APOPTOSIS - THERAPEUTIC SIGNIFICANCE IN THE TREATMENT OF ANDROGEN-DEPENDENT AND ANDROGEN-INDEPENDENT PROSTATE-CANCER

To improve survival in men with metastatic prostatic cancer, a therape utic modality that can effectively eliminate androgen-independent canc er cells is needed desperately. Combination of such an effective modal ity with androgen ablation could affect all of the heterogeneous popul ations within prostate tumors of individual patients, thus optimizing the chances of complete cure. Such a therapeutic approach will probabl y require two types of agents, one with antiproliferative activity aff ecting the small number of dividing androgen-independent cells and one with the capacity to increase the rate of cell death among the non-pr oliferating androgen-independent prostatic cancer cells present, i.e. the majority. Androgen-responsive human prostate cancer cells are able to undergo programmed cell death after androgen ablation (even if the cells are not in the proliferative cell cycle). Androgen-independent human prostate cancer cells, however, do not activate this apoptotic p athway of cell death in response to androgen ablation. In contrast, an drogen-independent human prostate cancer cells can be induced to under go apoptosis following such alternative treatment modalities as: (a) n on-androgen ablative cytotoxic drugs, such as fluorinated pyrimidines, which result in the ''thymineless state'', and (b) ionizing irradiati on. The apoptotic effect induced by radiation can be significantly pot entiated by post-irradiation treatment of the cells with suramin. In c ontrast, this radiation-induced apoptosis can be substantially inhibit ed by pretreatment of cells with suramin, probably through suramin's a bility to arrest proliferating cells in the G(o)/G(l) phase of the cel l cycle. These results suggest that treatment of prostate cancer patie nts with suramin prior to irradiation is likely to inhibit radiation p alliation. On the other hand, radiation therapy followed by suramin tr eatment may yield enhanced effectiveness. Androgen-independent human p rostate cancer cells, therefore, although they do not activate the gen etic program of cell death in response to androgen deprivation, still retain the ability to activate the apoptotic pathway in response to no n-androgen ablative stimuli. Moreover, the relative timing of combinat ion treatment for the simultaneous induction of apoptosis among androg en-dependent and androgen-independent clones may have significant ther apeutic implications in the treatment of advanced prostate cancer.