Mini-Reviews in Medicinal Chemistry, 2012, 12, 1239-1249
Doxorubicin vs. ladirubicin: methods for improving osteosarcoma
P.I.P. Soares1, S.J.R. Dias2,3, C.M.M. Novo3,4, I.M.M. Ferreira1 and J.P. Borges*,1
1CENIMAT/I3N, Departamento de Ciência dos Materiais, Faculdade de Ciências e Tecnologia, FCT, Universidade
Nova de Lisboa, 2829-516 Caparica, Portugal; 2Centro de Investigação de Patologia Molecular, Instituto Português de
Oncologia de Lisboa, Francisco Gentil (CIPM/IPO Lisboa), Lisboa, Portugal; 3CEDOC, Faculdade de Ciências
Médicas, UNL, Lisboa, Portugal and Instituto Gulbenkian Ciência, Oeiras, Portugal; 4UEIPM, Instituto de Higiene e
Medicina Tropical, UNL, Rua da Junqueira 100, 1349-008 Lisboa, Portugal
Abstract: Osteosarcoma is the most common primary bone tumor in children and adolescents, with a 5-year disease free
survival rate of 70%. Current chemotherapy regimens comprise a group of chemotherapeutic agents in which doxorubicin
is included. However, tumor resistance to anthracyclines and cardiotoxicity are limiting factors for its usage. Liposomal
formulations of doxorubicin improve its anti-cancer effects but are still insufficient. The research in this area has lead to
the production of anthracyclines analogues, such as ladirubicin, the leading compound of alkylcyclines. This new
anticancer agent has shown promising results in vivo and in vitro, being effective against osteosarcoma cell lines,
including those with a multidrug resistant phenotype. In phase I clinical trials, this molecule caused mild side effects and
did not induce significant cardiotoxicity at doses ranging from 1 to 16 mg/m2, resulting in a peak plasma concentration
(Cmax) ranging from 0.5 to 1.5 ?M. The recommended doses for phase II studies were 12 and 14 mg/m2 in heavily and
minimally pretreated/non-pretreated patients, respectively. Phase II clinical trials in ovary, breast, colorectal cancer,
NSCLC and malignant melanoma are underway. Given the improved molecular targeting efficacy of these new
compounds, ongoing approaches have sought to improve drug delivery systems, to improve treatment efficacy while
reducing systemic toxicity. The combination of these two approaches may be a good start for the discovery of new
treatment for osteosarcoma.
Keywords: Anthracyclines family, doxorubicin, laudorubicin, osteosarcoma treatment.
bone tumor and has a high incidence in children and
adolescents, since it accounts for approximately 60% of
primary malignant bone tumors diagnosed in the first two
decades of life. It is characterized by an extremely
aggressive clinical route with rapid development of
metastases in 40-50% of patients, occurring mainly in lung
[1, 2]. Conventional therapies for osteosarcoma include
surgery (frequently amputation),
radiotherapy . Until 1970, osteosarcoma treatment was
based on amputation or radiotherapy, and death occurred in a
short period of time due to lung metastasis; the 5-year
disease free survival rate was about 12%. In 1978
neoadjuvant chemotherapy was introduced with the
combination of doxorubicin (DOX), methotrexate (MTX),
cisplatin and ifosfamide, significantly improving the clinical
results in osteosarcoma treatment . Current neoadjuvant
chemotherapy protocols for high-grade osteosarcoma are
based on DOX, high-dose MTX, and cis-dichloro-diammine-
platinum (CDDP), with the addition of ifosfamide in the
Osteosarcoma is the most common primary malignant
*Address correspondence to this author at the CENIMAT/I3N,
Departamento de Ciência dos Materiais, Faculdade de Ciências e
Tecnologia, FCT, Universidade Nova de Lisboa, 2829-516 Caparica,
Portugal; Tel: +351 21 2948564; Fax: +351 21 2947810;
post-operative phase, increasing the 5-year disease free
survival rate to 70%, in patients without metastasis .
However, current treatments for osteosarcoma have not
resulted in improved prognosis during the last decade
providing incentive for the development of new treatment
adjuvant chemotherapy proved to be beneficial . The
currently used drugs include cyclophosphamide, vincristine,
melphalan, adriamycin (DOX), MTX, cisplatin, decarbazine,
bleomycin, dactinomycin, actinomycin, and leucovorin
rescue. The current standard treatment for osteosarcoma
includes preoperative chemotherapy followed by surgery and
postoperative chemotherapy. Preoperative chemotherapy
aims to induce tumor necrosis in primary tumor, facilitating
surgical resection and the eradication of micro-metastases.
Postoperative chemotherapy, to manage metastases is chosen
based on: the initial therapy; the site and the number of
metastases or recurrent tumors; the length of the disease-free
interval and the type of chemotherapy previously applied to
the patients . Although a multidrug regimen is used to
treat osteosarcoma, the need
chemotherapeutic drugs to enhance prognosis remains a
problem. Additionally some patients can be treated with
radiation but only for radiosensitive tumors.
Osteosarcoma is one of the first solid tumors for which
for high doses of
is multidrug resistance (MDR). MDR has been correlated
The major cause of failure of chemotherapeutic regimens
1???-????/12 $58.00+.00 © 2012 Bentham Science Publishers
1240 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 Soares et al.
detoxification of the drugs through increased metabolism,
decreased drug uptake, a reaction with increased levels of
intracellular nucleophiles, enhanced repair of the drug-
induced damage to DNA, or through overexpression of
membrane-bound drug transporter proteins, such as P-
glycoprotein (Pgp, ABCB1), multidrug resistance-associated
proteins (MRP1, ABCC1 and MRP2, ABCC2) and the breast
cancer resistance protein (BCRP, ABCG2) [1, 8].
multi-factorial processes such as: enhanced
heterogeneous population of cells that differ in their relative
states of differentiation . During the last years, the cancer
stem cells (CSC) theory emerged as a model to account for
the heterogeneity and renewal capacity of tumor cells. The
CSC theory postulates that the greater part of a tumor mass
contains more differentiated cells that are susceptible to
radiation and chemotherapy because of their close vicinity to
non- tumorigenic tissues and sufficient blood flow due to
induced angiogenesis, or blood vessel growth . In
contrast, a small subset of cells with stem-like properties that
is responsible for initiating and sustaining tumor growth
were termed cancer stem cells because of the properties they
share with normal stem cells, including their ability to self-
renew and undergo differentiation . Similar to the
normal tissue stem cells, in some tumors, the CSCs are
believed to reside in less oxygenated areas in a quiescent
state. In fact, CSCs have several features that make them
naturally resistant to conventional therapies. Most of the
drugs used in cancer treatment target DNA and induce
irreversible damage leading to cell death. CSCs seem to have
enhanced DNA repair mechanisms allowing them to resist
do damage induced by conventional therapies . The
multidrug resistance trait of CSCs is associated with an
overexpression of proteins from the BCL-2 family, which
protects CSCs from apoptosis and leads to an increase in
expression of membrane proteins responsible for drug
resistance . In addition, an increased expression of
transporting proteins such as MDR1 and ABC transporters is
an important factor in chemotherapy resistance .
