Morgan M W, O'Hare M J
Cancer. 1979 Mar;43(3):969-79. doi: 10.1002/1097-0142(197903)43:3<969::aid-cncr2820430328>3.0.co;2-5.
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.
非增殖性成人肾上腺皮质细胞的原代单层培养物已被用于筛选18种癌症化疗中使用的细胞毒性药物对皮质类固醇生成的直接影响。除5-氟尿嘧啶（5-FU）及其代谢物5-氟脱氧尿苷外，所测试的药物在与皮质细胞活力相容的水平和/或治疗期间可能遇到的水平下均未显示出显著活性。然而，这两种抗代谢物在促肾上腺皮质激素（ACTH）和单丁酰环磷酸腺苷（cAMP）刺激的以及未刺激的人类细胞培养物中，均导致皮质类固醇生成缓慢但持久的可逆性抑制。因此，在没有任何明显细胞毒性证据的情况下，10微克/毫升的浓度在处理七天后导致的抑制率低于80%。高压液相色谱显示所有分泌的紫外线吸收类固醇均受到抑制。对处理后细胞的超微结构检查显示线粒体形态有显著变化，这表明5-氟尿嘧啶抗类固醇生成作用的可能作用位点。这些体外实验结果提示，在长期或高剂量输注5-FU化疗期间，体内可能会出现肾上腺抑制。
