IN VITRO ANTINEOPLASTIC DRUG TOXICOLOGY CHARACTERIZATION

THE CLINICAL UTILITY OF MANY ANTICANCER AND ANTI-HIV DRUGS IS FREQUENTLY LIMITED BY THEIR SERIOUS TOXICITIES, MYELOTOXICITY BEING THE MOST COMPROMISING DOSE-LIMITING COMPLICATION. FURTHERMORE, ALL PRECLINICAL DRUG TOXICOLOGY IS PERFORMED IN VIVO, WHICH IS OFTEN VERY COSTLY AND TIME CONSUMING. THIS PHASE I PROJECT HAS DEVELOPED ASSAYS THAT BETTER CHARACTERIZE AND PROBE THE MYELOTOXICITY OF ANTICANCER AND ANTI-HIV AGENTS. BECAUSE THESE ASSAYS UTILIZE NORMAL HUMAN MARROW, THEY ARE DESIGNED TO BE OF DIRECT CLINICAL RELEVANCE. PHASE I EFFORTS EXPLOITED THE AVAILABILITY OF RECOMBINANT HEMATOPOIETIC REGULATORY FACTORS TO STANDARDIZE IN VITRO HUMAN AND MURINE BONE MARROW PROGENITOR ASSAYS. THESE ASSAYS HAVE BEEN USED TO QUANTITATE THE PRECLINICAL HEMATOTOXICITIES OF KNOWN ANTICANCER AND ANTI-HIV DRUGS. A CORRELATION BECAME EVIDENT BETWEEN THE IN VITRO HEMATOTOXICITY AND KNOWN IN VIVO MYELOTOXICITIES IN MICE. DIRECT EVIDENCE HAS BEEN OBTAINED VALIDATING THE ABILITY OF THE IMPROVED IN VITRO HEMATOPOIETIC ASSAY TO PREDICT MYELOTOXICITY IN VIVO. IN PHASE I, THE FEASIBILITY OF SUCH AN IN VITRO/IN VIVO PROTOCOL USING DRUGS WHOSE IN VITRO AND IN VIVO MYELOTOXICITIES ARE WELL ESTABLISHED WAS DOCUMENTED. HAVING ESTABLISHED THE FEASIBILITY OF THIS IMPROVED SYSTEM, INVESTIGATIONAL NEW DRUGS WILL BE EXPLORED IN PHASE II.