15 DNA Topoisomerases in Clinical Oncology

Abstract

I. INTRODUCTION
There is a compelling reason for studying human disease as the ultimate experimental system. This approach, highly practical and direct, can use already available information correlating clinical status, pathology, and pharmacology. This data base may help investigators to reevaluate current trends and to develop new directions in therapy. In this chapter, DNA topoisomerase research is discussed in the relation to biology and chemotherapy of selected malignancies.

It was recently recognized that some of the most valuable anticancer drugs interact with topoisomerase II in cell-free systems, as well as in intact cells (for review, see Chen and Liu 1986; Potmesil 1988). In addition, topoisomerase I was identified as a target for the plant alkaloid camptothecin (Hsiang et al. 1985; Hsiang and Liu 1988). The interactions between the drug and topoisomerase involve mostly natural products of microbial or plant origin and their analogs. This results in a complex of a topoisomerase molecule bound covalently to cleaved DNA (Chen and Liu 1986), which is, most likely, the initial event leading to cell death. Drug interaction with either topoisomerase I or II plays a crucial role in drug-exerted cytotoxicity.

II. ANTICANCER DRUGS INHIBITING TOPOISOMERASE I
In the early 1970s, camptothecin, a plant alkaloid isolated from Camptotheca acuminata of the Nyssaceae plant family (Wall et al. 1966), was briefly tested in phase-I and -II clinical trials (Gottlieb et al. 1970; Moertel et al. 1971; Muggia et al. 1972). Myelosuppression was the dose-limiting toxicity in cancer patients treated with camptothecin sodium salt, and cystitis...