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Abstract

The periwinkle plant, Cantharanthus roseus G. Don (Vinca rosea Linn.) is endemic to the island of Madagascar, and has long been ascribed a wide assortment of medicinal properties ranging from the treatment of diabetes to wound healing. Of the over fifty alkaloids present in minute quantities within the plant, only two (vincristine and vinblastine) have been isolated, synthesized, and are widely used as chemotherapeutic agents [1, 2]. The antitumor activity of the vinca alkaloids was identified by two independent groups both investigating extracts of Vinca rosea for hypoglycemic activity in the late 1950s [2, 3]. Numerous other natural alkaloids were also investigated but not pursued due to severe toxicity [4]. Now the vinca alkaloids have become part of the standard of care for more than 30 years. A number of semisynthetic derivates have since been identified and tested. Two of these, vindesine and vinorelbine, are currently used in clinical practice. A third, vinflunine, is presently in phase III clinical trials [5, 6].
Chapter 2
The Vinca Alkaloids
Nicole Coufal and Lauge Farnaes
2.1 Introduction
The periwinkle plant, Cantharanthus roseus G. Don
(Vinca rosea Linn.) is endemic to the island of
Madagascar, and has long been ascribed a wide assort-
ment of medicinal properties ranging from the treat-
ment of diabetes to wound healing. Of the over fifty
alkaloids present in minute quantities within the plant,
only two (vincristine and vinblastine) have been iso-
lated, synthesized, and are widely used as chemothera-
peutic agents [1, 2]. The antitumor activity of the vinca
alkaloids was identified by two independent groups
both investigating extracts of Vinca rosea for hypo-
glycemic activity in the late 1950s [2, 3]. Numerous
other natural alkaloids were also investigated but not
pursued due to severe toxicity [4]. Now the vinca alka-
loids have become part of the standard of care f or more
than 30 years. A number of semisynthetic derivates
have since been identified and tested. Two of these,
vindesine and vinorelbine, are currently used in clin-
ical practice. A third, vinflunine, is presently in phase
III clinical trials [5, 6].
These compounds are commonly administered as
sulfate salts to enhance solubility and increase stabil-
ity. All members of this family of molecules enact
their cytotoxic activity primarily by binding to tubulin
and inhibiting polymerization or extension of micro-
tubules. Microtubules are crucial for a wide range of
cellular activities, including mitotic spindles formation
necessary for cell division. The naturally occurring
N. Coufal ()
UCSD Department of Medicine, 9500 Gilman Drive, La Jolla,
CA 92093, USA
e-mail: ncoufal@ucsd.edu
vinca alkaloids have been used in the treatment of a
wide range of malignancies, most prominently hema-
tological cancers such as leukemia and lymphoma, but
also testicular cancer. The semi-synthetics have exhib-
ited clinical activity against lung, ovarian, and breast
malignancies.
2.2 Chemistry
The vinca alkaloids are bulky molecules with closely
related structures (Fig. 2.1), containing both an indole
nucleus (catharanthine portion) and a dihydroindole
nucleus (vindoline portion) connected by a carbon–
carbon ring with variable substituents attachment to
the rings. Vincristine differs from vinblastine, vinde-
sine, and vinorelbine as it has an acetaldehyde group
at the nitrogen atom at position one (see vincristine
in Fig. 2.1 for numbering) in the vindoline nucleus
instead of a methyl group. Vincristine, vinblastine, and
vinorelbine all have a methyl ester moiety attached to
carbon 3 in the vindoline nucleus while vindesine has
an amide attached at this same site. Vincristine, vin-
blastine, and vinorelbine are all acetylated at carbon
4 while vindesine has a hydroxyl group. Vinorelbine
also has a different structure in the catharanthine por-
tion of the molecule with the 11-membered ring being
replaced with a 10-membered ring by the elimination
of carbon 7
.
2.3 Mechanism of Ac tion
The vinca alkaloids interact with tubulin thereby dis-
rupting the mitotic spindle apparatus [79]. Tubulin
is usually present as a heterodimer of α-tubulin and
25
B.R. Minev (ed.), Cancer Management in Man: Chemotherapy, Biological Therapy,
Hyperthermia and Supporting Measures, Cancer Growth and Progression 13,
DOI 10.1007/978-90-481-9704-0_2, © Springer Science+Business Media B.V. 2011
26 N. Coufal and L. Farnaes
N
H
N
N
O
O
O
O
O
O
O
O
N
H
N
H
N
N
O
O
OH
O
O
O
O
O
O
N
H
Vincristine
Vinblastine
N
H
N
N
OOH
OH
OH
O
O
O
NH
2
N
H
N
H
N
N
O
O
OH
O
O
O
O
O
O
N
H
Vindesine Vinorelbine
7'
1
3
4
Fig. 2.1 The structure of the vinca alkaloids
β-tubulin each with a molecular weight of 55 kDa.
The heterodimers polymerize to form microtubules
which are involved in mitosis and meiosis through
the formation of the spindle apparatus which sepa-
rates the chromosomes. In addition microtubules are
involved in cell shape, axonal transport, and secre-
tion [10]. The biological function of microtubules is
determined largely by their polymerization dynamics
[11]. The two main types of dynamic behavior are
“dynamic instability” and “treadmilling.” The assem-
bly and disassembly of the microtubule polymers are
regulated by the binding of tubulin and guanosine
5-triphoshpate (GTP) [12]. All microtubules have a
plus end of the microtubule that polymerizes faster
and thereby grows faster than the opposing minus
end. Dynamic instability is characterized by changes
in the length of the microtubule structure, primarily at
the plus end whereas treadmilling is characterized by
the movement of cellular components along a tubule
that is maintained at constant length, with equal addi-
tion at the minus end and subtraction at the plus
end. It has been suggested that treadmilling might
be particularly important in mitosis [13]. In mitosis
the microtubules form the spindle apparatus which
aligns the chromosomes along the metaphase plate and
then pulls the chromosomes apart during the mitotic
process.
