IN VITRO TEST OF INTESTINAL TOXICITY OF ANTICANCER DRUGS

INTESTINAL TOXICITY IS A MAJOR SIDE EFFECT OF CANCER CHEMOTHERAPY. THE PROCEDURES TO ISOLATE AND CULTURE RAT SMALL INTESTINAL, EPITHELIAL CRYPT CELLS, WHICH ARE THE TARGET CELLS FOR DRUG TOXICITY, HAVE RECENTLY BEEN DEVELOPED. THE OVERALL OBJECTIVE OF THIS STUDY IS TO ESTABLISH AN IN VITRO METHOD TO QUANTIFY THE IN VIVO INTESTINAL TOXICITY OF ANTICANCER DRUGS. THE PHASE I STUDY WILL EXAMINE THE FEASIBILITY OF USING AN IN VITRO TOXICITY ASSAY TO PREDICT THE INTESTINAL TOXICITY OF ANTICANCER DRUGSUSING THE RAT AS AN ANIMAL MODEL. THE RESEARCH PLAN IS TO EVALUATE AND CORRELATE THE DRUG-INDUCED RAT INTESTINAL CRYPT-CELL TOXICITY IN VITRO AND THE INTESTINAL DISTURBANCESIN INTACT ANIMALS. TWO ANTIMETABOLITES, 5-FLUOROURACIL AND METHOTREXATE, HAVE BEEN SELECTED AS THE TEST DRUGS. DRUG TOXICITY WILL BE DETERMINED BY THE CONCENTRATION AS WELL AS THE DURATION OF EXPOSURE TO THE DRUG. TO MAKE A VALID COMPARISON OF THE IN VITRO AND IN VIVO TOXICITIES, THE IN VITRO AND IN VIVO STUDIES WILL BE DONE UNDER SIMILAR DRUG CONCENTRATION-TIME (AUC) PROFILES. THE CRYPT CYTOTOXICITY AND THE INTESTINAL DISTURBANCES, OBSERVED UNDER THE SAME AUC OF THE DRUG, WILL BE COMPARED, AND A QUALITATIVE AND QUANTITATIVE CORRELATION WILL BE SOUGHT. THE PHASE II STUDY WILL EXAMINE THE GENERAL APPLICABILITY OFTHE IN VITRO ASSAY USING AT LEAST THREE DRUGS FROM EACH OF THE MAJOR DRUG CLASSES, INCLUDING ANTIMETABOLITES, ALKYLATORS, AND DNA REACTING AGENTS, AND WILL COMPARE THE RAT AND HUMAN CELLS. COMPARISON OF THE CYTOTOXIC RESPONSES OF RAT AND HUMAN CRYPT CELLS IS NECESSARY TO UNDERSTAND THE APPLICABILITY AND LIMITATIONS OF THE CRYPT CYTOTOXICITY ASSAY TO PREDICT FOR DRUG TOXICITY IN PATIENTS.