Programmed cell death as a new target for prostatic cancer therapy.

To increase survival of men with metastatic prostatic cancer, a modality that can effectively eliminate androgen independent cancer cells is desperately needed. By combining such an effective modality with androgen ablation, all of the heterogeneous populations of tumour cells within a prostatic cancer patient can be affected, thus optimizing the chances of cure. Unfortunately, such effective therapy for the androgen independent prostatic cancer cell is not yet available. This therapy will probably require two types of agents, one having antiproliferative activity affecting the small number of dividing androgen independent cells, and the other able to increase the low rate of cell death among the majority of non-proliferating (ie interphase) androgen independent prostatic cancer cells present. Androgen dependent prostatic epithelial cells can be made to undergo programmed death by means of androgen ablation, even if the cells are not in the proliferative cell cycle. Androgen independent prostatic cancer cells retain the major portion of this programmed cell death pathway, only there is a defect in the pathway such that it is no longer activated by androgen ablation. If the intracellular free Ca2+ is sustained at an elevated level for a sufficient time, androgen independent cells can be induced to undergo programmed death. The long term goal is therefore to develop some type of non-androgen ablative method that can be used in vivo to induce a sustained elevation in Ca2+ in androgen independent prostatic cancer cells. To accomplish this task, a more complete understanding of the biochemical pathways involved in programmed cell death is urgently needed. At present, studies are focusing on the mechanism involved in the Ca2+ elevation in the normal and malignant androgen dependent cell induced following androgen ablation and the role of the TRPM-2 protein in this process.