All the vinca alkaloids bind to tubulin with high
affinity and inhibit further polymerization. Since
microtubules are in a constant dynamic state of poly-
merization and depolymerization the inhibition of
polymerization by the vinca alkaloids functions to cre-
ate a state of net depolymerization. The interaction of
the vinca alkaloids with the microtubules of the spin-
dle apparatus disrupts the spindle apparatus and leads
to metaphase arrest. Vinorelbine, vincristine, and vin-
blastine have all been shown to possess roughly equal
tubulin binding constants [8] and cause metaphase
block at roughly the same concentrations. It has been
suggested that the differences in the relative potencies
of the vinca alkaloids may not be due to their binding
efficiencies but rather to differences in their intracel-
lular retention times or the stability of the drug-tubulin
complexes [14]. In addition, vincristine is a much more
potent inhibitor of axonal microtubule formation [15].
While the disruption of the mitotic process is the
key feature of the vinca alkaloids the final effect of
this metaphase arrest is the death of the cell through
activation of apoptotic pathways [16, 17]. In vitro
experiments with these agents have shown that expo-
sure can lead to apoptosis through both p53-dependent
and p53-independent pathways [1820]. Tumor cells
that have been exposed to the agents show charac-
teristic morphological and molecular changes that are
2 The Vinca Alkaloids 27
associated with the induction of apoptosis in a dose
and time dependent fashion. Since the drugs attempt
to induce apoptosis by halting the cell in mitosis,
cytotoxicity is strongly dependent on the duration of
exposure.
A number of other cellular effects beyond micro-
tubule inhibition have also been reported for the vinca
alkaloids. These include inhibition of amino acid
metabolism [21], calmodulin-dependent Ca
2+
ATPase
activity [22], nucleic acid synthesis [4]. In order to
achieve these other effects though the concentrations
of the drugs had to be at much higher levels than are
achieved in vivo.
2.4 Clinical Use
The vinca alkaloids are broad acting mitotic inhibitors
used in the treatment of numerous malignancies [23].
They have been used for both curative and palliative
aims in the treatment of a variety of tumors, most often
Hodgkin’s disease, acute lymphocytic leukaemia, tes-
ticular cancer, breast carcinoma, ovarian cancer, and
non-small-cell lung cancer (NSCLC). Other malig-
nancies treated with vinca alkaloids include Wilms’
tumor, Ewing’s sarcoma, neuroblastomas, hepatoblas-
toma, and rhabdomyosarcoma.
Vincristine is part of a front-line therapy for the
treatment of acute lymphocytic leukaemia. It is also
commonly used in pediatric oncology owing to the
higher level of sensitivity of pediatric malignancies
and the better tolerance of therapeutic doses in chil-
dren. Vincristine is also a standard treatment for non
Hodgkin’s lymphoma as part of the chemotherapy reg-
imen CHOP (Cytoxan, Hydroxyrubicin (Adriamycin),
Oncovin (Vincristine), Prednisone) [24] and as a treat-
ment of Hodgkin’s lymphoma as part of MOPP or
COPP. Vincristine is also generally used in the treat-
ment of multiple myeloma as a bolus or daily infusion
in combination with doxorubicin and dexamethasone
[25]. Vinblastine is used in combination with other
agents as a front-line therapy for the t reatment of
Hodgkin’s disease and testicular cancer. It is also
approved for use as a single agent or in combina-
tion with cisplatin for the treatment of NSCLC and
advanced breast cancer [26, 27]. Vindesine is used
in combination with other agents, such as myto-
mycin C and/or platinating agents in the treatment of
NSCLC [28]. Vinorelbine is the only vinca which can
be administered orally, and resistance to vinorelbine
develops more slowly and is less cross-resistant with
resistance to vincristine and vinblastine. Vinflunine is
currently being investigated for use in the treatment of
metastatic breast cancer and NSCLC trials [5, 6].
The vinca alkaloids are routinely administered by
direct intravenous injection. They are extreme vesi-
cants (see Section 2.8) so are often administered as
a rapid bolus. Vinorelbine can be administered orally.
The s ingle dose cap for vincristine is 2.0 (mg/m
2
) due
to substantial neurotoxicity reported at higher doses.
However, significant interpatient variability exist, and
some patients can tolerate much higher doses with
limited toxicity [29, 30]. For vinblastine, initial dose
recommendations are 2.5 and 3.7 mg/m
2
for children
and adults, respectively, with gradual dose escalation
based on hematologic tolerance. Vinesine has been
evaluated for weekly and biweekly administrations,
and is most commonly administered at 2–4 mg/m
2
every 7–14 days [27]. Additionally, prolonged infu-
sion schedules have been evaluated to increase the
critical threshold concentration of vincristine, vinblas-
tine, and vindesine, and all indicate an increased dose
can be administered safely without major toxicity for
1–2 days (vindesine) or up to 5 days (vincristine)
[27]. However, there is little evidence that prolonged
infusions are more effective than bolus schedules.
Vinorelbine is most commonly administered at a dose
of 30 mg/m
2
weekly or biweekly. It can be admin-
istered as a slow infusion or bolus, although evi-
dence indicates decreased local venous toxicity with
a bolus [31].
2.5 Mechanisms of R esistance
Resistance to the vinca alkaloids develops rapidly
and can occur through alterations in numerous cell
pathways.
For chemotherapeutic agents, resistance is com-
monly due to decreased drug accumulation and reten-
tion within target tumor cells. The most widely doc-
umented mechanism of vinca alkaloid efflux is by
members of the ATP-binding cassette (ABC) trans-
porter family, a huge gene family of transmembrane
transporters which efflux large endobiotic and xeno-
biotic compounds from cells in an ATP dependent
fashion. Resistance via multidrug resistance channels
28 N. Coufal and L. Farnaes
(MDR) can be innate or acquired. These transporters
not only confer resistance to the vinca alkaloids, but
also to a variety of other well known pharmacologic
agents such as taxanes, anthracyclines, epipodophyl-
lotoxins, dactinomycin and colchicine [32]. The two
most investigated members of this family in regards
to vinca alkaloid resistance are the permeability gly-
coprotein (P-gp)/MDR1 endcoded gene product (ABC
subfamily B1;ABCB1) and the multidrug resistance
protein MRP (ABC subfamily C2; ABCB1) [3337].
