LACK OF MUTAGENICITY AND METABOLIC INACTIVATION OF APHIDICOLIN BY RAT LIVER MICROSOMES

In view of the possible utilization of aphidicolin, a specific inhibitor of DNA polymerase .alpha., in the treatment of neoplastic diseases, it seemed important to assess the mutagenic effect of the drug and the possible modification induced by metabolic activation in the liver. Aphidicolin lacks mutagenicity in the Ames' Salmonella typhimurium-microsome test in agreement with the previous observation that it does not induce DNA repair synthesis in HeLa [human cervical carcinoma] cells. Aphidicolin was converted to inactive derivative(s) by rat liver microsomal oxidases. The reaction is dependent on time and temperature and requires NADP+ and glucose-6-phosphate. The metabolites are not mutagenic and they do not induce DNA repair synthesis in HeLa cells. The possible anti-cancer use of aphidicolin is not hampered by its partial metabolic inactivation in liver. Aphidicolin will possibly be clinically useful at concentrations higher than those expected from studies with human DNA polymerase .alpha. in vitro and human neoplastic cell lines in vivo. The metabolic derivative(s) of aphidicolin is inactive both against cellular DNA polymerase .alpha. and Herpes simplex viral DNA polymerase.