Sequencing hormonal ablation and radiotherapy in prostate cancer: a molecular and therapeutic prespective (Review)

Current therapeutic modalities for advanced prostate cancer are palliative in nature, with no effective treatment increasing survival in patients with metastatic prostate cancer. Apoptosis as a molecular process of genetically regulated cell death has a critical endpoint that coincides with the goal of successful treatment of prostate cancer. Expression of key regulators of the apoptotic pathway such as bcl-2 and caspases within individual prostate tumors appear to correlate with the prostate cancer cell's sensitivity to traditional therapeutic modalities, including androgen ablation and radiotherapy. Androgen-dependent prostate tumors undergo apoptosis in response to androgen-ablation. Cancer regression after radiation occurs by disruption of the reproductive integrity of the tumor cells and via activation of the apoptotic pathway. Increasing the sensitivity of prostate tumor cells to die via apoptosis increases the efficacy of fractionated therapy by reducing tumor cell survival. Thus signaling interaction between androgen ablation and radiotherapy may be synergistic in maximally activating the apoptotic potential of prostate cancer cells. The role of molecular technology in identifying apoptosis regulation in association with combination hormonal ablation and radiotherapy for the treatment of advanced prostate cancer holds tremendous promise, as any approach significantly decreasing the apoptotic threshold may lead to total synergistic killing of tumor cells. This review is an attempt to summarize the current knowledge of the clinical consequences of sequencing androgen ablation and radiotherapy in the treatment of prostate cancer patients and the molecular parameters underlying a potential optimization of such a combination strategy.