Journal of Oncology Pharmacy Practice

 

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Journal of Oncology Pharmacy Practice, Vol. 6, No. 3, 92-108 (2000)
DOI: 10.1177/107815520000600303

Dual topoisomerase I/II inhibitors

R van Gijn, PhD

Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

RRH Lendfers

Department of Biomedical Analysis, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

JHM Schellens

Department of Biomedical Analysis, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands, Division of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

A Bult

Department of Biomedical Analysis, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

JH Beijnen

Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands, Department of Biomedical Analysis, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

Topoisomerase (topo) I and II are nuclear enzymes, which play a major role in the topological rearrangement of DNA during replication and transcription processes. In the course of years, many different agents have been found which can inhibit the topos and thereby exploit cytotoxicity, also against tumour cells. Selective inhibition of the topo I enzyme can, however, induce a reactive increase in topo II levels, and vice versa. This mechanism is associated with the development of drug resistance. Dual inhibition of both topo I and II may, theoretically, overcome this resistance problem. In this review, the most important and promising dual topo I/II inhibitors designed as anticancer agents will be discussed. Thus far, only the indolyl quinoline derivative TAS-103, the 7H-benzo [e] pyrido [4,3-b] indole derivative intoplicine, and the acridine derivative PZA have been shown to be dual topo inhibitors with high cytotoxicity.

Key Words: Topoisomerase I/II • dual inhibitors • multidrug resistance • TAS-103 • PZA • intoplicine


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