Topoisomerases in Human Leukemia

David Peereboom, Martin Charron, Scott H. Kaufmann

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

The chapter reviews the regulation of topoisomerases in lymphohematopoietic tissues, describes the clinical use of topo-directed agents in the treatment of leukemia, and suggests areas for future research on mechanisms of resistance to the agents in the clinical setting. There is discussion on topoisomerase II in human leukemia–topoisomerase II in normal lymphohematopoietic cells, antileukemic activity of topoisomerase II-directed agents, and resistance to topoisomerase II-directed agents. Mammalian cells contain two isoforms of topo ll, denoted topo llα and topo IIβ. These two enzymes are the targets for several different classes of cytotoxic agents. The chapter delves into the role of the multidrug transporter as a cause of resistance in leukemia. Topo II levels in bone marrow aspirates from adult patients with acute non lymphocytic leukemia (ANLL) vary over a 10-fold range; average levels of topo II are lower in samples from patients with ANLL than in any human ANLL cell line; both topo II isoforms are expressed in approximately equal amounts in most human ANLL specimens; and there is no correlation between average content of topo II and response of the tumor cells to topo II-directed therapy in vitro or in vivo. Topo II levels vary among individual cells in a population of human tumor cells. Resistance can also result from qualitative changes in topo II. Successful treatment with currently available topo I-directed agents requires a series of discrete events—accumulation of the agent in tumor cells, stabilization of topo I-DNA adducts, and conversion of the reversible topo I-DNA adducts to cytotoxic lesions. Animal studies revealed that CPT-11 (7-ethyl-10-[4-(1-piperidyl)-1-piperidyl] carbonyloxy-camptothecin] has activity against anthracycline- and anthracenedione-resistant sublines of P388, suggesting a role in the treatment of refractory leukemias. Progress in the study of drug resistance might be facilitated by analysis of the mechanism of action of the topoisomerase-directed agents.

Original languageEnglish (US)
Pages (from-to)33-50
Number of pages18
JournalAdvances in Pharmacology
Volume29
Issue numberPB
DOIs
StatePublished - Jan 1 1994

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ASJC Scopus subject areas

  • Pharmacology

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