Solid tumors, including osteosarcoma, consist of a
of CSCs in osteosarcoma. Gibbs et al.  have successfully
isolated the CSCs subpopulation from nine established
cultures from untreated osteosarcoma biopsies and a
osteosarcoma cell line (MG 63) through sphere formation
assay. Sarcospheres-derived cells expressed the MSC surface
markers Stro-1, CD105 and CD44 and over-expressed
embryonic stem cells pluripotency markers (OCT4 and
Nanog). Wang et al.  observed similar results in four
more human osteosarcoma cell lines. Murase et al.  also
reported the existence of a subset of CSCs in human
osteosarcoma cell lines identified through the extrusion of
Hoechst 33324. These cells revealed higher tumorigenic
potential in vivo and in vitro. These findings strongly suggest
that osteosarcoma is enriched in cells with stem-like
properties and that these cells may be responsible for drug
Recent studies have successfully identified the presence
difficulties in its treatment suggest new treatment options.
This work firstly reviews a family of chemotherapeutic
agents – anthracyclines – commonly used in osteosarcoma
The high incidence of MDR in osteosarcoma and the
treatment, and one of its members, DOX. Secondly, it
reviews a new chemotherapeutic drug, ladirubicin, the
prototype drug of alkylcyclines, used to evade tumor
resistance and to improve chemotherapy results.
anticancer drugs ever developed . The first members of
this family were originally isolated from the pigment-
producing Streptomyces peucetius in the 1960s and were
named doxorubicin (DOX) and daunorubicin (DNR) .
Anthracyclines belong to the group of the most effective
Fig. (1). Chemical structure of DOX.
According to (Figs. 1 and 2), the only difference between
DOX and DNR is the termination of side chain. DOX
terminates with a primary alcohol whereas DNR terminates
with a methyl group. Consequently, DOX is active against
breast cancer, childhood solid tumors (like osteosarcoma),
soft tissue sarcomas, and aggressive lymphomas while DNR
is more active against acute lymphoblastic or myeloblastic
Fig. (2). Chemical structure of DNR.
Doxorubicin vs. ladirubicin
Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 1241
cardiotoxicity leading to congestive heart failure and the
development of spontaneous and acquired resistance.
Intensive research to find analogues that circumvent these
problems lead to the development of more than 300 new
compounds, whereas more than 2000 analogues were issued
from structural modifications of natural compounds or from
synthesis . However, from those only few members of
the anthracycline family have reached the stage of clinical
development and approval, including (Table 1): DOX, DNR,
epirubicin (EPI, 4’-epi-doxorubicin or Farmorubicin®),
idarubicin (IDA, 4-demethoxy-daunorubicin or Zavedos®),
aclacinomycin A (aclarubicin) and mitoxantrone [17, 19].
EPI is a semi-synthetic derivate of DOX obtained by an
axial-to-equatorial epimerization of the hydroxyl group at C-
4’ in daunosamine (Fig. 3). This structural change has little
effect on its mode of action and spectrum of activity
compared to DOX but
pharmacokinetic and metabolic changes, like increased
volume of distribution (Vd), 4-O-glucuronidation, and
consequent enhanced total body clearance (CL) or shorter
terminal half-time . Moreover, EPI may be used at
higher doses than DOX, without increased cardiotoxicity
The major drawbacks of these compounds are their
it introduces significant
Fig. (3). Chemical structure of EPI.
IDA is an analogue of DNR obtained after removal of the
4-methoxy group in ring D (Fig. 4) and is active in acute
myelogenous leukemia, multiple myeloma, non-Hodgkin’s
lymphoma, and breast cancer . IDA presents a higher
spectrum of activity when compared to DNR, probably due
to its increased lipophilicity and cellular uptake as well as
improved stabilization of a ternary drug-topoisomerase II-
DNA complex .
subsequently marketed in Europe with the designation of
Theprubicin®. This compound has discrete improvements
over DOX in terms of drug resistance, and induces much less
cardiotoxicity [17, 19].
Pirarubicin (Fig. 5) was synthesized in Japan  and
Fig. (4). Chemical structure of IDA.
Fig. (5). Chemical structure of Pirarubicin.
also demonstrated little improvement over DNR in terms of
drug resistance but was shown to be active and cardiac
tolerable in adult patients with acute myeloblastic leukemia
Aclarubicin (Fig. 6) is a trissaccharide anthracycline that
anthraquinone that is active in breast cancer, acute
promyelocytic or myelogenous leukemia, and androgen-
independent prostate cancer. Its advantage in terms of
cardiotoxicity compared to other family members is still
Mitoxantrone (Fig. 7) is a substituted aglyconic
1242 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 Soares et al.
Table 1. Members of the Anthracyclines Family that Reached the Stage of Clinical Development and Approval; Pirarubicin and
Aclarubicin are Not Currently Marketed. Information About Commercial Designation, Formulation, Therapeutic
Indications and First Approval Date are Provided for the Remaining Members of the Anthracyclines Family
Formulation Therapeutic Indications
Metastatic breast cancer, advanced ovarian cancer, progressive multiple
myeloma in combination with bortezomib, AIDS-related Kaposi’s
21 June 1996 
Treatment of metastatic breast cancer in combination with
13 July 2000 
Acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid)
and acute lymphocytic leukemia.
Advanced HIV-associated Kaposi's
Adjuvant therapy in patients with evidence of axillary node tumor
involvement following resection of primary breast cancer.
Acute myeloid leukemia (AML).
Acute nonlymphocytic leukemia.
Acute nonlymphocytic leukemia, breast cancer in advanced stages.
Not current marketed
Not current marketed
Secondary (chronic) progressive, progressive relapsing, or worsening
relapsing-remitting multiple sclerosis; advanced hormone-refractory
prostate cancer, acute nonlymphocytic leukemia (ANLL), including
myelogenous, promyelocytic, monocytic, and erythroid acute leukemias.
Metastatic breast cancer, non-Hodgkin’s lymphoma, acute
nonlymphocytic leukemia, palliative treatment of primary hepatocellular
carcinoma; advanced prostate cancer hormone-resistant.
Fig. (6). Chemical structure of Aclarubicin.
Fig. (7). Chemical structure of Mitoxantrone.