Although these two transport systems have the same
end result, they appear to utilize slightly different
mechanisms. For instance, P-gp vesicles have been
shown to directly transport vinca alkaloids, whereas
MRP vesicles transport in a glutathione dependent
fashion [34].
MDR1 is a 170-kD P-gp transmembrane pump
that regulates efflux of large amphipathic hyrdophic
substances in an energy dependent fashion. Drug resis-
tance is proportional to the amount of channel present
in the cell membrane [36]. Innate resistance is offered
by tissues which constitutively express a high amount
of the channel, such as endothelium and epithelial tis-
sue, especially renal epithelium and colonic endothe-
lium [38]. This channel is highly expressed in tumors
arising from constitutively expressing tissues (kidney
and colon cancer). Secondarily tumors can overexpress
MDR1 or related ABC transporters as a result of treat-
ment with vinca alkaloids, a phenomenon which has
been observed in post-treatment leukemia, lymphoma,
and multiple myeloma. MRP is a 190-kD transmem-
brane protein with a 15% homology to MDR1 which
has been shown to mediate vinca alkaloid resistance
as well as resistance to other chemotherapeutic agents
such as methotrexate [32, 3941]. Although many
other ABC transporters have been characterized and
implicated in vinca alkaloid resistance, their role is
even less apparent than that of MDR1 and MRP.
One important feature of MDR1 and MRP resis-
tance is that is reversible in specific conditions,
such as after treatment with calcium channel block-
ers, detergents, progesterone or estrogenic antag-
onists, antibiotics, antihypertensives, antimalarials,
antiarrhythmics, and immunosuppressives [32]. All of
these agents bind directly to the channel and inhibit
efflux, thereby increasing intracellular concentrations
of chemotherapeutic agents. To date the usefulness
of this observation has been limited as these agents
also act to enhance drug uptake into normal cells,
thereby decreasing biliary elimination and decreasing
drug clearance, ultimately lead to enhanced toxicity
[4244]. In addition, MDR1 has been shown to
respond to environmental stress by producing multiple
alternative proteins, which could explain the unsat-
isfactory outcomes from pharmacologic modulations
efforts thus far [32].
Other mechanisms of resistance to the vinca alka-
loids have also been identified, although primarily in
preclinical models. Each of these represents a different
modification in the mechanism of vinca alkaloid action
or of downstream signaling to allow the tumor cell to
escape programmed cell death. For instance, changes
in tubulin expression or tubulin binding [45] can lead
to resistance. Resistant tumors have been found to con-
tain mutations which lead to amino acid substitutions
or posttranslational modifications such as acetylation
or phosphorylation and thereby change the structure of
tubulin [46, 47]. Although the mechanism of resistance
in these cases is not entirely clear, it is thought to be as
a result of hyper-stabilization of tubulin rather than a
change in the drug binding affinity of the vinca alka-
loids [48]. In addition, changes in heat shock response
[49] or alterations in apoptotic signaling allowing
cells to escape apoptosis [50, 51]. Typically apop-
tosis in response to the vinca alkaloids is initiated
through a lengthy set of signaling pathways comprising
c-jun and stress-activated protein kinase activation
[19]. Therefore, overexpression of anti-apoptotic genes
such as Bcl-2 and Bcl-XL has been shown to afford
resistance to a wide assortment of chemotherapeutic
agents including vincristine and vinblastine [52
, 53].
2.6 Pharmacokinetics
Pharmacokinetic data on t he vinca alkaloids has been
hampered by a lack of sensitive, specific, and reli-
able detection methods in the past. Since the vinca
alkaloids are given in such minute amounts it had
been necessary to trace them with radioactively labeled
drugs. This was a difficult process as the vinca alka-
loids can be somewhat unstable and rapidly form
degradation products which can be separated by high-
pressure liquid chromatography (HPLC) [54]. In an
effort to further understand the distribution of the
vinca alkaloid, radioimmuno assay and enzyme-linked
immunosorbent assay (ELISA) have been developed
that can observe the vinca alkaloids in the picomolar
2 The Vinca Alkaloids 29
concentraton range [27]. These assays were originally
performed with polyclonal antisera which were ham-
pered by reactions with possible metabolites but in
the interim monoclonal antibodies were raised which
have allowed for more precise tracking of the vinca
alkaloids in vivo.
The vinca alkaloids are most commonly given intra-
venously by bolus injection or brief infusion and
their pharmacokinetic profile most closely fits a three
compartment model [27]. Characteristics of the vinca
alkaloids include large volumes of distribution, high
clearance rates, long terminal half lives (T
1/2
), signifi-
cant hepatic metabolism, and biliary/fecal metabolism.
With a normal adult dose peak plasma concentrations
of 100–500 nmol are maintained for only a few min-
utes with concentrations of 1–2 nmol persisting for
longer durations [55, 56]. There can be a significant
variation in the pharmacokinetics of these drugs in dif-
ferent patients. This may be due to variations in protein
or tissue binding, hepatic metabolism and/or biliary
clearance [57]. Although prolonged infusion schedules
may help to avoid excessively toxic peak concentration
levels and increase the duration of drug exposure, there
is no evidence that prolonged infusion schedules are
more effective than bolus schedules [58].
Vincristine, vinblastine, and vindesine are only
given by an intravenous route but vinorelbine can
be given both by intravenous and oral routes. Oral
absorption of vinorelbine is rapid with maximal drug
concentrations achieved in 1–2 h with an absolute
bioavailability of approximately 27% with a range of
10–60% [58] when given in soft gelatin capsules. The
oral clearance of vinorelbine approaches hepatic flow
(0.8 L/H/Kg) suggesting a significant first-pass effect.
Due to the large first pass effect, oral doses may need
to be up to three times larger than intravenous doses
to achieve the same effect. In addition the bioavailabil-
ity of oral vinorelbine may be lowered slightly by food
[59] (Table 2.2).
