Cytotoxic drugs and the human adrenal cortex: a cell culture study.

Primary monolayer cultures of nonproliferating adult human adrenocortical cells have been used to screen 18 cytotoxic drugs used in cancer chemotherapy for direct effects on corticosteroidogenesis. None of the drugs tested, with the exception of 5-fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine, showed significant activity at levels compatible with cortical cell viability and/or likely to be encountered during therapy. These two antimetabolites, however, resulted in a slow but long-lived reversible suppression of corticosteroidogenesis in both ACTH- and monobutyryl cyclic AMP-stimulated, as well as unstimulated cultures of human cells. Thus 10 micrograms/ml resulted in less than 80% inhibition after seven days treatment without any evidence of overt cytotoxicity. High-pressure liquid chromatography showed a suppression of all UV-absorbing steroids secreted. Examination of the ultrastructure of the treated cells showed significant changes in mitochondrial morphology, suggesting a possible site of action for the antisteroidogenic effects of 5-fluorouracil. These in vitro results suggest the possibility of adrenal suppression in vivo during long-term or high dose infusion 5-FU chemotherapy.