Mechanism of Action
growth is still not completely clear and multiple pathways
are thought to be involved in the cytotoxicity of this class of
anticancer drugs. According to Gewirtz  anthracyclines
act by eight different mechanisms: 1) intercalation into
DNA, leading to inhibited synthesis of macromolecules; 2)
The mechanism by which anthracyclines inhibit cancer
Doxorubicin vs. ladirubicin
Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 1243
generation of free radicals, leading to DNA damage or lipid
peroxidation; 3) DNA binding and alkylation; 4) DNA cross-
linking; 5) interface with DNA unwinding or DNA strand
separation and helicase activity; 6) direct membrane effects;
7) initiation of DNA damage via inhibition of topoisomerase
II; and 8) induction of apoptosis in response to
topoisomerase II inhibition. However, these mechanisms did
not occur all at the same dosage; more so, some of them
were observed at concentrations considered too high to be
administrated to patients.
concentrations, anthracyclines may act as topoisomerase
inhibitors or may induce apoptosis through DNA damage
and p53. In the first case, anthracyclines act by stabilizing a
reaction intermediate in which DNA strands are cut and
covalently linked to tyrosine residues of topoisomerase II,
eventually impeding DNA resealing. The formation and
stability of an anthracycline-DNA-topoisomerase II ternary
complex is crucial for anthracyclines activity; moreover, the
external (non-intercalating) moieties of the anthracycline
molecule (i.e., the sugar residue and the cyclohexane ring)
seem to play an important role in formation and stability of
this ternary complex. Topoisomerase II mediated DNA
damage is followed by growth arrest in G1 and G2 and
programmed cell death . It follows that tumor cells may
become resistant to anthracyclines because of altered
topoisomerase II gene expression or activity .
Minotti et al.  considers that, at clinically relevant
it is known that DOX activates p53-DNA binding. However,
the role of p53 in anthracycline-induced apoptosis is not
certain, with contradictory reports [36, 37]. These
uncertainties may be attributed to various factors such as the
heterogeneity of the tumors examined or the methods used
for assessing p53 status and tumor response. As for the role
of p53 in regulating cell cycle transition, it is established that
DOX-dependent p53 activation contributes to the induction
of the WAF1/CIP1 p21 gene product, a strong inhibitor of
cyclin-dependent kinases involved in G1 to S transition.
Although these mechanisms may contribute to G1 arrest of
p53 proficient cells, WAF1 expression might protect cells
from DOX because the G1 block facilitates DNA repair
before the cells undergo replication. On the other hand, the
ability of p53-deficient cells to progress through the S phase
may be a favorable event since the expression of the ?-
isoform of topoisomerase II is increased during DNA
synthesis. Furthermore, Dunken et al.  shown that p53
might be important not only in connecting DNA damage to
downstream execution of apoptosis but also in determining
the levels of DNA strand breaks induced by DOX.
As for the second mechanism of action of anthracyclines,
and anthracycline-induced apoptosis and the contradictory
reports about related mechanisms may also be justified by
the presence of alternative networks that are not bound to an
inhibition of topoisomerase II nor do they always require
functional p53 .
Uncertainties about the complex interplay between p53
related to cumulative dose-dependent
One of the major problems of anthracyclines usage is
responsible for developing
Anthracycline-induced secondary cardiotoxicity is seen in 5-
23% of patients [39, 40]. The mechanism behind the
anthracyclines cardiac toxicity and their specificity to
myocyte cells remains controversial and not completely
understood. Sawyer et al.  propose several mechanisms
to explain the cardiotoxicity of anthracyclines, including
(Fig. 8): 1) generation of oxidative stress through formation
of hydroxyl radical, leading to myocyte cell dead; 2)
inducing apoptosis via a mitochondrial pathway involving
Bax, cytochrome c and caspase-3 activation; 3) inducing
apoptosis through intercalation between base pairs in DNA,
originating DNA damage; 4) DNA damage by suppression
of expression and/or activity of transcription factors that
modulate sarcomere synthesis, as well as cell survival; 5)
suppression of sarcomere
mechanisms may not occur all at once, they are probably
induced by different doses of the chemotherapeutic agent.
late-onset heart failure.
protein synthesis. These
being its cardiotoxicity a major limitation, efforts to
circumvent this problem include: limiting dose exposure;
encapsulated anthracyclines in liposomes to reduce
myocardial uptake; administering concurrently with the iron
chelator dextrazone to reduce free iron-catalyzed reactive
oxygen species formation; and modify anthracyclines
structure in an effort to reduce myocardial toxicity .
Since anthracyclines are interesting therapeutic agents
Alternative Formulations of Current Anthracyclines
chemotherapeutic treatment, so its clinical unresponsiveness
is a major concern. Liposomal doxorubicin (Caelyx® in
Europe, Doxil® in USA) is currently approved for cancer
treatment and its formulation has the advantage of enhancing
the antitumor effect, reducing toxicity, and improving
pharmacokinetics, when compared to free DOX. These
improvements are due to several factors: the polyethylene
glycol (pegylated) coating reduces the uptake of the
liposomes by cells of the reticuloendothelial system (RES),
thus prolonging the time of circulation; because normal
blood vessels are not as fenestrated as tumor vessels,
liposomes are confined to the intravascular space, reducing
toxicity in normal tissues . Besides Caelyx®, another two
liposomal formulations of anthracyclines have showed
promising results: an uncoated formulation in which citrate
is included for increasing DOX encapsulation above the
levels predicted by the maintenance of a transmembranar pH
gradient; and a liposomal DNR (DaunoXome) . The first
formulation is not as advantageous as the pegylated
liposomal DOX, but still is better than free DOX and its
main indication is treatment of metastatic breast cancer .
Liposomal DNR also showed improved results when
compared to free DNR and it is used as a first-line therapy of
AIDS-related Kaposi’s sarcoma, although it also has activity
against refractory or relapsed acute myeloblastic leukemia,
recently diagnosed or recurrent/refractory multiple myeloma
and non-Hodgkin’s lymphoma .
Doxorubicin plays an important role in osteosarcoma
system composed by chitosan-dextran sulphate using a
combinational coacervation method. DOX was successfully
encapsulated into these microparticles and the in vitro
Tan et al.  produced an alternative drug delivery
1244 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 Soares et al.
studies demonstrated a reduction in SaOS-2 cell viability
through various cell death mechanisms such as necrosis,
apoptosis and mitosis. Treatment of mice bearing orthotopic
osteosarcoma with DOX microparticles decreased tumor
volume, bone lysis, and reduced secondary metastasis to the
lungs. Also the treated mice maintained their weight and did
not appear to suffer from any visible side effects such as
heart failure or dry skin.
cardiotoxicity is by its encapsulation into nanoparticles.
