Current Medicinal Chemistry - Anti-Cancer Agents, Vol. 4, No. 4, 2004
Contents
Chromosomal
Aberrations and Genomic Instability Induced by Topoisomerase-Targeted
Antitumour Drugs Pp 317-325
[Abstract]
Topoisomerase I-DNA
Complex Stability Induced by Camptothecins and Its Role in Drug Activity# Pp
327-334
Randy M. Wadkins,
David Bearss, Govindarajan Manikumar, Mansukhlal C. Wani, Monroe E. Wall, and
Danie D. Von Hoff
[Abstract]
Development of DNA
Topoisomerase-Related Therapeutics: A Short Perspective of New Challenges Pp
335-345
Giovanni Capranico,
Giuseppe Zagotto and Manlio Palumbo
[Abstract]
Recent Advances in
Experimental Molecular Therapeutics for Malignant Gliomas Pp 347-361
Gautam Prasad, Hui
Wang, Donald L. Hill and Ruiwen Zhang
[Abstract]
Lamellarins, from A to
Z: A Family of Anticancer Marine Pyrrole Alkaloids Pp 363-378
Christian Bailly
[Abstract]
Effect of Prostaglandins
on the Regulation of Tumor Growth Pp 379-387
Shunji Ishihara,
M.A.K. Rumi, Toshihiko Okuyama and Yoshikazu Kinoshita
[Abstract]
Abstracts
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Chromosomal Aberrations
and Genomic Instability Induced by Topoisomerase-Targeted Antitumour Drugs
Francesca Degrassi,
Mario Fiore and Fabrizio Palitti
The present review discusses recent evidence on the mechanisms of formation of structural and numerical chromosome aberrations by anti-topoisomerase drugs. Among “cleavable complex”poisoning drugs, DNA topoisomerase II inhibitors induce DNA double strand breaks that lead to chromosomal aberrations independently of the phase of the cell cycle in which the treatment has been performed. Inhibitors of DNA topoisomerase I induce DNA single strand breaks that are transformed in DSB when the trapped “cleavable complex” collides with the replication fork, producing chromatid-type aberrations. Recently, ongoing chromosome condensation and RNA transcription have been shown to play a crucial role in the formation of chromatid-type aberrations by topoisomerase I poisons for treatments in the G2 phase of the cell cycle.
Mutations of single genes are also induced by anti-topoisomerase drugs. These consist mostly of deletions, duplications and insertions and are often localized at the topoisomerase cleavable sites. This suggests that alterations at the chromatin level may be responsible for inactivation of gene function after topoisomerase inhibitors.
Anti-topoisomerase drugs promote also numerical chromosome aberrations as DNA topoisomerases are involved in chromosome condensation and segregation at mitosis. Polyploid cells are induced as a consequence of the total inhibition of sister chromatid separation before anaphase and aneuploid cells may arise when sister chromatid separation is defective. Gene mutations, chromosomal aberrations and aneuploidy may influence the stability of the genome further producing structural aand numerical aberrations at successive cell cycle divisions. Knowledge of the mechanisms producing gene mutations, chromosome aberrations and genomic instability after drugs interacting with topoisomerases is essential for developing effective therapeutical approaches.
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Topoisomerase I-DNA
Complex Stability Induced by Camptothecins and Its Role in Drug Activity#
Randy M. Wadkins,
David Bearss, Govindarajan Manikumar, Mansukhlal C. Wani, Monroe E. Wall, and
Danie D. Von Hoff
The mechanism of cytotoxicity of the camptothecin family of antitumor drugs is thought to be the consequence of a collision between moving replication forks and camptothecin-stabilized cleavable DNA-topoisomerase I complexes. One property of camptothecin analogs relevant to their potent antitumor activity is the slow reversal of the cleavable complexes formed with these drugs. The persistence of cleavable complexes with time may be an essential property for increasing the likelihood of a collision between the replication fork and a cleavable complex, giving rise to lethal DNA lesions. In this paper, we examined a number of camptothecin analogs forming cleavable complexes with distinctly different stabilities. Absolute reaction rate analysis was carried out for each derivative. Our results indicate that the stability of the cleavable complex is dominated by the activation entropy (DS‡) of the reversal process. We measured the relative lipophilicity of the CPT analogs by reverse-phase HPLC, but the DS‡ of complex reversal is not directly related to the lipophilicity of the CPT analog being used. We suggest that solvent ordering around the 7- through 10-position of the CPT ring may be responsible for reversal rate's dependence on DS‡. We demonstrate that the cleavable complex stability conferred by each camptothecin analog is directly correlated with the induction of apoptosis and cytotoxicity to tumor cells.
