Mitotane (o,p'-DDD) is an adrenalytic drug used in the treatment of adrenal cancer and benign Cushing's syndrome. When given in effective doses, its use is limited by toxicity.
The aim of this investigation is to develop more effective protocols for the administration of Mitotane and Mitotane analogs which should yield greater adrenalytic effects and decreased toxicity. Based on our previous studies with Mitotane and Mitometh and reports on the activation metabolism of p,p'-DDD and other halogenated hydrocarbons, we postulate that the adrenalytic action of Mitotane is linked to the ability of the dichloromethyl group to become metabolically oxidized to an activated electrophylic species, an acyl chloride, which covalently binds to metabolically important macromolecules in the adrenal cortex. We plan to study this mechanism further using a dog model in which the adrenalytic effect will be assessed by suppression of cortisol and increase in ACTH levels, adrenal response to ACTH stimulation, histological evidence of adrenal necrosis and in vitro suppression of transformation of radiolabeled Mitotane to DDA. We will determine if the administration of cytochrome P-450 enzyme mitochondrial inhibitors can block Mitotane effects by suppressing its metabolism and if the administration of P-450 inducers can enhance the adrenalytic effects of the drug. We will determine by autoradiographic morphological studies the cellular site(s) of Mitotane metabolism and action. In order to increase activity of Mitotane, we plan to synthesize bromochloro and bromofluoro analogs. These substitutions may render compounds which are more cytotoxic to the adrenal. Another goal of the study is to ascertain ways in which toxicity of Mitotane may be ameliorated. Toxicity will be evaluated in the dog by assessing changes in serum cholesterol, SGOT, SGPT, alkaline phosphatase and histological evidence of hepatic necrosis. We plan to determine if there are differences in metabolic pathways in adrenal as compared to liver in regards to the effects of Mitotane and its analogs and to investigate the role of glutathione in the bioactivation or detoxification of Mitotane metabolites. Assuming that the toxicity of Mitotane may be due, in part, to its high lipophilicity and poor absorption, we plan to synthesize Mitotane analogs in which one or both of the aromatic chlorines is replaced with amino groups. By these changes, we may obtain a better balance between lipophilicity and hydrophilicity in order to improve absorption and adrenal bioavailability. If enzyme inducers are able to enhance the activity of Mitotane in the adrenal without added toxicity and if the new Mitotane analogs appear to have a more favorable therapeutic index, we plan to carry out a pilot study in which these compounds will be used in dogs with Cushing's disease and adrenal cancer. We also plan to determine if it is possible to predict the response to therapy by measuring metabolic activity in vitro using incubation of adrenal tumor homogenates.