Betancour et al.  reported acid-copped poly(lactic-co-
glycolic acid) nanoparticles as a carrier for DOX that deliver
the drug into MDA-MB-21 breast cancer cells quickly and in
higher quantity than free DOX. Janes et al.  showed
similar results using chitosan nanoparticles in human
Another approach to decrease anthracyclines
melanoma A375 cells. Bisht et al.  reviewed the usage of
nanoparticles in solid tumors therapy and showed that
nanoparticles in the range of 10-100 nm diameter are able to
deliver chemotherapeutic drugs to solid tumor. Susa et al. 
incorporated DOX into a lipid-modified dextran based
polymeric nano-system and demonstrated improved anti-
proliferative effects against osteosarcoma cell lines
compared to free DOX.
encapsulated in chitosan
multidrug resistance in MCF-7/ADR cancer cells using a
drug delivery system that tethers DOX onto the surface of
gold nanoparticles with a poly(ethylene glycol) spacer via an
acid-labile linkage (DOX-Hyd@AuNPs).
nanoparticles release DOX in response to pH of acidic
Wang et al.  demonstrated a way to overcome
Fig. (8). Possible mechanisms by which anthracyclines causes cardiac toxicity. The formation of reactive species is induced by the quinone
moiety of anthracyclines and by induction of nitric oxide synthase, leading to nitric oxide and peroxynitrite formation. Another method of
anthracyclines cardiotoxicity is to intercalate into nucleic acids, causing suppression of DNA, RNA, and protein syntheses, as well as
damaging some transcriptional regulatory proteins that seem important for regulation of cardiac-specific genes. Anthracyclines also
accelerate myofilament degradation, leading to a net negative balance of sarcomeric proteins (“cardiac sarcopenia”) and induce changes in
adrenergic function and adenylate cyclase as well as abnormalities in Ca2+ handling, functions that are critical for cardiac function. By last,
anthracyclines also induce necrosis and apoptosis of myocyte cells. ROS – reactive oxygen species; JNK – c-Jun N-terminal kinases; bax –
Bcl-2-associated X protein; NOS – nitric oxide synthase; GATA4 – gene name, member of GATA family of zinc-finger transcription factors;
MHC – myosin heavy chain; CARP – cardiac ankyrin repeat protein and cardiac adriamycin-responsive protein .
Doxorubicin vs. ladirubicin
Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 1245
organelles after endocitosis, inducing elevated apoptosis in
cancer cells. This process may be monitored by the
fluorescence of DOX from quenching due to the nanosurface
energy transfer between the doxorubicinyl groups and the
New Anthracyclines Family Member
activity and to decrease its cardiotoxicity is by chemical
modification. It was shown that substitution in the sugar
position at C-3’ is critical for the ability of drugs to interfere
with DNA topo II  and that the configuration of C-3’-
NH2 is fundamental for the ability of drugs to overcome
Another approach to increase anthracyclines anti-tumor
– was obtained by alkylation of position C-3’ of the
aminosugar of anthracyclines such as idarubicin, which
increases lipophilicity and reduces the chemical reactivity of
these molecules. This new class of compounds showed high
cytotoxicity in cell lines resistant to doxorubicin and
idarubicin [49, 50].
A new class of anthracyclines derivatives – alkylcyclines
3’-aziridinyl-4’-methylsulphonyl-daunorubicin) (Fig. 9), the
leading compound of this new class is characterized by the
presence of an aziridinyl moiety at C-3’ and esterification of
–OH at C-4’ with a methylsulfonic group, which is
responsible for its high lipophilicity and for an increased
stability of the alkylating moiety. This new class of
compounds causes DNA damage, not by interaction with
topoisomerase II but via the anthracyclines backbone
binding covalently to guanines at the N7 position and
adenines at N3 position via the reactive alkylating group in
the sugar .
Ladirubicin (PNU-159548, 4-demethoxy-3’-deamino-
Fig. (9). Chemical structure of ladirubicin.
Gerani et al.  evaluated the antitumor activity of
ladirubicin by an in vitro and in vivo cancer cell line panel
and investigated its mode of action; also, they performed
toxicity and pharmacokinetic studies. Ladirubicin was found
to be active against both murine and human tumor cell lines
in vitro, using a concentration 33 times smaller than the
required for DOX, probably due to its higher lipophilicity.
Moreover, the presence of bulky substituents at C-3’ position
of the amino sugar prevents drug stimulation of DNA
topoisomerase II cleavage, making ladirubicin effective on
cells presenting the topoisomerase II-related MDR. The in
vivo studies indicated a wide spectrum antitumor activity
against rapidly proliferating murine leukemias and on slowly
growing transplantable human tumor xenografts. The
toxicological profile of ladirubicin was pre-clinically defined
in mice, rats, and dogs, and target organs were identified
after single and repeated-cyclic-dose administration. The
collateral toxic effects are dose-related and reversible and
consisted in myelosuppression, lymphoid organ cell
depletion, and intestinal toxicity. Conversely, in animals
ladirubicin showed a cardiotoxicity remarkably lower then
DOX at equimyelotoxic doses.
to evaluate ladirubicin antitumor activity. Their results
demonstrated that ladirubicin is active against cells
expressing the MDR phenotype associated to MDR-1 gene
overexpression or to an alteration in the topoisomerase II
gene (altered MDR). Ladirubicin was also active against
cells showing resistance to several alkylating agents
(cisplatin, cyclophosphamide, melphalan) and topoisomerase
Marchini et al.  performed in vitro and in vivo studies
activity against 32 human osteosarcoma cell lines, including
cell lines resistant to DOX, methotrexate or cisplatin. In their
results ladirubicin maintained its activity in DOX-resistant
osteosarcoma cell lines, which present a MDR phenotype as
a consequence of MDR-1 gene amplification/overexpression
and increased levels of P-glycoprotein. The intracellular
uptake of ladirubicin was not influenced by the presence of
high levels of P-glycoprotein. When the authors used
osteosarcoma cell lines resistant to methotrexate or cisplatin,
ladirubicin exhibited similar efficacy to that found in drug-
sensitive cell lines, indicating absence of cross-resistance
mechanism between ladirubicin and methotrexate or
cisplatin. They investigated as well the possibility of
effectively combining ladirubicin
anticancer drugs. The results revealed additive or synergistic
interactions with DOX and cisplatin and antagonist effects
with methotrexate, concluding that probably ladirubicin has
effects on cell cycle, considering that methotrexate efficacy
is strictly related to the presence of actively growing cells.
Pasello et al.  evaluated ladirubicin to antitumor
active against several human tumor xenografs: MX1
mammary carcinoma, DU 145 prostatic carcinoma, M14
melanoma, A431 epidermoid carcinoma, A2780, H207 and
IGROV1 ovarian carcinomas, N592 SCL carcinoma, H460
NSCL carcinoma, HCT-116 colon carcinoma. Also,
borderline activity was observed
adenocarcinoma and HT29 colon carcinoma . In
addition, due to its high lipophilicity, ladirubicin is able to
cross the blood-brain barrier, being effective against
intracranial tumors, and the dose-limiting toxicity is
myelosuppression whereas lack of cardiotoxicity may be
The preclinical studies demonstrated that ladirubicin is
on A549 lung
1246 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 Soares et al.
explained, at least partially, by high plasma clearance .
The in vivo studies demonstrated activity on MDR (P-
glycoprotein and topoisomerase II related MDR) tumor cells.
It does not inhibit topoisomerase II and it reaches similar
intracellular levels in sensitive and MDR tumor cells.
