IN VITRO ANTINEOPLASTIC DRUG TOXICOLOGY CHARACTERIZATION

AMONG THE MAJOR DOSE-LIMITING TOXICITIES OF CURRENTLY USED ANTICANCER DRUGS ARE THOSE AFFECTING THE BONE MARROW, CARDIOVASCULAR SYSTEM, LUNGS, GASTROINTESTINAL TRACT AND THE NERVOUS SYSTEM. HOWEVER, HEMATOTOXICITIES CONSTITUTE THE MOST COMMON AND OFTEN MOST SIGNIFICANT SIDE EFFECT OF THE MAJORITY OF AGENTS. WE PROPOSE THE FURTHER DEVELOPMENT AND CHARACTERIZATION OF IN VITRO SYSTEMS FOR HUMAN MYELOPOIESIS (CFU-GM), ERYTHROPOIESIS (CFU-E/BFU-E) AND MEGAKARYOPOIESIS (CFU-MEG) WITH WHICH TO QUANTIFY AND CHARACTERIZE MYELOTOXICITIES INDUCED AT CLINICALLY ACHIEVABLE DRUG EXPOSURES FOR CIS-PLATINUM, METHOTREXATE, BCNU, VINCRISTINE AND CHLOROZOTOCIN. SURVIVING COLONIES WILL BE STAINED AND ASSESSED MORPHOLOGICALLY AND CYTOCHEMICALLY. OBSERVED IN VITRO TOXICITIES WILL BE CORRELATED WITH THE KNOWN CLINICAL TOXICITIES OF THESE AGENTS. IN PHASE II OF THE CONTRACT A WIDER RANGE OF ANTICANCER AGENTS WILL BE EVALUATED USING THESE SYSTEMS AND THE KINETICS OF TOXICITY INDUCTION INVESTIGATED IN GREATER DETAIL. DELAYED AND CUMULATIVE TOXICITY WILL BE INVESTIGATED USING LONG-TERM BONE MARROW CULTURES. IN ORDER TO IMPROVE THE THERAPEUTIC INDICES OF THE MOST SIGNIFICANTLY MYELO-SUPPRESSIVE AGENTS, CYTO- AND CHEMOPROTECTIVE AGENTS WILL BE EVALUATED FOR THEIR ABILITY TO SELECTIVELY PROTECT BONE MARROW CELLS AGAINST DRUG-INDUCED DAMAGE.