N-Trifluoroacetyladriamycin-14-valerate (AD 32) is an adriamycin (ADR) analog prepared and developed in these laboratories. Compared to ADR, AD 32 is therapeutically superior and less toxic (which includes less cardiotoxicity) in animal test systems. AD 32 is presently in early Phase II trial; clinical antitumor activity has been documented in connection with Phase I evaluation. The present research proposal is aimed at exploring various aspects of AD 32, including the complete elucidation of its metabolic fate in laboratory animals and explanation of interspecies differences in metabolism. The clinical pharmacology of AD 32 will be determined. Studies will be directed toward improving the clinical utility of this new drug and improvements will be sought in drug formulation and delivery systems. Additional aspects of cardiac toxicity will be investigated. It is expected that results from proposed pharmacologic and biochemical studies with AD 32 and metabolites will shed light on the AD 32 mechanism of antitumor action, which, at present, remains speculative. In addition, the methodologies and experience gained in connection with studies on AD 32 will be applied to the development of other promising anthracycline agents prepared in connection with our parallel ADR analog program. The use of sensitive high performance liquid chromatography/fluorescence assay systems, developed in connection with work on AD 32, will continue to be applied to questions of ADR pharmacology and improved clinical efficacy, as well.
Showing the most recent 10 out of 19 publications
