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

To improve survival in men with metastatic prostatic cancer, a therapeutic modality that can effectively eliminate androgen-independent cancer cells is needed desperately. Combination of such an effective modality with androgen ablation could affect all of the heterogeneous populations within prostate tumors of individual patients, thus optimizing the chances of complete cure. Such a therapeutic approach will probably require two types of agents, one with antiproliferative activity affecting the small number of dividing androgen-independent cells and one with the capacity to increase the rate of cell death among the non-proliferating 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 pathway of cell death in response to androgen ablation. In contrast, androgen-independent human prostate cancer cells can be induced to undergo apoptosis following such alternative treatment modalities as: (a) non-androgen ablative cytotoxic drugs, such as fluorinated pyrimidines, which result in the ''thymineless state'', and (b) ionizing irradiation. The apoptotic effect induced by radiation can be significantly potentiated by post-irradiation treatment of the cells with suramin. In contrast, this radiation-induced apoptosis can be substantially inhibited by pretreatment of cells with suramin, probably through suramin's ability to arrest proliferating cells in the G(o)/G(l) phase of the cell cycle. These results suggest that treatment of prostate cancer patients with suramin prior to irradiation is likely to inhibit radiation palliation. On the other hand, radiation therapy followed by suramin treatment may yield enhanced effectiveness. Androgen-independent human prostate cancer cells, therefore, although they do not activate the genetic program of cell death in response to androgen deprivation, still retain the ability to activate the apoptotic pathway in response to non-androgen ablative stimuli. Moreover, the relative timing of combination treatment for the simultaneous induction of apoptosis among androgen-dependent and androgen-independent clones may have significant therapeutic implications in the treatment of advanced prostate cancer.