Current Cancer Drug Targets, Volume 5, No. 6, 2005
Contents
Tumor Necrosis Factor: How to Make a Killer
Molecule Tumor-Specific? Pp.381-392
Rudolf
Lucas, Matthias Kresse, Markus Latta and Albrecht Wendel
New Indications for Established Drugs:
Combined Tumor-Stroma-Targeted Cancer Therapy with PPARγ Agonists, COX-2
Inhibitors, mTOR Antagonists and Metronomic Chemotherapy Pp.393-419
Christian
Hafner, Albrecht Reichle and Thomas Vogt
Purine Nucleoside Analogues for the Treatment
of Hematological Malignancies: Pharmacology and Clinical Applications Pp.421-444
T.
Robak, A. Korycka, M. Kasznicki, A. Wrzesien-Kus and P. Smolewski
Strategies for Targeting the Multidrug
Resistance-1 (MDR1)/P-gp Transporter in Human Malignancies Pp.445-455
Daruka
Mahadevan and Nikhil Shirahatti
P-Glycoprotein – Implications of Metabolism
of Neoplastic Cells and Cancer Therapy Pp.457-468
Albert
Breier, Miroslav Barancik, Zdenka Sulova and Branislav Uhrik
Abstracts
[Back to top] Tumor Necrosis Factor: How to Make a Killer
Molecule Tumor-Specific?
Rudolf
Lucas, Matthias Kresse, Markus Latta and Albrecht Wendel
The interest in TNF,
discovered at the interface between inflammation and cancer, as an anti-cancer
agent, has phased out in recent years. Indeed, despite its profound cytostatic
and cytotoxic effects in primary tumors, the cytokine’s systemic toxicity in
general and its hepatotoxic and pro-metastatic nature in particular, prevent
its routine use in cancer patients. An elegant approach to circumvent these
problems consists in the local application of TNF in an isolated limb or organ
setting, preferentially in the presence of cytostatic and alkylating agents,
such as melphalan. However, this treatment, when locally applied during the
perfusion of liver tumors, results in hepatotoxicity in a significant number of
the patients, by means of a still unknown mechanism. The hemorrhagic necrosis
of the tumors induced by TNF seems to be predominantly mediated by an induction
of apoptosis as well as by an anti-angiogenic effect in the endothelial cells
of the microvasculature supplying the tumor. These cells therefore represent a
prime target for the action of anticancer drugs. In this review, we discuss
preclinical studies which elucidated the mechanism of melphalan- and
TNF-associated hepatotoxicity and, as a consequence, provided insights for
preventing the adverse reactions of the drug. Moreover, we review recent
findings aimed at improving the TNF molecule by means of specific mutations, or
searching for alternative factors lacking the systemic toxicity of TNF.
[Back to top] New Indications for Established Drugs:
Combined Tumor-Stroma-Targeted Cancer Therapy with PPARγ Agonists, COX-2
Inhibitors, mTOR Antagonists and Metronomic Chemotherapy
Christian
Hafner, Albrecht Reichle and Thomas Vogt
In search of new
strategies for the treatment of cancer, the interaction between tumor and
stroma attracts more and more attention. Disruption of stroma functions, e.g.
angiogenesis, has evolved into a promising target for cancer therapies. Since
stromal cells are genetically stable, stroma-targeted therapies seem to be less
susceptible to the development of drug resistance. Several well-established
drugs, which had initially been developed for other indications, also exhibit
antitumor activity. Among those, PPARγ agonists, COX-2 inhibitors, and
mTOR antagonists are the most remarkable examples. Current research data and
clinical experience suggest that these drugs target stroma functions in cancer,
in particular angiogenesis, but immunological mechanisms and direct antitumor
effects seem to participate as well. In addition to these drugs, frequent
administration of low-dose chemotherapeutics, referred to as metronomic
chemotherapy, reveals profound anti-angiogenic effects. In the meantime, a
multitude of preclinical and clinical studies have been undertaken, which
demonstrate the efficacy of these drugs in cancer therapy. Combinatorial use of
these agents has been suggested to be superior in terms of antitumor efficacy
and prevention of drug resistance. The toxicity of these therapies is
surprisingly low compared with conventional high-dose chemotherapy regimens.
Patients with advanced disease, often heavily pretreated and presenting
multiple drug resistance, could particularly profit from such
tumor-stroma-targeted therapies. However, larger randomized clinical trials are
required for further evaluation and optimization of this concept.
[Back to top] Purine Nucleoside Analogues for the Treatment
of Hematological Malignancies: Pharmacology and Clinical Applications
T.