The vinca alkaloids all bind strongly to plasma
proteins including albumin, lipoproteins, and α1-acid
glycoprotein [61]. The primary binding protein for the
vinca alkaloids is α1-acid glycoprotein with an approx-
imately 10 fold higher affinity for these compounds
than for albumin [62, 63]. At drug concentrations
similar to those achieved in vivo protein binding of
vincristine and vinblastine is 99% suggesting that the
total binding sights for the vinca alkaloids are saturat-
able [64]. In addition to the binding of vinca alkaloids
to serum proteins the vinca alkaloids also rapidly bind
to platelets and lymphocytes after intravenous infusion
[61, 65]. Platelet bound drug accounts for approxi-
mately 80% of the blood bound drug. The distribution
of the drug into platelets and lymphocytes is
1
/
2
hfor
vinorelbine, 1 h for vinblastine, and 3 h for vincristine
[61, 65]. Since the binding of the drug to platelets is
a reversible process and the release of vincristine is
much slower than it is vinblastine or vinorelbine this
may explain the differences in their respective T
1/2
(see
Table 2.1).
Table 2.1 Properties of the vinca alkaloids
Vincristine Vinblastine Vindesine Vinorelbine
Mechanism of action Low concentrations inhibit changes in microtubule length (treadmilling and dynamic instability)
whereas high concentrations inhibit polymerization of tubulin
Standard Dose (mg/m
2
) 1–1.4 every 3 weeks 6–8 every week 3–4 every 1–2 weeks 15–30 every 1–2 weeks
Route of administration Intravenous Intravenous Intravenous Intravenous, oral
Metabolism Predominantly P450
IIIA
Predominantly P450
IIIA
Predominantly P450
IIIA
Predominantly P450
IIIA
Elimination Biliary/Fecal Biliary/Fecal Biliary/Fecal Biliary/Fecal
Terminal half-life (h) (T
1/2
) 95 (range 19–155) 25 (range 7–47) 24 (range 12–42) 33 (range 14–44)
Principal toxicity Peripheral Neuropathy Neutropenia Neutropenia Neutropenia
Table 2.2 Disposition of vinca alkaloids by bolus injection in patients with normal organ function [60]
Volume of
distribution (l/kg)
Elimination
half-life (h) Clearance (l/h/kg)
Fecal Clearance
(%) Renal Clearance (%)
Vincristine 7.2 (3.1–11.0) 45.1 (8.2–144) 0.16 (0.1–0.3) 69 4–13.5
Vinblastine 24.7 (17.3–35.1) 25.6 (19.6–29.2) 0.79 (0.7–0.9) 25–41 5.5–34
Vindesine 8.6 (6.8–10.5) 23.6 (19.0–34.8) 0.22 (0.1–0.3) ND 4–19
Vinorelbine 54.3 (44.7–75.6) 41.2 (31.2–62.4) 0.95 (0.8–1.3) 40–58 3.3–24.6
30 N. Coufal and L. Farnaes
Animal studies using radiolabeled drugs show that,
following intravenous administration the vinca alka-
loids are rapidly and widely distributed throughout
the body [6670]. After treatment with radiolabeled
vincristine, vinblastine, or vindesine radioactivity is
concentrated in the spleen, liver, kidney, lymph nodes,
and thymus. Moderate levels are found in lungs, heart,
and skeletal muscle. Brain and fat contain low levels.
Not all of these studies were able to clearly distinguish
between drug and degradation products. Vinorelbine
also accumulates in the spleen, liver, kidney, and to
very high levels in the lungs. Tracing the distribution
of radioactively labeled vinorelbine in patients shows
that the concentration of drug in the lungs may be up to
300 times greater than that in the serum and 3.4–13.8
fold higher than the lung concentration that is achieved
by vincristine or vindesine [71]. This higher concentra-
tion of vinorelbine in the lungs is a primary reason for
its preferential use in the treatment of non-small cell
lung cancer. In addition, vinblastine is more actively
sequestered in tissue than is vincristine as demon-
strated by a retention of 73% of radioactivity in the
body six days post-treatment [72].
The vinca alkaloids have poor penetration into the
central nervous system (CNS). Although these drugs
have a high lipophilicity their extensive lymphocyte,
platelet and protein binding prevents them from pen-
etrating the blood brain barrier (BBB). Additionally,
since the vinca alkaloids are substrates for permeabil-
ity glycoprotein (P-gp) and this protein is an active
part of the blood brain barrier, any vinca alkaloid that
does pentrate the BBB is actively removed. It has been
found that mice that lack P-gp have a 22 fold higher
accumulation of the vinca alkaloids when compared to
mice that express wild-type P-gp [73].
Accumulation and uptake of the vinca alkaloids
shows a direct correlation to their respective lipophilic-
ities. Since vinorelbine is the most lipophilic of the
vinca alkaloids it also exhibits the most liver uptake
of the vinca alkaloids [74].
In vitro experiments using freshly isolated
hepatocytes have shown that vincristine, vinblastine,
vindesine, and vinorelbine are almost totally converted
to water soluble metabolites which are then excreted
into the extracellular fluid [56, 70, 75]. The nature of
the metabolites that have been identified so far suggest
that the vinca alkaloids are metabolized by the hepatic
cytochrome P-450 mixed function oxidase CYP3A
[26, 54, 56, 7678]. The importance of CYP3A
in the metabolism of the drug is the observation
of increased clearance of the drug when used in
conjunction with drugs that induce CYP3A, such
as phenytoin and carbamazepine and the incidence
of increased toxicity with CYP3A inhibitors such as
itraconazole [77, 79]. It also appears that the individual
vinca alkaloids inhibit the biotransformation of one
another indicating a common metabolic pathway
that is saturable. Although few of the metabolites of
the vinca alkaloids have been actively studied, low
levels of deacetylated vinblastine and vinorelbine
have been detected in the feces, urine and tissues of
animals [80, 81]. In human patients only deacetylated
vinorelbine has been observed in a very small amount
in the urine. It appears though that the deacetylated
metabolite of vinorelbine is equipotent to the parent
compound [81].
