus small doses of
fentanyl on natural killer cell cytotoxicity in the perioper-
ative period. Anesth Analg 1996;82:492e7.
 Beilin B, Shavit Y, Cohn S, Kedar E. Narcotic-induced
suppression of natural killer cell activity in ventilated and
nonventilated rats. Clin Immunol Immunopathol 1992;64:
 Franchi S, Panerai AE, Sacerdote P. Buprenorphine amelio-
rates the effect of surgery on hypothalamusepituitarye
adrenal axis, natural killer cell activity and metastatic
colonization in rats in comparison with morphine or fentanyl
treatment. Brain Behav Immun 2007;21:767e74.
and timingstudy. Neuro-
Drugs of anaesthesia and cancer79
 Atcheson R, Rowbotham DJ, Lambert DG. Fentanyl inhibits
the release of [3H]noradrenaline from SH-SY5Y human
neuroblastoma cells. Br J Anaesth 1994;72:98e103.
 Coles JP, Leary TS, Monteiro JN, Brazier P, Summors A,
Doyle P, et al. Propofol anesthesia for craniotomy: a dou-
bleblind comparison of remifentanil, alfentanil, and fen-
tanyl. J Neurosurg Anesthesiol 2000;12:15e20.
 Tipps LB, Coplin WM, Murry KR, Rhoney DH. Safety and
feasibility of continuous infusion of remifentanil in the
neurosurgical intensive care unit. Neurosurgery 2000;46:
 Lobo F, Beiras A. Propofol and remifentanil effect-site
concentrations estimated by pharmacokinetic simulation and
bispectral index monitoring during craniotomy with intra-
operative awakening for brain tumor resection. J Neurosurg
 Djian MC, Blanchet B, Pesce F, Sermet A, Disdet M,
Vazquez V, et al. Comparison of the time to extubation after
use of remifentanil or sufentanil in combination with pro-
pofol as anesthesia in adults undergoing nonemergency
intracranial surgery: a prospective, randomized, double-
blind trial. Clin Ther 2006;28:560e8.
 Fodale V, Schifilliti D, Conti A, Lucanto T, Pino G,
Santamaria LB. Transcranial Doppler and anesthetics. Acta
Anaesthesiol Scand 2008;52:319e26.
 Valie ´n JL, Hernando AN, Gasco ´n AH, France ´s RC, Lobera JC.
Cellular immune response to 3 anesthetic techniques for
simple abdominal hysterectomy. Rev Esp Anestesiol Reanim
 Jaeger K, Scheinichen D, Heine J, Andre ´ M, Bund M,
Piepenbrock S, et al. Remifentanil, fentanyl, and alfentanil
have no influence on the respiratory burst of human
neutrophils in vitro. Acta Anaesthesiol Scand 1998;42:
 De Leon-Casasola OA, Lema MJ. Epidural bupivacaine/su-
fentanil therapy for postoperative pain control in patients
tolerant to opioid and unresponsive to epidural bupivacai-
ne/morphine. Anesthesiology 1994;80:303e9.
 Solte ´sz S, Biedler A, Silomon M, Scho ¨pflin I, Molter GP.
Recovery after remifentanil and sufentanil for analgesia and
sedation of mechanically ventilated patients after trauma or
major surgery. Br J Anaesth 2001;86:763e8.
 Weinstabl C, Mayer N, Richling B, Czech T, Spiss CK. Effect of
sufentanil on intracranial pressure in neurosurgical patients.
 Manfredi PL, Chandler SW, Patt R, Payne R. High-dose
epidural infusion of opioids for cancer pain: cost issues. J
Pain Symptom Manage 1997;13:118e21.
 El Azab SR, Rosseel PM, De Lange JJ, van Wijk EM, van
Strik R, Scheffer GJ. Effect of VIMA with sevoflurane versus
TIVA with propofol or midazolam-sufentanil on the cytokine
response during CABG surgery. Eur J Anaesthesiol 2002;19:
 Helmy SA, Wahby MA, El-Nawaway M. The effect of anaes-
thesia and surgery on plasma cytokine production. Anaes-
 Wiffen PJ, McQuay HJ. Oral morphine for cancer pain.
Cochrane Database Syst Rev 2007;4. CD003868.
 Miura H, Taira O, Hiraguri S, Kato H. Morphine for the
management of pain in lung cancer. Nippon Rinsho 2002;60:
 Donnelly S, Davis MP, Walsh D, Naughton M, World Health
Organization. Morphine in cancer pain management: a prac-
tical guide. Support Care Cancer 2002;10:13e35.
 Kato Y, Kato A. Role of continuous intravenous infusion of
morphine in the cancer pain relieving therapy. Nippon Rinsho
 Gilmer-Hill HS, Boggan JE, Smith KA, Wagner Jr FC. Intra-
thecal morphine delivered via subcutaneous pump for
intractable cancer pain: a review of the literature. Surg
 Simon RH, Arbo TE. Morphine increases metastatic tumor
growth. Brain Res Bull 1986;16:363e7.