Robak, A. Korycka, M. Kasznicki, A. Wrzesien-Kus and P. Smolewski
The purine
nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine,
2-CdA) and pentostatin (2’-deoxycoformycin, DCF) represent a group of cytotoxic
agents with high activity in lymphoid and myeloid malignancies. PNAs share
similar chemical structure and mechanism of action. Several mechanisms could be
responsible for their cytotoxicity both in proliferating and quiescent cells,
such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation
of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway,
direct binding to apoptosome or modulation of p53 expression all lead to
apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit
significant differences, especially in their interaction with enzymes involved
in adenosine and deoxyadenosine metabolism. Synergistic interactions between
PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor
antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both
preclinical and clinical studies. PNAs are highly effective in chronic lymphoid
leukemias and low grade B- and T-cell non-Hodgkin’s lymphomas, including
Waldenström’s macroglobulinemia. DCF and 2-CdA are currently the drugs of
choice in hairy cell leukemia. Moreover, clinical studies have confirmed the
efficacy of PNAs alone or in combination protocols in the treatment of acute
myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA,
play an important role in non-myeloablative conditioning regimens for allogenic
stem cell transplantation in high-risk patients. The toxicity profiles of PNAs
are similar for all agents and consist mainly of dose-limiting myelotoxicity
and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine
and immucillin-H are currently being evaluated clinically.
[Back to top] Strategies for Targeting the Multidrug
Resistance-1 (MDR1)/P-gp Transporter in Human Malignancies
Daruka
Mahadevan and Nikhil Shirahatti
ATP-binding
cassette (ABC) transporters are a super family of channel proteins that include
multidrug resistance 1 (MDR1/P-gp) and multi-drug resistance related proteins
(MRPs) whose functions include the efflux of ions, nutrients, lipids, amino
acids, peptides, proteins and drugs. The three-dimensional structures of
bacterial and human ABC transporters demonstrate that these proteins are
ATP-dependent molecular machines that scan the inner membrane leaflet for
lipids/drugs and flip them to the outer membrane leaflet. In many human
cancers, the level of expression of MDR1 is an important independent prognostic
factor that determines response to combination chemotherapy. Intrinsic and
acquired resistance to chemotherapy exposure are due to a high level of MDR1
expression that enhances drug efflux, with associated poor clinical outcome and
lower complete remission (CR) rates. Recent clinical trials in hematological
and solid malignancies have shown promise for a prolonged remission and
improved overall survival when the MDR1 P-gp is inhibited when combined with
chemotherapy. Structure-based homology modeling of these ABC transporters may
help design novel drug candidates to both the membrane-spanning domain (MSD)
and the nucleotide-binding domain (NBD) located within the cytoplasm. This
review will highlight advances in the utilization of homology modeling in the
drug discovery process and how this will impact on fundamental insights to the
development of novel therapeutics that could alter and/or inhibit their
functions.
[Back to top] P-Glycoprotein – Implications of Metabolism
of Neoplastic Cells and Cancer Therapy
Albert
Breier, Miroslav Barancik, Zdenka Sulova and Branislav Uhrik
Multidrug
resistance (MDR) of neoplastic tissues is a major obstacle in cancer
chemotherapy. The predominant cause of MDR is the overexpression and drug
transport activity of P-glycoprotein (P-gp, a product of the MDR gene).
P-gp is a member of the ATP binding cassette (ABC) transporters family, with
broad substrate specificity for several substances including anticancer drugs,
linear and cyclic peptides, inhibitors of HIV protease, and several other
substances.
The development of
P-gp-mediated MDR is often associated with several changes in cell structure
and metabolism of resistant cells. In the present review are discussed the
relations between glucosylceramide synthase activity, Pregnane X receptor and
development of P-gp mediated MDR phenotype. Attention is also focused on the
changes in protein kinase systems (mitogen-activated protein kinases, protein
kinase C, Akt kinase) that are associated with the development of MDR phenotype
and to the possible role of these kinase cascades in modulation of P-gp
expression and function. The overexpression of P-gp may be associated with
changes in metabolism of sugars as well as energy production. Structural and
ultrastructural characteristics of multidrug resistant cells expressing P-gp
are typical for cells engaged in a metabolically demanding process of protein
synthesis and transport. P-gp mediated MDR phenotype is often also associated
with alterations in cytoskeletal elements, microtubule and mitochondria
distribution, Golgi aparatus, chromatin texture, vacuoles and caveolae
formation.
The current review
also aims at bringing some state-of–the-art information on interactions of
P-glycoprotein with various substances. To capture and transport the numerous
unrelated substances, P-gp should contain site(s) able to bind compounds with a
molecular weight of several hundreds and comprising hydrophobic and/or base
regions that are protonated under physiological conditions. Drug binding sites
that are able to recognize substances with different chemical structures may
have a complex architecture in which different parts are responsible for
binding of different drugs. For P-gp substrates and inhibitors, a
pharmacophore-based model has been described. The pharmacophores have to
contain parts with hydrophobic and aromatic characteristics and functional
groups that can act as hydrogen-bond donors and/or acceptors. Several drugs are
known to be P-glycoprotein antagonizing agents. They represent a large group of
structurally unrelated substances that can act via direct interaction
with P-gp and inhibition of its transport activity, or via possible
modulation of processes (such as phosphorylation) regulating P-gp transport
activity. Effects of MDR reversal agents on the P-gp expression have also been
reported. Function and expression of P-gp can be affected indirectly as well,
e.g. through cyclooxygenase-2 or carbonic anhydrase-IX expression and effects.