The vinca alkaloids are primarily eliminated by the
hepatobiliary system. There is some variation in the
percentages of metabolites that are excreted in the
feces or the urine between the various vinca alkaloids
but roughly between 33 and 80% excreted in the feces
with up to 40% consisting of metabolites and 12 and
30% excreted in the urine most of which is unme-
tabolized [26, 56, 67, 69, 72, 76
, 8184]. Vincristine
is rapidly excreted into the bile with an initial bile
to plasma concentration ratio of 100:1 which declines
to 20:1 by 72 h post treatment [67]. As a result of
compounds being eliminated through the hepatobiliary
system extra care must be exercised in patients with
compromised liver function such as liver metastases or
cirrhosis of the liver.
2.7 Doses and Schedules
The vinca alkaloids are most commonly adminis-
tered by direct intravenous injection. Only experienced
oncology personnel should administer these agents as
extravasation causes severe soft tissue injury.
2.7.1 Vincristine
Vincristine may be given to pediatric patients weighing
less than 10 kg (body surface area <1 m
2
) at 0.05–
0.065 mg/kg weekly. In children weighing more than
10 kg (body surface area 1m
2
) a bolus injection dose
2 The Vinca Alkaloids 31
of 1.5–2.0 mg/m
2
may be given weekly. For adults
the common dose is 1.4 mg/m
2
weekly. There have
been efforts to create a prolonged infusion scheme as
a result of some evidence that the duration of exposure
above a critical concentration is important for cytotox-
icity [27, 85]. A restriction of the absolute single dose
of 2.0 mg/m
2
has been adopted due to early reports
of substantial neurotoxicity at higher doses. There is
some evidence now that this cap should be reconsid-
ered [86]. The setting of a cap for the maximum dose is
further complicated by the large amount of interpatient
variability in the tolerance of and metabolism of these
compounds. Vincristine dosage modification should be
based on the appearance of toxicity such as the appear-
ance of peripheral or autonomic neuropathy [87]. The
dosage should not be reduced for mild peripheral neu-
ropathy especially if it is being used in a curative set-
ting. If there are more serious toxic effects associated
with serious neurotoxicity such as sensory changes,
motor or cranial nerve changes or ileus then the dosage
should be modified until there is an adequate reduction
of symptoms of toxicity. In palliative settings it may
be advisable to reduce dosage or select an alternative
agent for moderate toxicity. Due to the hepatobil-
iary elimination of vincristine a 50% dose reduction
is indicated for patients with plasma total bilirubin
levels of 1.5–3.0 mg/dl and a 75% dose reduction
for patients with a serum total bilirubin >3.0 mg/ml.
There is no dosage reduction indicated for renal
dysfunction [88, 89].
2.7.2 Vinblastine
Vinblastine may be given to pediatric patients on a
weekly schedule starting at 2.5 mg/m
2
followed by
dose escalation of 1.25 mg/m
2
each week based on
hematological tolerance of the drug. It is not recom-
mended to administer a dose higher than 12.5 mg
in pediatric patients although most patients have
myelosuppression before this dose level is reached.
Adults may be given a weekly schedule starting at
3.7 mg/m
2
followed by dose escalation of 1.8 mg/m
2
each week based on hematological tolerance of the
drug. It is not recommended to use a dose higher
than 18.5 mg in adult patients although most patients
have myelosuppression at submaximal doses regard-
less. Vinblastine is also commonly used as a bolus
injection of 6 mg/m
2
in cyclic combination chemother-
apy regimens. Because leukopenia occurring with the
administration of vinblastine can vary widely with
identical doses, vinblastine should not be adminis-
tered more than once per week. Although there are
no specific guidelines for dose reduction in patients
with compromised liver function it would most likely
be necessary to significantly reduce the dosage of the
drugs due to the hepatic role in the clearing of these
drugs.
2.7.3 Vindesine
Vindesine is most commonly given as an intravenous
bolus of 2–4 mg/m
2
weekly to biweekly which is
associated with antitumor activity and a tolerable toxi-
city prolfile [27]. Intermittent or continuous schedules
usually infuse 1–2 mg/m
2
per day for 1–2 days or
1.2 mg/m
2
for 5 days every 3–4 weeks [27, 56]. As
with the other vinca alkaloids a dose reduction is
warranted if the patient has hepatic dysfunction.
2.7.4 Vinorelbine
Vinorelbine is commonly given intravenously at dose
of 30 mg/m
2
as an injection using the sidearm port
of a running infusion. Alternatively vinorelbine may
be given as a slow bolus injection followed by flush-
ing with 0.9% sodium chloride or a short infusion over
20 min. It appears that the shorter infusions are asso-
ciated with a decrease in local venous toxicity [31].
Patients with hepatic dysfunction should be given a
lower dose [90]. Dosage reductions for hepatic dys-
function include a 50% reduction in patients with
serum total bilirubin between 1.5 and 3.0 mg/dl and
a 75% reduction in patients with serum total bilirubin
>3.0 mg/dl. As with the other vinca alkaoids dosage
reductions are not indicated in patients with renal
insufficiency.
2.8 Toxicity
Despite the structural and pharmacologic resemblance
between vinca alkaloid family members, a broad
range of adverse reactions have been noted, and
32 N. Coufal and L. Farnaes
there are striking differences in the severity and inci-
dence of adverse reactions for each. There is no pre-
cise explanation for these side-effects, however the
affinity for tubulin and the cellular uptake rate is
likely the culprit. The predominant toxicity for vin-
cristine is neurotoxicity, whereas myelosuppresion is
most frequent with vinblastine, vinesine, and vinorel-
bine. However, peripheral neurotoxicity and myelo-
suppresion can be associated with any vinca alka-
loid as a result of prolonged treatment, unintentional
high-dose treatment, or in highly susceptible patients
(e.g., individuals with hepatic dysfunction or the
elderly).
