Growth inhibition by diethylstilbestrol and relapse of the Noble rat prostatic tumor.

The response of androgen-sensitive Noble (Nb) rat prostatic adenocarcinoma [2Pr-121D (1)] to varying doses (50 approximately 1,000 micrograms/kg body weight) of diethylstilbestrol (DES) was investigated and characterized with respect to cytosol and nuclear androgen binding profiles, histology and pattern of relapse. Inhibition of tumor growth was closely related to the dose of DES. Treatment at all but the lowest dose (50 micrograms/kg) initially caused tumor regression, whereas serum testosterone concentrations in all groups, including that receiving the lowest dose, were decreased to castrate levels. Histologically, while extensive cellular destruction was clearly evident at higher doses of DES, some active tumor cells appeared to survive. Tumors eventually relapsed when higher doses of DES were stopped or with the continued administration of low doses. The cytosol dihydrotestosterone (DHT) receptor in this tumor line, as determined by sucrose density gradient, dextran charcoal and Sephadex column methods, was negative. Nuclear binding, however, was positive. Salt-extractable and salt-resistant fractions of nuclei derived from the untreated primary tumor and relapsed tumor following DES treatment contained high affinity androgen receptor. Comparison of binding constants revealed no significant differences. Our findings, based on the Nb rat prostatic tumor model, indicate that DES acts not only by eliminating circulating testosterone, but also by a direct cytotoxic effect on malignant cells. The results also suggest the lack of an apparent relationship between the loss of hormone responsiveness associated with recurrence of prostatic tumor growth and nuclear androgen binding parameters.