 Yeager MP, Colacchio TA. Effect of morphine on growth of
metastatic colon cancer in vivo. Arch Surg 1991;126:
 Kuraishi Y. Effects of morphine on cancer pain and tumor
growth and metastasis. Nippon Rinsho 2001;59:1669e74.
 Sasamura T, Nakamura S, Iida Y, Fujii H, Murata J, Saiki I,
et al. Morphine analgesia suppresses tumor growth and
metastasis in a mouse model of cancer pain produced by
orthotopic tumor inoculation. Eur J Pharmacol 2002;441:
 Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A,
Terno G, et al. The effects of tramadol and morphine on
immune responses and pain after surgery in cancer patients.
Anesth Analg 2000;90:1411e4.
 Harimaya Y, Koizumi K, Andoh T, Nojima H, Kuraishi Y, Saiki I.
Potential ability of morphine to inhibit the adhesion, inva-
sion and metastasis of metastatic colon 26-L5 carcinoma
cells. Cancer Lett 2002;187:121e7.
 Tegeder I, Gro ¨sch S, Schmidtko A, Ha ¨ussler A, Schmidt H,
Niederberger E, et al. G protein-independent G1 cell cycle
block and apoptosis with morphine in adenocarcinoma cells:
involvement of p53 phosphorylation. Cancer Res 2003;63:
 Hatsukari I, Hitosugi N, Ohno R, Hashimoto K, Nakamura S,
Satoh K, et al. Induction of apoptosis by morphine in human
tumor cell lines in vitro. Anticancer Res 2007;27:857e64.
 Hatsukari I,Hitosugi N,
Sakagami H. Induction of early apoptosis marker by morphine
in human lung and breast carcinoma cell lines. Anticancer
 Cheng WF, Chen LK, Chen CA, Chang MC, Hsiao PN, Su YN,
et al. Chimeric DNA vaccine reverses morphine-induced
immunosuppression and tumorigenesis. Mol Ther 2006;13:
 King T, Vardanyan A, Majuta L, Melemedjian O, Nagle R,
Cress AE, et al. Morphine treatment accelerates sarcoma-
induced bone pain, bone loss, and spontaneous fracture in
a murine model of bone cancer. Pain 2007;132:154e68.
 Hashiguchi S, Morisaki H, Kotake Y, Takeda J. Effects of
morphine and its metabolites on immune function in
advanced cancer patients. J Clin Anesth 2005;17:575e80.
 Chrubasik S, Chrubasik J, Friedrich G. Clinical use of alfen-
tanil. Anaesthesiol Reanim 1994;19:60e6.
 Cairns R. The use of oxycodone in cancer-related pain:
a literature review. Int J Palliat Nurs 2001;7:522e7.
 Biancofiore G. Oxycodone controlled release in cancer pain
management. Ther Clin Risk Manage 2006;2:229e34.
 Kumar MG, Lin S. Hydromorphone in the management of
cancer-related pain: an update on routes of administration
and dosage forms. J Pharm Pharm Sci 2007;10:504e18.
 Sacerdote P, Bianchi M, Manfredi B, Panerai AE. Effects of
tramadol on immune responses and nociceptive thresholds in
mice. Pain 1997;72:325e30.
 Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P.
The analgesic drug tramadol prevents the effect of surgery
on natural killer cell activity and metastatic colonization in
rats. J Neuroimmunol 2002;129:18e24.
 Amann A, Rieder J, Fleischer M, Niedermu ¨ller P, Hoffmann G,
Amberger A, et al. The influence of atracurium, cis-
atracurium, and mivacurium on the proliferation of two
human cell lines in vitro. Anesth Analg 2001;93:690e6.
80 L.B. Santamaria et al.
 Magorian T, Wood P, Caldwell J, Fisher D, Segredo V, Download full-text
Szenohradszky J, et al. The pharmacokinetics and neuro-
muscular effects of rocuronium bromide in patients with
liver disease. Anesth Analg 1995;80:754e9.
 Sessler DI. Does regional analgesia reduce the risk of cancer
recurrence? A hypothesis. Eur J Cancer Prev 2008;17:269e72.
 Sessler DI. Regional anaesthesia and cancer recurrence risk.
Rev Esp Anestesiol Reanim 2008;55:133e4.
 Arain MR, Buggy DJ. Anaesthesia for cancer patients. Curr
Opin Anaesthesiol 2007;20:247e53.
 Groetelaers RP, van Berlo CL, Nijhuis PH, Schapers RF,
Gerritsen HA. Axillary recurrences after negative sentinel
lymph node biopsy under local anaesthesia for breast cancer:
a follow-up study after 5 years. Eur J Surg Oncol 2008 [Epub
ahead of print].
 Kumar CM, Corbett WA, Wilson RG. Spinal anaesthesia with
a micro-catheter in high-risk patients undergoing colorectal
cancer and other major abdominal surgery. Surg Oncol 2008;
 Greengrass R, O’Brien F, Lyerly K, Hardman D, Gleason D,
D’Ercole F, et al. Paravertebral block for breast cancer
surgery. Can J Anaesth 1996;43:858e61.