The ability of the vinca alkaloids to bind tightly to
microtubules present in peripheral nerves, which are
essential for axonal transport and secretory functions
makes neurotoxicity unavoidable. Axonal degenera-
tion and decreased axonal transport result, and can
be measured as diminished amplitude of sensory and
motor nerve action potentials and prolonged distal
latencies [26, 91]. Despite being highly lipophilic, the
large size and significant platelet and protein binding
activity of these agents prevents them from crossing
the blood-brain barrier. Additionally, MDR1 is highly
expressed in brain capillary endothelium, resulting in
drug efflux [92]. As a result, neural toxicity is primar-
ily as a result of peripheral nerve damage, and central
nervous system toxicity is rare [2]. There are numer-
ous reports of seizures after administration, but due
to low CNS penetration, are unlikely to be directly
due to vinca alkaloid administration. They are more
likely a result of intracranial metastasis, infection, or
as a result of hyponatremia s econdary to inappropriate
antidiuretic hormone secretion which can be caused by
vincristine [93].
Neurotoxicity as a result of vinca alkaloid treat-
ment is characterized by peripheral, symmetric
mixed sensory, motor, and autonomic polyneuropathy
[26, 94, 95]. Neurotoxicity occurs as a well-
documented progression in most patients, usually
beginning with asymptomatic Achilles tendon reflex
loss [93], followed by paresthesias in the hands and
feet. This is followed by neuritic pain, and can
progress to foot drop, wrist drop, muscle pain, weak-
ness, ataxia, and paralysis. Deficits are symmetrical
and may persist for weeks or months after therapy
is discontinued [93]. Rarely the cranial nerves are
affected, resulting in dipolopia, hoarseness, and facial
palsies. Severe jaw pain has been reported shortly
after administration, but does not usually persist [93].
Autonomic neuropathies are common, ranging from
constipation, bloating, and abdominal pain to para-
lytic ileus in the more severe cases. Paralytic ileus,
intestinal necrosis, and perforation have lead to several
deaths as a consequence of vinca alkaloid treatment
[93, 96]. Gastrointestinal effects are generally most
severe with vincristine [2, 58]. Autonomic neurotoxic-
ity secondary to vincristine may produce bladder atony
and resulting polyuria, dysuria, and urinary reten-
tion [97]. Cardiovascular autonomic neurotoxicities
have also been reported, most frequently hypertension
and hypotension, but also rarely cardiac ischemia and
massive myocardial infarctions when vinca alkaloids
are combined with cisplatin and bleomycin [98, 99].
Frequently mild autonomic neuropathies precede more
severe peripheral neuropathies.
Attempts to reverse or prevent neurotoxicity have
been largely unsuccessful, as a result supportive care
and dose adjustments are the primary treatments
[94, 100]. There has been limited success with folinic
acid (not folic acid) which has been shown to pro-
tect against an otherwise lethal dose of vincristine in
animal models, and used in several overdose patients
[88, 89]. Also shown to have some efficacy is glu-
atmic acid and a mixture of gangliosides to reduce
neurotoxicity [101, 102]. Patients should be routinely
treated with dietary bulk, stool softeners, and laxatives
to prevent severe constipation.
All the vinca alkaloids have been shown to act
directly on the hypothalamus, posterior pituitary, or
neurohypophyseal tract (where the blood-brain barrier
is the least robust) and can cause syndrome of inap-
propriate antidiuretic hormone secretion (SIADH).
Patients who are already receiving extensive hydra-
tion are particularly susceptible to hyponatremia as a
result of SIADH and can result in generalized seizures
[2, 27]. Usually elevated plasma ADH levels return to
normal within two to three days. Hyponatremia should
be treated with fluid restriction, as SIADH would be
treated from other causes.
Bone marrow suppression is a common side effect
of the vinca alkaloids. Leukopenia is common, peak-
ing 5–10 days after drug administration. Extent and
duration of leucopenia is dose dependent. White
cell count returns to normal within 1–2 weeks,
and myelosuppression is not typically cumulative.
Thrombocytopenia and anemia are less common and
severe, unless used in combination with radiation or
2 The Vinca Alkaloids 33
other agents. Leukopenia is least pronounced with vin-
cristine, and is therefore the agent of choice if bone
marrow suppression is dose-limiting.
Vincristine, vinblastine, and vindesine are strong
vesicants, and extreme caution should be taken in their
administration to avert leakage into surrounding tis-
sues. They should never be administered intramuscu-
larly, subcutaneously, or intraperitoneally. Inadvertent
intrathecal injection, which has occurred in clini-
cal accidents, induces severe myeloencephalopathy
including ascending motor and sensory neuropathies
and rapid death [103]. It is recommended that these
agents be administered as a bolus whenever possi-
ble to minimize risk of extravasation. Injection site
reactions include erythema, pain, and venous discol-
oration. There is a risk of phlebitis if veins are not
flushed after administration. If extravasation is sus-
pected, treatment should cease, and aspiration of any
residual drug attempted [104]. Extravasation has been
successfully treated with corticosteroids to limit tis-
sue damage [104]. Immediate surgical consultation to
consider early debridement should be considered.
Dosage modifications should be based on toxicity,
although mild toxicity is acceptable in a curative set-
ting. Severe toxicities, such as ileus and sensory, motor,
and cranial nerve deficits indicate a need for dose mod-
ification. In palliative situations, modifying doses or
increasing dosing intervals may be justified even with
moderate neurotoxicity. Due to their hepatic clearance,
vinca alkaloid dose modifications should be consid-
ered for patients with low hepatic function [100]. A
75% dose reduction is recommended for patients with
serum total bilirubin levels < 3.0 mg/dL, and a 50%
dose reduction for patients with plasma total biliru-
bin of 1.5–3.0 mg/dL [88, 89]. Dose reductions is
not indicated for patients with renal dysfunction [88,
89]. Lastly, dose reductions should be considered with
elderly patients, who often exhibit reduced hepatic
function.
