HORMONAL THERAPY OF PROSTATIC CARCIK:( J?,! 4 : IS THERE A RATIONALE FOR DELAYED TREAT\IE:?:‘l-:;

The report by Huggins and Hodges in 1941’ that endocrine manipulation caused a decrease in acid phosphatase dramatically changed the treatment of metastatic prostatic cancer. Since that time, case reports have clearly described objective responses to hormonal manipulation of this disease.2.3 Nevertheless, although it is generally accepted that hormonal therapy produces subjective remissions in a large proportion of patients with symptomatic metastases, controversies remain regarding the effect of hormonal manipulation on survival and the timing of therapy, i.e., should treatment be started at the time of the initial diagnosis of metastatic disease or at the onset of symptoms.4 The question of whether or not hormonal therapy actually improves survival can be addressed from both basic science and clinical perspectives. Animal models have consistently demonstrated that endocrine manipulation causes growth inhibition of the hormone sensitive Dunning R-3327-H and R-3327-G rat prostatic adenocarcinomas.5m7 However, despite the beneficial effect of hormonal manipulation in this model, continued treatment does not prevent tumor relapse. Tumor regrowth is associated with an increase in the aneuploid cell population approaching the control level.s Isaacs and Coffey9 have demonstrated that the hormonally sensitive Dunning R-3327-H adenocarcinoma contains both androgen dependent and independent tumor cells. The finding that this tumor continues to demonstrate hormone responsiveness, without cure, despite multiple passages provides evidence that the growth rates of the hormone sensitive and resistant cells are similar, because, if one cell type had a significant growth advantage over the other, extended in vivo passage would be associated with the elimination of the other cell type* The differences between androgen sensitivity and androgen resistance may be quantitative as well as qualitative. Orchiectomy results in irreversible progression to a hormone insensitive state in the R-3327-H model of prostatic carcinoma. The situation is different with the R3327-G cell line which is poorly differentiated but hormonally sensitive. Pollack and associates’O have demonstrated that both orchiectomy and hormonal therapy decrease the tumor growth rate compared to intact rats. In their model, diethylstilbestrol had a greater effect on tumor cell growth than orchiectomy, and orchiectomy suppressed but did not eliminate tumor cells that were hormone responsive. These experiments suggest that three cell types can be functionally defined: hormone dependent cells which require androgen for survival: hormone sensitive cells which grow faster in the presence of androgen; and hormone independent cells which are unresponsive to androgen. The response of prostate cancer to hormonal manipulation depends on the distribution of these three cell types and their growth rates. There is relatively little information available regarding human prostatic adenocarcinomas except for clinical data. Human prostatic tumors are often heterogeneous” and probably contain a mixture of both hormonally sensitive and insensitive cells. However, most of the human prostate cancer cell lines that have been established have limited hormone sensitivity. An exception is PC82, a hormone responsive human prostatic carcinoma that is serially transplantable in athymic nude mice.12 PC82