Structural requirements for mitotane activity: development of analogs for treatment of adrenal cancer.

Mitotane is used in adrenal cancer as adjuvant therapy, monotherapy or combined with other cytotoxic agents in advanced disease, but only 30% of patients respond. The aim of this study was to define the structural requirements for drug activity and to develop analogs with improved adrenalytic action. Nine analogs of [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2dichloroethane] (o,p'-DDD) were tested by measuring suppression of cortisol secretion and the presence of inflammatory changes in the dog adrenal and inhibition of cell proliferation and cortisol production by NCI-H295 human adrenal cancer cells. In addition to mitotane, o,p'-DDClBr and o,p'-DDBr(2), were active in vitro and in vitro: Their effects were comparable to that of o,p'-DDD when tested at 50 μM concentration, but o,p'DDBr(2) was significantly more active at the lower 20 μM concentration. A dihalogenated methine carbon is required for adrenalytic activity. A change in the aromatic portion of the mitotane molecule causes loss of activity. Because of its greater activity at lower concentrations, o,p'-DDBr(2) has potential application in the treatment of patients with adrenal cancer.