We propose a program of anticancer drug development consisting of phase I clinical trials with integrated laboratory studies in four areas. In a program of nucleoside analogue development we propose clinical studies of the new agent chlorofluoro ara-A associated with studies of triphosphate pharmacokinetics. In a second program of development of Topoisomerase active agents we propose clinical studies of the Topoisomerase I active drug 9-amino-camptothecin, associated with measurements of drug sensitivity and Topoisomerase levels in malignant cells, and circulating lymphocytes. We also propose the phase I development of the combinations of Taxol with Methotrexate and Taxol with Edatrexate. These studies are based on preclinical scheduling studies completed and will be accompanied by studies of cell cycle analysis based on pretreatment BuRD infusions, microtubule/tubulin studies and studies to detect apoptosis. Finally, we propose a program of early clinical development of new retinoids exemplified by a study of liposomal encapsulated all Trans Retinoic Acid based on preclinical studies demonstrating its potential pharmacologic advantages over the conventional formulation. This trial, and the trials mentioned above will be associated with classical pharmacokinetic studies.
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