Relevance of Low Androgen Levels and Adrenal Androgens in the Growth of Transplantable Human Prostatic Carcinomas

Abstract

The objectives of this study were to investigate the necessity of total androgen ablation therapy in prostate cancer patients and to study the effect of adrenal androgens on prostate tumor growth. The androgen dependent human prostatic tumor lines PC-82 and PC-EW were used as models. Female and castrated male nude mice were transplanted with the PC-82 or PC-EW tumor and simultaneously substituted with Silastic implants containing testosterone (T). When tumors were exponentially growing, T implants were removed for a short period of time (12 and 5 days, respectively) in order to deplete the tumor tissue from androgens. Subsequently, mice were supplemented with Silastic capsules containing cholesterol mixed with different proportions of T. These implants resulted in plasma levels of androgens varying from 0.2 to 20 nmol/I.

The PC-82 tumor started to regress when plasma T levels were below 0.3 nmol/I, whereas reduction of PC-EW tumor burden was induced at a slightly higher plasma T level (0.5 nmol/I). The regression of the PC-EW tumor was significantly faster (t-test P<0.005) than the decrease in PC-82 tumor volume (74 ± 10 % and 42 ± 13 % in 28 days, respectively). Intratumor concentrations of T and DHT in the various groups of PC-EW tumor bearing mice were significantly smaller than the androgen levels in the PC-82 tumors of the corresponding T supplemented groups, except for the 0 %T-substituted mice. However, the threshold level for T stimulated tumor growth was found to be the same for both tumor lines, i.e. an intratissue DHT concentration of approximately 3 pmol/g tissue (intratumor T levels of 5 to 10 pmol/g tissue). These androgen levels, which are well above the concentrations found in castrated mice, did not result in any net growth of the tumors, although a maximal regression of the tumors was not induced either. From these results it is concluded, that a total withdrawal of androgens is not necessary to prevent growth of the human prostate cancer models PC-82 and PC-EW.

In addition, the same protocol was used for investigation of the growth of the PC-82 tumor in mice supplemented with Silastic implants filled with the main adrenal androgens androstenedione (A) and dehydroepiandrosterone (DHEA). The resulting plasma levels of A and DHEA were 13.5 ± 1.3 and 9.2 ± 1.7 nmol/I, respectively, which is higher than the peripheral levels found in castrated men. Substitution with A led to a plasma T level of 10.7 ± 1.6 nmol/I and accordingly to an increase in PC-82 tumor burden. DHEA substitution did not result in tumor growth stimulation. It is concluded that high levels of A, causing androgen levels exceeding the threshold level for DHT stimulated tumor growth, can playa role in growth activation of the human prostatic carcinoma PC-82.