 Hashimoto T, Hashimoto S, Hori Y, Nakagawa H, Hosokawa T.
Epidural anaesthesia blocks changes in peripheral lympho-
cytes subpopulation during gastrectomy for stomach cancer.
Acta Anaesthesiol Scand 1995;39:294e8.
 Sharma S, Rajagopal MR, Palat G, Singh C, Haji AG, Jain D. A
phase II pilot study to evaluate use of intravenous lidocaine
for opioid-refractory pain in cancer patients. J Pain Symptom
Manage 2008 [Epub ahead of print].
 Massey GV, Pedigo S, Dunn NL, Grossman NJ, Russell EC.
Continuous lidocaine infusion for the relief of refractory
malignant pain in a terminally ill pediatric cancer patient. J
Pediatr Hematol Oncol 2002;24(7):566e8.
 Sakaguchi M, Kuroda Y, Hirose M. The antiproliferative effect
of lidocaine on human tongue cancer cells with inhibition of
the activity of epidermal growth factor receptor. Anesth
 Mammoto T, Higashiyama S, Mukai M, Mammoto A, Ayaki M,
Mashimo T, et al. Infiltration anesthetic lidocaine inhibits
cancer cell invasion by modulating ectodomain shedding of
heparin-binding epidermal growth factor-like growth factor
(HB-EGF). J Cell Physiol 2002;192:351e8.
 Martinsson T, Fowler CJ. Local anaesthetics do not affect
protein kinase C function in intact neuroblastoma cells. Life
 Di Padova M, Barbieri R, Fanciulli M, Arcuri E, Floridi A. Effect
of local anesthetic ropivacaine on the energy metabolism of
Ehrlich ascites tumor cells. Oncol Res 1998;10:491e8.
 Feinstein DL, Murphy P, Sharp A, Galea E, Gavrilyuk V,
Weinberg G. Local anesthetics potentiate nitric oxide syn-
thase type 2 expression in rat glial cells. J Neurosurg Anes-
 Villar-Garea A, Fraga MF, Espada J, Esteller M. Procaine is
a DNA-demethylating agent with growth-inhibitory effects in
human cancer cells. Cancer Res 2003;63:4984e9.
 Mariggio ` MA, Cafaggi S, Ottone M, Parodi B, Vannozzi MO,
Mandys V, et al. Inhibition of cell growth, induction of
apoptosis and mechanism of action of the novel platinum
amino-benzoate, N(4)]-chloride platinum (II) monohydro-
chloride monohydrate. Invest New Drugs 2004;22:3e16.
 Viale M, Pastrone I, Pellecchia C, Vannozzi MO, Cafaggi S,
Esposito M. Combination of cisplatineprocaine complex DPR
with anticancer drugs increases cytotoxicity against ovarian
cancer cell lines. Anticancer Drugs 1998;9(5):457e63.
 Angileri FF, Aguennouz M, Conti A, La Torre D, Cardali S,
Crupi R, et al. Nuclear factor-kappaB activation and differ-
ential expression of survivin and Bcl-2 in human grade 2-4
astrocytomas. Cancer 2008;112(10):2258e66.
 Sessler DI, Ben-Eliyahu S, Mascha EJ, Parat MO, Buggy DJ.
Can regional analgesia reduce the risk of recurrence after
breast cancer? Methodology of a multicenter randomized
trial. Contemp Clin Trials 2008;29:517e26.
List of abbreviations used in the text
3LL: Lewis lung carcinoma;
Abeta: Amyloid beta protein;
APP: Amyloid precursor protein;
Bax: BCL2-associated X protein;
Bcl2: B-cell CLL/lymphoma 2;
Ca2þ: Calcium ion with a 2þ charge;
CGRP: Calcitonin gene-related peptide;
CO2: Carbon dioxide;
DNA: Deoxyribonucleic acid;
EAAT3: Excitatory amino acid transporter type 3;
ER: Neuronal endoplasmic reticulum;
GABA: Gamma-aminobutyric acid;
GABA-A: Gamma-aminobutyric acid type A;
HIF-1: Hypoxia inducible factor 1;
IC50: 50% Inhibitory concentration;
IL-1 beta: Interleukin-1 beta;
IL-1beta: Interleukin 1beta;
IL-4: Interleukin 4;
IL-8: Interleukin 8;
iNOS: Inducible Nitric Oxide Synthase;
mRNA: Messenger RNA;
N2O: Nitrous Oxide;
NF-kB: Nuclear Factor kappa B;
NK: Natural Killer;
NKCC: Natural Killer Cell Cytotoxicity;
NMBDs: Neuromuscular Blocking Drugs;
PGE2: Prostaglandina E2;
poly I:C: PolyinosinicePolycytidylic Acid;
Rho A: Ras homolog gene family, member A;
RNA: Ribonucleic Acid;
Th1/Th2: T helper 1/T helper 2;
TIVA: Total Intravenous Anaesthesia;
TNF: Tumour Necrosis Factor;
TNF-alpha: Tumour Necrosis Factor-Alpha;
Xy/Ke: Xylazine plus Ketamine
Drugs of anaesthesia and cancer81