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Development of DNA
Topoisomerase-Related Therapeutics: A Short Perspective of New Challenges
Giovanni Capranico,
Giuseppe Zagotto and Manlio Palumbo
Antitumor agents targeting DNA and DNA-associated processes are widely used in the treatment of human cancers and produce significant increases in the survival of patients. DNA topoisomerases remain the most significant target of these cytotoxic drugs and constitute a growing family of nuclear enzymes that regulate DNA topology during DNA replication and recombination, DNA transcription, chromosome condensation-decondensation and segregation. Major progress has been attained in recent years in the understanding of the structures of these enzymes and their main cellular functions, hopefully providing new opportunities for pharmacological interventions. New leads and derivatives of known structures have been reported recently, and here they will be discussed highlighting the challenges to find innovative and more effective drugs. Moreover, we will review novel and diverse approaches relevant to the development of new topoisomerase-related therapeutics.
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Recent Advances in
Experimental Molecular Therapeutics for Malignant Gliomas
Gautam Prasad, Hui
Wang, Donald L. Hill and Ruiwen Zhang
The current lack of effective therapy for malignant gliomas has prompted the development of three primary foci of molecular research: anti-angiogenesis therapy, immunotherapy, and DNA- and RNA-based therapies. Angiogenesis inhibitors, designed to exploit the highly vascularized nature of gliomas, target endothelial cells and/or the extracellular matrix and bypass many of the problems of conventional chemotherapy. There may be easy access to the molecular target (e.g. blood vessels), reduced induction of drug resistance, and general lack of host toxicity. The relatively immunoprivileged status of the brain has also prompted use of immune stimulation as an anti-glioma strategy. Lines of attack include global cytokine therapy, vaccination with specific tumor antigens, dosing with monoclonal antibodies conjugated to radioisotopes or toxins, and ex vivo priming of lymphocytes. With regard to DNA- and RNA-based therapy, numerous oncogenic proteins have been targeted by antisense molecules administered alone or in combination with conventional chemotherapy and radiation. In one tactic, termed “suicide” gene therapy, herpes simplex thymidine kinase has been transfected into glioma cells via a retrovirus; subsequent introduction of ganciclovir causes cytotoxicity in the transduced cells. Although considerable preclinical data have been accumulated, promising results for therapy of human glioma have only recently appeared.
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Lamellarins, from A
to Z: A Family of Anticancer Marine Pyrrole Alkaloids
Christian
Bailly
The lamellarins form a group of more than 30 polyaromatic pyrrole alkaloids, isolated from diverse marine organisms, mainly but not exclusively ascidians and sponges. These molecules fall in three structural groups, with the central pyrrole ring fused or unfused (lamellarins O-R) to adjacent aromatic rings and with the quinoline moiety containing a 5, 6-single – as in lamellarins I-L - or a double bond, as it is the case for lamellarins D and M which are both potent cytotoxic agents. The family also includes sulphated members, such as the integrase inhibitor lamellarin a 20- sulfate. This review presents the origin and structure of the lamellarins and summarizes the various chemical pathways which have been proposed to synthesize all lamellarins and different structurally related marine pyrrole alkaloids, including ningalins, storniamides and lukianols. The mechanisms of actions of these marine products are also discussed. Inhibition of HIV-1 integrase by lamellarin a 20-sulfate and human topoisomerase I by lamellarin D and Molluscum contagiosum virus topoisomerase by lamellarin H, along with other effects on nuclear proteins, provide an experimental basis indicating that DNA manipulating enzymes are important targets for the lamellarins. Some of these marine compounds exhibit cytotoxic activities against tumor cells in vitro and are insensitive to Pgp-mediated drug efflux. The structure-activity relationships are discussed. Other compounds in the series, without being strongly cytotoxic, can reverse
the multidrug resistance phenotype and thus may be useful to promote the therapeutic activity of conventional cytotoxic drugs toward chemoresistant tumors. A complete description of the chemistry and pharmacological profiles of the lamellarins is presented here to shed light on this undervalued family of marine alkaloids.
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Effect of Prostaglandins
on the Regulation of Tumor Growth
Shunji Ishihara, M.A.K. Rumi, Toshihiko Okuyama and Yoshikazu Kinoshita
Prostaglandins (PGs) are involved in mediating or regulating many physiological as well as pathological processes. Important roles of PGs in the pathophysiology of carcinogenesis offer potentials of targeting PG synthesis and PG receptors in developing novel anti-cancer therapy. Although initial studies suggested direct growth inhibitory role of PGs from in vitro studies, it has been widely demonstrated that in general, PGs stimulate tumor growth. However, cyclopentenone PGs, especially 15d-PGJ2, which can activate peroxisome proliferator activated receptor (PPAR) g, exhibited anti-proliferative and proapoptotic effects on many types of cancer cells. But recent studies indicate that growth inhibitory effects of the cyclopentenone PGs might also be a nonspecific effect due to its highly reactive cyclopentenone ring. We have explored the published studies on PGs to specify its known regulatory roles on tumor growth with an objective of targeting the PGs or pathways activated by these lipids in treating cancers.