Furthermore, in vivo studies demonstrated an antitumor
efficacy clearly superior and minimal cardiotoxicity
compared to DOX. With this pre-clinical evidences,
ladirubicin has been selected for Phase I clinical trials on
patients with a variety of solid tumors, with the purpose of
testing the feasibility and describe the clinical toxicity and
pharmacokinetics of ladirubicin when administrated I.V.
over a 10 min infusion . The dose-limiting toxicity
(DLT) of ladirubicin was thrombocytopenia and mild
neutropenia, and the most prominent non-hematological side
effects were nausea and vomiting, which were rare when in
combination with 5-hydroxytryptamine-3
antagonists. A less frequent but prominent side-effect was a
complex of symptoms consisting of fever with chills, facial
erythema and edema, and dyspnea, which was interpreted as
an hypersensitivity reaction that developed during or shortly
after the infusion and ceased, either spontaneously at
interruption of the drug administration or following
antihistamine therapy. The evaluation of the cardiac function
demonstrated that ladirubicin did not induce significant
cardiotoxicity at doses ranging from 1 to 16 mg/m2, resulting
in a peak plasma concentration (Cmax) between 0.5 to 1.5
?M. Based on this study, the recommended dose for phase II
studies was 12 and 14 mg/m2 in heavily and minimally
pretreated/non-pretreated patients, respectively. Phase II
clinical trials of ladirubicin in ovary, breast, colorectal
cancer, NSCLC and malignant melanoma are underway
DOXORUBICIN VS. LADIRUBICIN
ladirubicin, some aspects are clear and can be compared.
Despite the lack of literature directly comparing DOX to
anthracyclines obtained and to exhibit an aglycolic and sugar
moieties. The aglycone consists of a tetracyclic ring with
adjacent quinone-hydroquinone groups in rings C-B, a
methoxy substituent at C-4 in ring D, and a short side chain
at C-9 with a carbonyl at C-13. The sugar (daunosamine) is
attached by a glycosidic bond at the C-7 of ring A and
consists of a 3-amino-2,3,6-trideoxy-L-fucosyl moiety.
Furthermore, DOX side chain terminates with a primary
alcohol. Instead, ladirubicin is characterized by the presence
of an aziridinyl moiety at C-3’ and esterification of –OH at
C-4’ with a methylsulfonic group. In addition, the side chain
of ladirubicin terminates with a methyl group, rather than a
primary alcohol .
In terms of chemical structure, DOX is one of the firsts
lipophilicity and cytotoxic mechanisms of both drugs.
Ladirubicin is much more lipophilic than DOX and
consequently has a higher volume of distribution ,
crosses the blood-brain-barrier and is able to delay the
growth of intracranially implanted tumors .
These structural differences lead to differences in the
different, which may justify the anti-tumoral activity of
The mechanisms of antitumoral activity of both drugs are
ladirubicin against DOX-resistant cell lines. DOX acts by
interacting with topoisomerase
topoisomerase II-DNA complexes, resulting in double-
strands breaks in the DNA and cell arrest in the cell cycle at
the G2 stage. In addition, as discussed earlier, DOX may
also be involved in p53 pathways and inductions of
programmed cell death. On the other hand, ladirubicin
causes cell damage through DNA intercalation via the
anthracycline backbone and bind covalently to guanines (N7
position) and adenines (N3 position) via the alkylating group
in the sugar. As such, even in tumor cells that exhibit altered
topoisomerase II gene expression or activity, ladirubicin is
II, stabilizing the
is the extent of cardiotoxicity as a result from treatment. In
the rat, ladirubicin induces chronic cardiotoxicity which is
less than one-20th of that caused by an equimyelotoxic dose
of DOX . Further, in phase I clinical trials, no cardiac
toxicity could be discerned .
Another aspect that distinguishes DOX from ladirubicin
al. , ladirubicin is more potent than DOX: the IC50
values of ladirubicin where in a range of 1.2 to 81.1 ng/ml,
while for DOX those values are in a range of 72-1365 ng/ml,
probably due to ladirubicin high lipophilicity, leading to
faster accumulation in tumor cells.
According to the in vitro studies performed by Geroni et
based on pre-operative chemotherapy, surgery and post-
operative chemotherapy. In pre-operative chemotherapy, the
current used drugs are cyclophosphamide, vincristine,
melphalan, DOX, MTX, cisplatin, decarbazine, bleomycin,
dactinomycin, actinomycin, and leucovorin rescue. Post-
operative chemotherapy includes DOX, high-dose MTX, and
CDDP [2, 7]. According to Pasello et al. , the first lineuse
of ladirubicin followed by DOX, MTX or CDDP results in
synergetic or additive effects. On the other hand, using
ladirubicin after administration of DOX, MTX of CDDP has
antagonistic effects in the majority of the cell lines used. In
addition, simultaneous exposure to ladirubicin and DOX or
CDDP has additive or synergetic effects, while simultaneous
exposure to ladirubicin and MTX result in antagonistic
effects. The finding may be critical for ladirubicin usage,
because its antitumoral effectiveness may not be superior to
DOX if in a combinatory regimen with MTX. Additionally,
based on these findings, ladirubicin would be more
beneficial in pre-operative chemotherapy regimens.
As stated earlier, standard osteosarcoma treatment is
certainly clarify these in vitro finding. Furthermore,
combinatory studies are needed to evaluate the more
beneficial combination with ladirubicin.
Phase II clinical trials are ongoing and the results will
become resistant to one or more chemotherapeutic agents. To
overcome drug resistance and reduce the side effects during
chemotherapy, as well as to improve drug delivery and
availability, nanotechnology holds a promising potential
utilizing targeted drug delivery. A number of nanoparticles
types are available: polymeric nanoparticles, dendrimers,
Cancer cells employ a host of different mechanisms to
Doxorubicin vs. ladirubicin
Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 1247
inorganic/metal nanoparticles, quantum dots, liposomes,
micelles, and several other types of nanoassemblies .
anthracyclines, may become a manifest as late as 20 years
after chemotherapy. Despite the intense research in this
subject, there is no consensus over the standard of care for
cardiac monitoring, prophylactic cardiac treatment, or
selective therapies to reverse
Cardiotoxicity, a well-known adverse effect of
chemotherapeutic agents used in osteosarcoma treatment, has
a high incidence in anthracyclines-induced cardiotoxicity.
The liposomal formulation of doxorubicin, Caelyx®, has
demonstrated to reduce the side effects and improve the anti-
cancer effects of doxorubicin. However, cardiotoxicity is
still observed in patients treated with Caelyx®  and its
safety has constantly been under scrutiny due to the adverse
side-effects still experienced by patients. For instance,
incidences of dermatological toxic reaction – palmar-plantar
erythrodysesthesia have been reported in up to 50% of all
patients , while another 50% of patients suffered from
various hematologic adverse reactions such as anemia,
leucopenia, and neutropenia . Alternative formulations
have been studied like polymeric nanoparticles based
delivery systems which offer a significant advantage over
other nanocarrier platforms as there is a tremendous
versatility in choice of polymeric matrices that can be used,
allowing for the tailoring of nanoparticles properties to meet
the specific needs they are intended to meet. Other
advantages of these formulations are: easy surface
modification; greater encapsulation efficiency of the
payload; payload protection; large surface area-to-volume
ratio; and slow or fast polymer erosion for temporal control
over the release of drugs.