2.9 Drug Interactions
Pharmacokinetic interactions have not been exten-
sively studied. Those pharmaceuticals which are
known to interact with the vinca alkaloids are pri-
marily those which utilize the same elimination path-
way, liver cytochrome P450 3A (CYP3A) metabolism.
This includes drugs such as quinine, cyclosporine, and
nifedipine which are also substrates for CYP3A, and
have been shown to inhibit vinca alkaloid metabolism
in vitro [75]. Nifedipine has been shown to decrease
patient’s plasma clearance of vincristine by 69%
[105]. Administration of vinca alkaloids in combina-
tion with drugs which actively inhibit CYP3A, such
as erythromycin and itraconazole, can lead to severe
toxicity.
There are several medications where administra-
tion concomitantly with vinca alkaloids can lead to
excessive toxicity. For instance, the use of mitomycin
C in combination with vinca alkaloids is associated
with pulmonary toxicity [106, 107]. These reactions
are usually either acute bronchospasm or subacute
reversible cough and dyspnea 1 h after treatment.
Furthermore, treatment with vinblastine in combina-
tion with either erythromycin or cyclopsorin leads
to greater than predicted vincristine toxicity [108,
109]. Similarly, vincristine associated toxicity is much
higher with concomitant etoposide treatment (another
substrate for CYP3A) [110]. Lastly, the large degree
of variability within and between individuals in vin-
cristine pharamcokinetics has been ascribed to unpre-
dictable CYP3A induction secondary to corticosteroid
therapy [111].
Pharmaceuticals which upregulate liver enzymes
may increase vinca alkaloid metabolism (e.g., pheny-
toin and phenobarbitol) and decrease their efficacy
[112, 113]. Conversely, treatment with vinca alkaloids
has precipitated seizures associated with subtherapeu-
tic plasma phenytoin concentrations, likely as a result
of CYP3A induction [86, 114]. Reduced phenytoin
levels have been documented 24 h–10 days post treat-
ment with vinblastine and vincristine.
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Chapter
Worldwide, breast cancer is the second most common cancer after lung cancer and it is the first most incident and prevalent cancer in women. Plant-derived natural products have historically been in drug discovery process as a source of chemotherapeutic agents against different kinds of cancers, including breast cancer. More than half of the anticancer drugs used in clinical uses have presently a natural origin. In this context, vinca alkaloids (vinblastine and vincristine), isolated from the Madagascar periwinkle plant Catharanthus roseus G. Don. (Apocynaceae), were the first natural products with potent antitumor properties for clinical use. Their main mechanism of action is related to their ability to interfere with the mitotic spindle apparatus and thus to trigger cellular arrest in metaphase during mitosis and consequently to cause apoptosis and tumor cell death. On the basis of the pharmacological interest of vinca alkaloids as anticancer agents, there have been developed semisynthetic analogs, including vinorelbine (5′-nor-vinca-alkaloid, modified on the catharanthine ring) and vinflunine (a bis-fluorinated vinorelbine derivative). Since the discovery of vinca alkaloids, both natural and synthetic origin, numerous clinical trials have been carried out to-date to evaluate the efficacy of these compounds against breast cancer. These anticancer agents are commonly used in combination chemotherapy regimens as well as a therapeutic option if other chemotherapy agents fail. The current chapter covers the historical outcome of vinca alkaloids, from the discovery of compounds of natural origin (vinblastine and vincristine) to the synthesis of analogs with anticancer activity (vinorelbine and vinflunine), together with a comprehensive review of the newest preclinical and clinical investigations on these compounds against breast cancer.
Article
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Drug delivery using natural biological carriers, especially erythrocytes, is a rapidly developing field. Such erythrocytes can act as carriers that prolong the drug’s action due to its gradual release from the carrier; as bioreactors with encapsulated enzymes performing the necessary reactions, while remaining inaccessible to the immune system and plasma proteases; or as a tool for targeted drug delivery to target organs, primarily to cells of the reticuloendothelial system, liver and spleen. To date, erythrocytes have been studied as carriers for a wide range of drugs, such as enzymes, antibiotics, anti-inflammatory, antiviral drugs, etc., and for diagnostic purposes (e.g. magnetic resonance imaging). The review focuses only on drugs loaded inside erythrocytes, defines the main lines of research for erythrocytes with bioactive substances, as well as the advantages and limitations of their application. Particular attention is paid to in vivo studies, opening-up the potential for the clinical use of drugs encapsulated into erythrocytes.
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Abstract: The aim of this work was to elucidate the certain parameters (morphological, physicochemical) of terpene-indole alkaloids (TIAs) encapsulated human erythrocytes as a drug delivery system, and in addition to providing insight into the functional state of erythrocytes subjected to extracorporeal saturation with TIAs. Methods ― A modified hypotonic pre-swelling method was implemented to obtain TIAs encapsulated erythrocytes. The content of entrapped TIAs in the erythrocytes was evaluated by a validated analytical method. The morphological and physicochemical properties of TIAs encapsulated erythrocytes were assessed by turbidity spectrum method and the osmotic resistance (OR) of encapsulated erythrocytes. Also, a series of in vitro tests have been carried out to characterize the drug release, haemoglobin leakage, and stability under storage condition. Results ― TIAs loaded erythrocytes with drug encapsulation efficiency – vincristine sulfate (VCR) 42.963 ± 2.648%, and vinblastine sulfate (VLB) 44.266±2.432% were achieved by a modified pre-swelling hypotonic lysis method. Achieving higher TIAs encapsulation efficiency considerably essential in order to deliver a therapeutic success, however using improved encapsulation techniques have been achieved – VCR: 61.071±2.582% and VLB: 62.425±2.5288%, respectively. In the experiments, it was established, the morphological and physicochemical parameters of the obtained TIAs loaded erythrocytes were varied from the control erythrocytes in the order ~20–30%, although loaded erythrocytes can be stored at +40C for 7 days while the encapsulate drug amount without falling below 95.964±0.472%. Conclusion ― The stability and functionality of TIAs loaded erythrocytes were demonstrating relatively good performance with comparison to control erythrocytes and can be suggested to conduct in vivo experiment in animals for evaluating therapeutic potential compared to free drug forms.
