Current Medicinal Chemistry - Anti-Cancer Agents, Vol. 3, No. 3, 2003
Contents
Drugs Acting on the Beta
Isoform of Human Topoisomerase II (p180) Pp. 173-185
B. Gatto and E. Leo
[Abstract]
The Interaction of
Histone Deacetylase Inhibitors and DNA Methyltransferase Inhibitors in the
Treatment of Human Cancer Cells Pp. 187-199
Wei-Guo Zhu and Gregory A. Otterson
[Abstract]
Signal Transduction
Inhibitors in the Treatment of Breast Cancer Pp. 201-216
Rita Nahta , Gabriel
N. Hortobagyi and Francisco J. Esteva
[Abstract]
The BCL2-Family of
Protein Ligands as Cancer Drugs: The Next Generation of Therapeutics Pp.
217-223
WenJing Liu , Anca
Bulgaru ,
[Abstract]
Pharmacogenetics of
Irinotecan Pp. 225-237
G. Toffoli , E.
Cecchin, G. Corona and M. Boiocchi
[Abstract]
Peroxisome Proliferator
Activated Receptor-Gamma Ligands as Potent Antineoplastic Agents Pp.
239-251
S. Theocharis , A. Margeli and G. Kouraklis
[Abstract]
Abstracts
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Drugs Acting on the
Beta Isoform of Human Topoisomerase II (p180)
B. Gatto and E. Leo
Topoisomerase II is the target of several anticancer agents. The discovery of a second enzyme, called topoisomerase II b, genetically distinct from a, prompted the investigation on the different functional roles of the two isoforms. Whereas the first recognized isozyme is essential for life due to its role in chromosome condensation and segregation, beta functions remained elusive, although its importance in neural development is appearing clearer.
Topoisomerase II b is regulated differently than a, and its level of expression does not change significantly during cell cycle. The presence of this isoform in non-proliferating cells suggests that drug preferentially aimed at b may be active in slow growing tumors. Topoisomerase II poisons were hence evaluated in light of their selectivity toward one or the other isozyme, indicating how the beta isoform may represent an important target for selected classes of drugs. Newer compounds were also synthesized and tested for their potential antitumor activity and their topoisomerase II beta poisoning. The literature dealing with “old” and “new” drugs targeted at topoisomerase II is reviewed trying to link, whenever possible, selective poisoning and cytotoxic effects to chemical structures, in the hope to indicate new lead compounds that will contribute to unveil molecular determinants of selectivity.
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The Interaction of
Histone Deacetylase Inhibitors and DNA Methyltransferase Inhibitors in the
Treatment of Human Cancer Cells
Wei-Guo Zhu and Gregory A. Otterson
The potential anticancer activities of histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors have been extensively studied in recent years. HDAC inhibitors suppress the activities of multiple HDACs, leading to an increase in histone acetylation. This histone acetylation induces an enhancement of the expression of specific genes that elicit extensive cellular morphologic and metabolic changes, such as growth arrest, differentiation and apoptosis. DNMT inhibitors, such as 5-aza-cytidine (5-aza-CR) and 5-aza-2’- deoxycytidine (5-aza-CdR) are also widely studied because DNA hypomethylation induces the re-activation of tumor suppressor genes that are silenced by methylation-mediated mechanisms. Recently, the combination of HDAC inhibitors or demethylating agents with other chemo-therapeutics has gained increasing interest as a possible molecularly targeted therapeutic strategy. In particular, the combination of HDAC inhibitors with demethylating agents has become attractive since histones are connected to DNA by both physical and functional interactions. To date, the accumulating evidence has confirmed the hypothesis that the combination of HDAC and DNMT inhibition is very effective (and synergistic) in inducing apoptosis, differentiation and/or cell growth arrest in human lung, breast, thoracic, leukemia and colon cancer cell lines. This review will discuss the in vitro effects of HDAC inhibitors, such as trichostatin A (TSA), sodium butyrate, depsipeptide (FR901228, FK228), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), and the demethylating agent, 5-aza-CdR used alone and in combination treatment of human cancer cells and the possible mechanisms involved.
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Signal Transduction
Inhibitors in the Treatment of Breast Cancer
Rita Nahta , Gabriel
N. Hortobagyi and Francisco J. Esteva
Signal transduction pathways are frequently altered in human breast cancer and are the targets of several novel therapies currently in clinical trials. Therapeutic strategies include extracellular blockade of tyrosine kinase receptors with the monoclonal antibodies C225 and trastuzumab. Competitive inhibitors of adenosine triphosphate binding sites on tyrosine and serine/threonine kinases are also being evaluated in phase I/II trials; these include ZD1839, OSI-774 and CI- 1033. Flavopiridol and UCN-01 are nonspecific cell cycle kinase antagonists with preliminary evidence of breast cancer cell growth inhibition. Several inhibitors of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling are also in various stages of preclinical or clinical development. Additionally, inhibitors of farnesyl transferase have demonstrated activity in breast cancer cells irrespective of ras status. Current evidence suggests that targeting of signaling molecules is a promising new approach to treatment of breast cancer.
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The BCL2-Family of
Protein Ligands as Cancer Drugs: The Next Generation of Therapeutics
WenJing Liu , Anca
Bulgaru ,
Selective aberrant cell suicide (ie., apoptosis or programmed cell death) is a hallmark of “nonneoplastic” tissue. In cells that have clonally evolved or in common parlance “cancer cells’, apoptosis is either itself aberrant or completely inhibited. Strategies to enhance apoptosis under conditions of cancer cellular stress is an evolving and actively investigated area of experimental therapeutics. Bcl2 proteins are key mediators of the process of apoptosis and ligands to these family of proteins have been described using modern combinatorial, computational and evolutionary small molecule screening approaches. Crystallization of several of the Bcl2 family members has provided clarification of the role of these ligands and provided a clearer mechanism of action for the consequences of ligand binding. In several cases, these ligands (e.g., HA14-1, 2-methoxy antimycin A) induce apoptosis even under conditions of Bcl2 overexpression and if developed
preclinically will be promising anticancer agents. This rationale becomes even more striking when one observes overexpression of Bcl2 in 70% of breast cancer, 30-60% of prostate cancer, 80% of B-cell lymphomas, 90% of colorectal adenocarcinomas, and many other forms of cancer.
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Pharmacogenetics of
Irinotecan
G. Toffoli , E.
Cecchin, G. Corona and M. Boiocchi
Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan {7-ethyl-10-[4-(1- piperidino)-1-piperidino]carbonyloxycamptothecin} is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leukothrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multiresistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
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Peroxisome Proliferator
Activated Receptor-Gamma Ligands as Potent Antineoplastic Agents
S.
Theocharis , A. Margeli and G.
Kouraklis
The Peroxisome Proliferator Activated Receptors (PPARs) are initially described as molecular targets for compounds inducing peroxisome proliferation. Among the three PPAR subtypes (alpha, beta, gamma), PPAR-gamma acting as a ligand-activated transcription factor, proved to be an important regulator of adipogenic differentiation and glucose homeostasis. Recent data support evidence for participation of PPAR-gamma, upon ligands activation, in the biological mechanisms underlying the carcinogenic evolution. Specific PPAR-gamma ligands affect cancer cells proliferation and differentiation acting as cell cycle modulators, suggesting their use as an important tool for future therapeutic approach in cancer. In this review, the latest knowledge on PPAR-gamma activation and molecular mechanisms of PPAR-gamma ligands mediated anti-tumoral activity are presented. In vitro and in vivo studies concerning the use of PPAR-gamma ligands in different cancer types are also included.