Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan.
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 camptothecin-derivatives in the future.
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, PO Box 5201, Rotterdam, 3008 AE, The Netherlands. mathijssen@onch.azr.nl
Ron H J
RH
Mathijssen
Walter J
WJ
Loos
Jaap
J
Verweij
Alex
A
Sparreboom
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D002166:Camptothecin