Doxorubicin, one of the most important
systems that combine carriers with cancer-targeting
molecules can potentially overcome the drawbacks presented
by conventional approaches . Salerno et al. 
developed biodegradable, biocompatible nanoparticles made
of a conjugate between poly (D, L lactide-co-glycolic) acid
and alendronate, suitable for systemic administration and
directly targeting the site of tumor induced osteolysis. These
nanoparticles were loaded with doxorubicin and the in vitro
and in vivo activity of the drug encapsulated in the carrier
system was analyzed in a panel of human cell lines,
representative for primary or metastatic bone tumors, and in
an orthotopic mouse model for breast cancer bone
metastasis. Their results showed a significant dose-
dependent growth inhibition of all cell lines.
Furthermore, the development of nanostructured delivery
combination of various anti-cancer strategies. For example,
some studies use magnetic nanoparticles loaded with
chemotherapeutic agents [58-62]. This combination is
suitable to use intracellular hyperthermia, a technique in
which the particles are concentrated at the tumor site and are
remotely heated using an applied magnetic field to the
required hyperthermic temperatures (42-45ºC), thus killing
the cancer cells with the heat generated [63, 64].
The use of polymeric nanocarriers allows the
promising results in vitro and in vivo and in phase I clinical
trials. It has anti-cancer activity against cell lines expressing
the MDR phenotype and cancer cells resistant to alkylating
agents and topoisomerase I-inhibitors. Also, in rats
ladirubicin induces chronic cardiotoxicity which is less than
one-20th of that caused by an equimyelotoxic dose of DOX
and significantly milder than the predicted based upon the
equivalent dose of IDA present in the drug´s backbone .
On the other hand, in drug resistant variants of osteosarcoma
cells, there was evidence that a first exposure to the drug
against which these cells are resistant, negatively affects and
limits their subsequent sensibility to ladirubicin through
mechanisms that still remain to be identified . However,
phase I clinical trials revealed some side effects such as
thrombocytopenia, mild neutropenia, nausea, vomiting and
Ladirubicin, the prototype of alkylcyclines, has shown
profiting of ladirubicin advantages may be the encapsulation
of ladirubicin into nanoparticles functionalized with tumor-
targeted agents. This technique would provide specificity to
the chemotherapy treatment, increase the anti-tumor activity,
mainly in resistant variants of the tumor cells, decrease the
side effects of ladirubicin and the cardiotoxicity would be
almost absent. This technique has already been experimented
for other cancer treatments. For example, Huh et al. 
used magnetic nanocrystals conjugated to Herceptin, a
cancer-targeting monoclonal antibody used for breast cancer
treatment, and successfully monitored in vivo selective
targeting events of human cancer cells implanted in live
An alternative way to overcome anthracyclines problems
covalently coupled to human albumin nanoparticles. DI17E6
is a monoclonal antibody directed against ?v integrins that
inhibit growth of melanomas in vitro and in vivo and also
angiogenesis due to interference with ?v?3 integrins.
Moreover, DOX was loaded in DI17E6 nanoparticles
showing increased cytotoxic activity in ?v?3-positive
melanoma cells compared to free drug.
Wagner et al.  used a monoclonal antibody, DI17E6,
with an overall incidence of 5 cases per million persons per
year. However, among
osteosarcoma is the eighth most common. Only leukemias,
lymphomas, and neurological malignancies are more
common. Osteosarcoma accounts for 8-9% of cancer-related
deaths in children and carries an overall 5-year survival rate
of 60%–70% . Doxorubicin is one of the most important
chemotherapeutic agents in
However, its cardiotoxicity and increase resistance are a
limitation in its usage. So, there is a need for new treatment
options. Also, ladirubicin is an analogue of idarubicin with
promising results in phase I clinical trials, as such, liposomal
formulations and anthracyclines analogues have been
exhaustively explored in the last years, leading to the
discovery of nanoparticles system able to deliver the drug to
a specific site, maintaining the anti-cancer activity of the
drug and reducing its side effects.
Osteosarcoma is a relatively uncommon malignancy,
1248 Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 Soares et al.
CONFLICT OF INTEREST
conflicts of interest.
The author(s) confirm that this article content has no
FCT-MEC through Strategic PEst-C/CTM/LA0025/2011
project and PhD grant-SFRH/BD/81711/2011 of the author
P. I. P. Soares.
Financial support for this work was provided by
Susa, M.; Iyer, A.K.; Ryu, K.; Hornicek, F.J.; Mankin, H.; Amiji,
M.M.; Duan, Z. Doxorubicin loaded polymeric nanoparticulate
delivery system to overcome drug resistance in osteosarcoma. BMC
Cancer, 2009, 9(399).
Pasello, M.; Hattinger, C.M.; Stoico, G.; Manara, M.C.; Benini, S.;
Geroni, C.; Mercuri, M.; Scotlandi, K.; Picci. P.; Serra, M. 4-
daunorubicin (PNU-159548): A promising new candidate for
chemotherapeutic treatment of osteosarcoma patients. European J.
Cancer, 2005, 41, 2184-2195.
Robert CB, Donald WK, Raphael EP, Ralph RW, James FH, Emil
FIII, Ted SG. Cancer Medicine. 5th ed. Canada 2000.
Sakamoto, A.; Iwamoto, I. Current status and perspectives
regarding the treatment of osteosarcoma: chemotherapy. Reviews
on recent Clinical Trials, 2008, 3, 228-231.
Lewis, V.O. What’s new in musculoskeletal oncology. J Bone Joint
Surg Am, 2007, 89, 1399-1407.
Patel, S. J.; Lynch, J. W. J.; Johnson, T.; Carroll, R. R.;
Schumacher, C. R. N.; Spanier, S.; Scarborough, M. Dose-intense
osteosarcoma in adults. American Journal of Clinical Oncology,
2002, 25, 489-495.
Ta, H.T.; Dass, C.R.; Choong P.F.M.; Dunstan D.E. Osteosarcoma
treatment: state of the art. Cancer Metastasis Rev, 2009, 28, 247-
Moitra, K.; Lou, H.; Dean, M: Multidrug efflux pumps and cancer
stem cells: Insights into multidrug resistance and therapeutic
development. Clinical Pharmacology & Therapeutics, 2011, 89
Dalerba, P.; Cho, R.W.; Clarke, M.F. Cancer stem cells: models
and concepts. Annu. Rev. Med., 2007, 58, 267-284.
Moserle, L.; Ghisi, M.; Amadori, A.; Indraccolo, S. Side
population and cancer stem cells: Therapeutic implications. Cancer
Letters 2010, 288, 1-9.
Miller, S.J.; Lavker, R.M.; Sun, T.T. Interpreting epithelial cancer
biology in the context of Stem Cells. Biochimica et Biophysica
acta, 2005, 1756, 25-52.
Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.;
Clarke, M.F. Prospective identification of tumorigenic breast
cancer cells. Proc Natl Acad Sci USA, 2003, 100, 3983-3988.
Jordan, C.T.; Guzman, M.L.; Noble, M.. Cancer stem cells. N Engl
J Med, 2006, 355, 1253-1261.
