CLINICAL SEQUENTIAL TOPOISOMERASE POISONING

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DESCRIPTION (APPLICANT'S DESCRIPTION) This proposal is designed to provide clinical and pharmacological data regarding the use of sequential topoisomerase I and II poisons in the treatment of cancer. These drugs are among the most effective cytotoxic antitumor agents. Considerable preclinical evidence suggests that sequential administration of drugs that poison both enzymes will lead to enhanced activity. What is needed is information regarding the optimal combination of these drugs in treating patients with cancer. Aim I involves a clinical trial of sequential therapy with 9-nitrocamptothecin and etoposide. The proposed study is based upon prior observations in a recent trial using 9-aminocamptothecin. Patient blood cells exhibited an increase in topoisomerase II protein expression during the 9-aminocamptothecin infusion. Similar increases in topoisomerase II expression have been seen in cell lines resistant to camptothecin, and have correlated with increased sensitivity to topoisomerase II poisons. These findings suggest that the properly timed addition of a topoisomerase II poison may enhance the clinical effectiveness of camptothecin analogues. The schedule proposed in this study involves dose escalation of an etoposide infusion administered after completion of a fixed dose of 9-nitrocamptothecin. Results from this study will determine the clinical feasibility of combining the two enzyme poisons in this manner and will provide a maximum-tolerated dose for etoposide. In order to optimize the schedule of administration of the two drugs in future trials, studies proposed in Aim II include repeated measurements of topoisomerase I and II levels. Additional studies in this Aim are designed to clarify potential clinical resistance mechanisms to camptothecins. Preliminary data from a trial with 9-aminocamptothecin suggest that blood cell topoisomerase I levels decline during drug administration. Data obtained from the proposed trial should allow determination of whether this phenomenon represents a general in vivo response to topoisomerase I poisons. In addition, studies are proposed to evaluate the occurrence in vivo of mutations in topoisomerase I that confer drug resistance.