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Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors and their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and γ-irradiation. In the present report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if these survival proteins could provide equivalent protection when challenged with chemotherapy or γ-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposide-induced cell death. In addition, Bcl-XL provided significantly greater cell viability than Bcl-2 against methotrexate, fluorouracil, and hydroxyurea, three S-phase specific agents. In apoptosis induced by γ-irradiation and cisplatin, two antitumor treatments that are cell-cycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against γ-irradiation, but Bcl-XL provided better protection than Bcl-2 against cisplatin. These results indicate that Bcl-XL and Bcl-2 confer a differential ability to protect against chemotherapy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase specificity.
Article
Bcl-2 and its homologue Bcl-XL are expressed in a variety of tumors and their expression modulates the sensitivity of tumor cells to a wide spectrum of chemotherapeutic agents and γ-irradiation. In the present report, we generated clones of FL5.12 lymphoid cells with similar levels of Bcl-2 and Bcl-XL using the Flag epitope to determine if these survival proteins could provide equivalent protection when challenged with chemotherapy or γ-irradiation. Using four M-phase specific chemotherapeutic agents, Bcl-XL and Bcl-2 provided similar protection against vincristine and vinblastine whereas Bcl-XL afforded as much as 50% greater cell viability than Bcl-2 against etoposide and teniposide-induced cell death. In addition, Bcl-XL provided significantly greater cell viability than Bcl-2 against methotrexate, fluorouracil, and hydroxyurea, three S-phase specific agents. In apoptosis induced by γ-irradiation and cisplatin, two antitumor treatments that are cell-cycle phase-nonspecific agents, both Bcl-XL and Bcl-2 conferred similar protection against γ-irradiation, but Bcl-XL provided better protection than Bcl-2 against cisplatin. These results indicate that Bcl-XL and Bcl-2 confer a differential ability to protect against chemotherapy-induced cell death, which appears to be dependent on the molecular mechanism targeted by the drug rather than its cell-cycle phase specificity.
Book
Publisher's Note: Products purchased from 3rd Party sellers are not guaranteed by the Publisher for quality, authenticity, or access to any online entitlements included with the product. Updated to include the newest drugs and those currently in development, Cancer Chemotherapy and Biotherapy, Fifth Edition is a comprehensive reference on the preclinical and clinical pharmacology of anticancer agents. Organized by drug class, the book provides the latest information on all drugs and biological agents-their mechanisms of action, interactions with other agents, toxicities, side effects, and mechanisms of resistance. Chapters emphasize pharmacology and mechanisms of action at the molecular and cellular levels, followed by clinical activity and toxicity, both acute and delayed. The authors explain the rationale for use of drugs in specific schedules and combinations and offer guidelines for dose adjustment in particular situations. This edition's introduction includes timely information on general strategies for drug usage, the science of drug discovery and development, economic and regulatory aspects of cancer drug development, and principles of pharmacokinetics. Eight new chapters have been added and more than twenty have been significantly revised. A companion website includes the fully searchable text and an image bank. © 2011 By Lippincott Williams & Wilkins, A Wolters Kluwer Business. All Rights Reserved.
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Single-step selections were used to obtain Chinese hamster ovary cell lines resistant to Colcemid and vinblastine. Verapamil was included in the selections to circumvent the isolation of cells with P-glycoprotein-mediated multidrug resistance and thereby enrich for cells with tubulin alterations. The isolated cell lines were 2-fold resistant to the selecting drug, exhibited cross-resistance to other drugs that inhibit microtubule assembly, and had enhanced sensitivity to the microtubule-stabilizing drug paclitaxel. The concomitant resistance to microtubule-destabilizing drugs and enhanced sensitivity to paclitaxel suggested that these cell lines have changes in microtubule assembly. Consistent with this interpretation, drug-resistant cell lines exhibited altered alpha- or beta-tubulin mobility on two-dimensional gels and higher levels (47-54%) of assembled tubulin compared with wild-type (39%) or paclitaxel-resistant cells (25%). Some drug-resistant cells also had bundled microtubules as judged by immunofluorescence. Genomic sequencing of 11 drug-resistant cell lines predicted five different alterations (D45Y, C211F, D224N, S234N, and K350N) in beta-tubulin and four different alterations (H283Y, E55K, A383V, and R390C) in alpha-tubulin. The amino acid substitutions are dispersed on the primary and tertiary structures of tubulin and, together with the other mutant properties, argue against a mechanism involving changes in drug binding. Rather, we propose that the alterations in alpha- and beta-tubulin increase microtubule stability by promoting longitudinal interdimer and intradimer interactions and/or lateral interactions between protofilaments. This enhanced stability of microtubules increases their resistance to drugs that inhibit assembly.
Article
The pharmacokinetics, metabolism, and excretion of aromatically labeled tritiated vincristine (VCR) was examined in 4 patients. Clearance of radioactivity from the blood was triphasic with half-life tV2 values of 0.85, 7.4, and 164 min. The initial phases probably represent distribution and binding to formed blood elements which exceeded 50% of the administered dose by 20 min. Excretion of radioactivity was principally fecal, with 33% recovered in the feces by 24 hr and 69% by 72 hr. Considerably less radioactivity (12%) was excreted in the urine over the 72-hr period. Approximately 40% of fecally excreted and 46% of urinary excreted radiolabel represented metabolites, which suggests that at least 34% of the VCR dose was excreted as metabolites. Plasma metabolites represented from less than 1 % to 30% or more of radioactivity in plasma. Ultraviolet spectral analysis of all metabolites revealed preservation of the intact VCR dimer, which suggests that metabolism involves alteration of side groups.
Article
The vinca alkaloids and the colchicine derivatives, although of widely disparate chemical structure, may be considered to constitute a single class of agents in view of the many similarities in their biochemical and biological actions, most notably in their ability to produce metaphase arrest. This resemblance extends to certain other unrelated compounds, including griseofulvin and podophyllotoxin.