Pharmacology of Topoisomerase I Inhibitors Irinotecan (CPT-11) and Topotecan

Authors: Mathijssen R.H.J.; Loos W.J.; Verweij J.; Sparreboom A.

Source: Current Cancer Drug Targets, Volume 2, Number 2, June 2002 , pp. 103-123(21)

Publisher: Bentham Science Publishers

Abstract:

Topotecan and irinotecan (CPT-11) are both anticancer agents active in the inhibition of topoisomerase I, an enzyme involved in DNA replication and RNA transcription. During the last decades, an immense amount of research into this class of anticancer agents has been conducted, the positive results of which led to the clinical use of topotecan and CPT-11 in ovarian cancer and colorectal cancer, respectively.

Here, we review the currently most important pharmacologic aspects of these drugs, including their mechanisms of action, metabolism, activity- and toxicity-profiles and mechanisms of resistance, to provide a global insight into their pharmacology. We also discuss the effects of combinations with other anticancer agents, which have been tested for synergistic antitumor effects. Pharmacokinetic and pharmacodynamic biomodulation, to enhance the bioavailability of the active anticancer agent or to reduce drug related toxicities have currently reached clinical application. As pharmacogenetics enters the clinical stage, this will lead to more “fine-tuning” in anticancer treatment (for instance by individualized dosing). The clarification of the mechanisms of action and resistance of topotecan and CPT-11 should enable us to understand their pharmacological behavior even better and might lead to the development of more potent camptothecinderivatives in the future.

Keywords: irinotecan; cpt-11; topotecan; topoisomerase I inhibitor; ovarian cancer; edorectal cancer; camptothecin

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568009023333890

Publication date: 2002-06-01

• Current Cancer Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular drug targets involved in cancer, e.g. disease specific proteins, receptors, enzymes, genes.
  Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cancer.
  As the discovery, identification, characterization and validation of novel human drug targets for anti-cancer drug discovery continues to grow; this journal has become essential reading for all pharmaceutical scientists involved in drug discovery and development.

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• In this Subject: Oncology ,  Pharmacology
• By this author: Mathijssen R.H.J. ;  Loos W.J. ;  Verweij J. ;  Sparreboom A.

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