Gibbs, C.P.; Kukekov, V.G.; Reith, J.D.; Tchigrinova, O.; Suslov,
O.N.; Scott, E.W.; Ghivizzani, S.C.; Ignatova, T. N.; Steindler,
D.A. Stem-like cells in bone sarcomas: implications for
tumorigenesis, Neoplasia, 2005, 7, 967-976.
Wang, L.; Park, P.; Lin, C.Y. Characterization of stem cell
attributes in human osteosarcoma cell lines. Cancer Biology &
Therapy, 2009, 8, 543-52.
Murase, M.; Kano, M.; Tsukahara, T.; Takahashi, A.; Torigoe, T.;
Kawaguchi, S.; Kimura, S.; Wada, T.; Uchihashi, Y.; Kondo, T.;
Yamashita, T.; Sato, N. Side population cells have the
characteristics of cancer stem-like cells/cancer-initiating cells in
bone sarcomas. Br J Cancer, 2009, 101, 1425-32.
Minotti, G.; Menna, P.; Salvatorelli, E.; Cairo, G.; Gianni, L.
Anthracyclines: Molecular advances
developments in antitumor activity and cardiotoxicity. Pharmacol
Rev, 2004, 56, 185-229.
Brockmann, H. Anthracyclinones
(Rhodomycinone, Pyrromycinone and Their Glycosides). Fortschr
Chem. Org. Naturst., 1963, 21, 121-82.
based chemotherapy for
Monneret, C. Recent developments in the field of antitumour
anthracyclines. Eur. J. Med. Chem., 2001, 36, 483-493.
Robert, J. Epirubicin. Clinical pharmacology and dose-effect
relationship. Drugs, 1993, 45 (2), 20-30.
Borchmann, P.; Hubel, K.; Schnell, R.; Engert, A. Idarubicin: a
brief overview on pharmacology and clinical use. Int J Clin
Pharmacol Ther 1997, 35, 80-83.
Umezawa, H.; Takahashi, Y.; Kinoschita, M.; Naganawa, H.;
Matsuda, T.; Ishizuka, M.;
Tetrahydropyranyl derivatives of daunomycin and adriamycin. J.
Antibiot., 1979, 32, 1082-1084.
European Medicines Agency - European Public Assessment
reports - Caelyx. http://www.ema.europa.eu/ema/index.jsp?curl=
d125. (Accessed April 3, 2011).
European Medicines Agency - European Public Assessment
reports - Myocet. http://www.ema.europa.eu/ema/index.jsp?curl=
d125&jsenabled=true. Accessed April 3, 2011).
Daunorubicin Official FDA information, side effects and uses.
http://www.drugs.com/pro/daunorubicin.html (Accessed April 3, 2011).
DaunoXome Official FDA information, side effects and uses.
http://www.drugs.com/pro/daunoxome.html. (Accessed April 3, 2011).
Epirubicin Official FDA information, side effects and uses.
http://www.drugs.com/pro/epirubicin.html (Accessed April 3, 2011).
Idarubicin Official FDA information, side effects and uses.
http://www.drugs.com/pro/idarubicin.html. (Accessed April 3, 2011).
Detalhes do medicamento.
lar=&pagina=1. (Accessed April 3, 2011).
Detalhes do medicamento.
r=&pagina=1. (Accessed April 3, 2011).
Mitoxantrone Official FDA information, side effects and uses.
http://www.drugs.com/pro/mitoxantrone.html. (Accessed April 3, 2011).
Detalhes do medicamento.
titular=&pagina=1. (Accessed April 3, 2011).
Gewirtz, D. A. A critical evaluation of the mechanisms of action
proposed for the antitumor effects of the anthracycline antibiotics
adriamycin and daunorubicin. Biochem Pharmacol, 1999, 57, 727-
Perego, P.; Corna, E.; De Cesare, M.; Gatti, L.; Polizzi, D.; Pratesi,
G.; Supino, R.; Zunino, F. Role of apoptosis and apoptosis-related
genes in cellular response and antitumor efficacy of anthracyclines.
Curr Med Chem, 2001, 8,31-37.
Lage, M.; Helbach, H.; Dietel, M.; Schadendorf, D. Modulation of
DNA topoisomerase II activity and expression in melanoma cells
with acquired drug resistance. Br J Cancer, 2000, 82, 488-491.
Ruiz-Ruiz, C.; Robledo, G.; Cano, E.; Redondo, J.M.; Lopez-
Rivas, A. Characterization of p53-mediated up-regulation of CD95
gene expression upon genotoxic treatment in human breast tumor
cells. J Biol Chem, 2003, 278:31667-31675.
Inoue, A.; Narumi, K.; Matsubara, S.; Sugawara, S.; Saijo, Y.;
Satoh, K.; Nukiwa, T. Administration of wild-type p53 adenoviral
vector synergistically enhances the cytotoxicity of anti-cancer
drugs in human lung cancer cells irrespective of the status of p53
gene. Cancer Lett, 2000, 157, 105-112.
Dunkern, T.R.; Wedemeyer, I.; Baumgärtner, M.; Fritz, G.; Kaina,
B. Resistance of p53 knockout cells to doxorubicin is related to
reduced formation of DNA strand breaks rather than impaired
apoptotic signalling. DNA Repair (Amst), 2003, 2, 49-60.
Sawyer, D.B.; Peng, X.; Chen, B.; Pentassuglia, L.; Lim, C.C.
Mechanisms of anthracycline cardiac injury: can we identify
strategies for cardioprotection? Progress in Cardiovascular
Diseases, 2010, 53, 105-113.
Geisberg, C.A.; Sawyer, D.B. Mechanisms of anthracycline
cardiotoxicity and strategies to decrease cardiac damage. Curr
Hypertens Rep., 2010, 12, 404-410.
Tatsuta, K.; Takeuchi, T.
Doxorubicin vs. ladirubicin Download full-text
Mini-Reviews in Medicinal Chemistry, 2012, Vol. 12, No. 12 1249
Davies, C. L.; Lundstrom, L. M.; Fregen, J.; Eikenes, L.; Bruland,
Ø. S.; Kaalhus, O.; Hjelstuen, M. H. B.; Brekken, C. Radiation
improves the distribution and uptake of liposomal doxorubicin
(Caelyx) in human osteosarcoma xenografts. Cancer Research,
2004, 64, 547-553.
Tan, M.L.; Friedhuber, A.M.; Dunstan, D.E.; Choong P.F.M.;
Dass, C.R. The performance of doxorubicin encapsulated in
chitosan-dextran sulphate microparticles in an osteosarcoma model.
Biomaterials 31 (2010) 541-551.
Betancourt, T.; Brown, B.; Brannon-Peppas, L. Doxorubicin-
loaded PLGA nanoparticles by nanoprecipitation: preparation,
characterization and in vitro evaluation. Nanomed, 2007, 2(2), 219.
Janes, K. A.; Fresneau, M. P.; Marazuela, A.; Fabra, A.; Alonso,
M. J. Chitosan nanoparticles as delivery systems for doxorubicin. J
Control Release, 2001, 73:255.
