Combined use of antisense oligonucleotides and chemotherapeutics in the treatment of refractory prostate cancer.

Throughout the past six decades, our understanding of cancer of the prostate and the treatment of the disease using endocrine therapy has been centred on the classical investigations of Charles Huggins, which established that tumor tissue of the prostate as well as the normal tissue of the gland retained some degree of androgen dependence. Attention must now be focussed on the 20-40% of patients who are resistant to endocrine therapy. These patients are non-responders to conventional endocrine treatment after 3 to 6 months, quickly progress and die of the disease. In terms of molecular endocrinology related to the progressive stage of the disease, it would be expected that the cancer is being driven by the uncontrolled action of growth factors. Experiments combining oligonucleotide treatment with cytotoxic chemotherapeutic agents demonstrated a marked increase in the sensitivity of the prostate cancer cells. Results indicate that despite the presence of Bcl-x pre-mRNA in a number of cell types, the effects of modification of its splicing by antisense oligonucleotides vary depending on the expression profile of the treated cells. The transition from androgen-dependent to androgen non-dependent prostate cancer is accompanied by a number of molecular genetic changes, including overexpression of the Bcl-2 gene. Overexpression of Bcl-2 protein decreases the pro-apoptotic response to such cellular insults as irradiation, chemotherapy, and androgen withdrawal. The future looks promising and this kind of treatment offers a novel approach to alternative therapeutic options for advanced prostate cancer. Although numerous chemotherapeutic regimens have been evaluated for patients with hormone-refractory prostate cancer, none has improved survival.