Bisht, S.; Maitra, A. Dextran-doxorubicin/chitosan nanoparticles
for solid tumor therapy. WIREs Nanomed Nanobiotechnol, 2009, 1,
Wang, F.; Wang, Y.; Dou, S.; Xiong, M.; Sun, T.; Wang, J.;
Doxorubicin-Tethered responsive gold nanoparticles facilitate
intracellular drug delivery for overcoming multidrug resistance in
Capranico, G., Supino, R., Binaschi, M., Capolongo, L., Grandi,
M., Suarato, A., and Zunino, F. Influence of structural
modifications at the 39 and 49 positions of doxorubicin on the drug
ability to trap topoisomerase II and to overcome multidrug
resistance. Mol. Pharmacol., 1994, 45, 908-915.
Priebe, W., and Perez-Soler, R. Design and tumor targeting of
anthracyclines able to overcome multidrug resistance: a double-
advantage approach. Pharmacol. Ther., 1993, 60, 215-234.
Marchini, S.; Damia, G.; Broggini, M.; Pennella, G.; Ripamonti,
M.; Marsiglio, A.; Geroni, C. 4-Demethoxy-3’-deamino-3’-
novel anticancer agent active against tumor cell lines with different
resistance mechanisms. Cancer Research, 2001, 61, 1991-1995.
Geroni, C.; Ripamonti, M.; Arrigoni, C.; Fiorentini, F.; Capolongo,
L.; Moneta, D.; Marchini, S.; Torre, P. D.; Albanese, C.; Lamparelli,
M. G.; Ciomei, M.; Rossi, R.; Caruso, M. Pharmacological and
toxicological aspects of 4-Demethoxy-3’-deamino-3’-aziridinyl-4’-
methylsulphonyl-daunorubicin (PNU-159548): a novel antineoplastic
agent. Cancer Research, 2001, 61, 1983-1990.
De Jonge, M. J.; Verweij, J.; Van Der Gaast, A.; Valota, O.; Mora,
O.; Planting, A.S.Th.; Mantel, M.A.; Van Den Bosch, S.; Lechuga,
M.J.; Fiorentini, F.; Hess, D.; Sessa, C. Phase I and
pharmacokinetic studies of PNU-159548, a novel alkycycline,
administered intravenously to patients with advanced solid
tumours. European Journal of Cancer, 2002, 38, 2407-2415.
Moneta, D.; Geroni, C.; Valota, O.; Grossi, P.; De Jonge, M.J.A.;
Brughera, M.; Colajori, E.; Ghielmini, M.; Sessa, C. Predicting the
maximum-tolerated dose of PNU-159548 (4-demethoxy-30-
humans using CFU-GM clonogenic assays and prospective
validation. European Journal of Cancer, 2003, 39, 675-683.
Della Torre, P.; Podesta, A.; Imondi, A.R.; Moneta, D.;
Sammartini, U.; Arrigoni, C.; Terron, A.; Brughera, M. PNU-
2011, available in
159548, a novel cytotoxic antitumor agent with a low cardiotoxic
potential. Cancer Chemother Pharmacol, 2001, 47, 355-360.
van Vlerken, L. E.; Vyas T. K.; Amiji M. M. Poly (ethylene glycol)
-modified Nanocarriers for Tumor - targeted and Intracellular
Delivery. Pharmaceutical research 2007, 24(8), 1405-13.
Lorusso, D.; Di Stefano, A.; Carone, V.; Fagotti, A.; Pisconti, S.;
Scambia, G. Pegylated liposomal doxorubicin-related palmar-
plantar erythrodysesthesia (‘hand-foot’syndrome). Ann Oncol,
Ortho-Biotech. DOXIL (R) - Doxorubicin HCL liposome injection
ortho-biotech, U.S. http://www.orthobiotech.com/orthobiotech/
doxil.html. (Accessed April 20, 2011).
Salerno, M.; Cenni, E.; Fotia, C.; Avnet, S.; Granchi, D.; Castelli,
F.; Micieli, D.; Pignatello, R.; Capulli, M.; Rucci, N.; Angelucci,
A.; Del Fattore, A.; Teti, A.; Zini, N.; Giunti, A.; Baldini, N. Bone-
Targeted Doxorubicin-Loaded Nanoparticles as a Tool for the
Treatment of Skeletal Metastases. Current Cancer Drug Targets,
2010, 10 (7), 649-659.
Widder, K. J.; Senyei, A. E.; Scarpelli, D. G. Magnetic
microspheres: a model system for site specific drug delivery in
vivo. Proc Soc Exp Biol Med, 1978, 58, 141-146.
Akiyoshi, K.; Taniguchi, I.; Fukui, H.; Sunamoto, J. Hydrogel
nanoparticle formed by self-assembly
polysaccharide. Stabilization of adriamycin by complexation. Eur.
J. Pharm. Biopharm., 1996, 42, 286-290.
Couvreur, P.; Kante, B.; Grislain, L.; Roland, M.; Speiser, P.
Toxicity of polyalkylcyanoacrylate nanoparticles. II. Doxorubicin
loaded nanoparticles. J. Pharm. Sci. 1982, 71, 790-793.
Cuvier, C.; Roblot-Treupel, L.; Millot, J. M.; Lizard, G.;
Chevillard, S.; Manfait, M.; Couvreur, P.; Poupon, M. F.
Doxorubicin-loaded nanospheres bypass tumor cell multidrug
resistance. Biochem. Pharmacol., 1992, 44, 509-517.
Janes, K. A.; Fresneau, M. P.; Marazuela, A.; Fabra, A.; Alonso,
M. J. Chitosan nanoparticles as delivery systems for doxorubicin.
Journal of Controlled Release, 2001, 73, 255-267.
Berry, C. Progress in functionalization of mNPs for applications in
biomedicine. Journal of physics D: Applied physics, 2009, 42,
Wada, S., Yue, L., Tazawa, K., Furuta, I., Nagae, H., Takemori, S.,
and Minamimura, T. New local hyperthermia using dextran
magnetite complex (DM) for oral cavity: experimental study in
normal hamster tongue. Oral Dis., 2001, 7, 192-195.
Huh, Y. M. In vivo magnetic resonance detection of cancer by
using multifunctional magnetic nanocrystals. J. Am. Chem. Soc.,
2006, 127, 12387-91.
Wagner, S.; Rothweiler, F.; Anhorn, M.G.; Sauer, D.; Riemann, I.;
Weiss, E.C.; Katsen-Globa, A.; Michaelis, M.; Cinatl Jr., J.;
Schwartz, D.; Kreuter, J.; von Briesen, H.; Langer, K. Enhanced
drug targeting by attachment of an anti ?v integrin antibody to
doxorubicin loaded human serum
Biomaterials, 2010, 31 (8), 2388-2398.
M. L. Broadhead, T. Akiyama, P. F. M. Choong, and C.R. Dass,
The pathophysiological role of PEDF in bone diseases. Current
Molecular Medicine, 2010, 10(3), 296-301.
Received: May 20, 2011
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Revised: January 30, 2012 Accepted: February 04, 2012