Therapeutic integration of c-myc and bcl-2 antisense molecules with docetaxel in a preclinical model of hormone-refractory prostate cancer.

Background: The response of hormone-refractory prostate cancer (HRPC) to chemotherapy remains modest, necessitating the search for new forms of treatment to improve the prognosis. Since an increased expression of oncogenes, including c-myc and bcl-2, accompanies the transition to HRPC, we evaluated whether the concomitant downregulation of these oncogenes by antisense strategy sensitized HRPC to chemotherapy.

Methods: PC-3 prostate cancer cells were exposed in vitro to c-myc (INX-6295) and bcl-2 (G3139) antisense oligodeoxynucleotides (ODNs) and docetaxel given alone or in combination. Therapeutic efficacy of the different treatments was also evaluated in xenografts.

Results: We show that the triple combination of drugs given in the sequence G3139/docetaxel/INX-6295 was the most active in reducing the survival of PC-3. Likewise, the combination triggered apoptosis in more than 80% of cells. A marked tumor weight inhibition was observed in PC-3 xenografts after G3139/docetaxel/INX-6295 treatment, with a complete tumor regression being noted in half the mice. A 111% overall increase in life survival and a complete cure in two out of eight mice was also reported. This treatment remained effective even when started at a very late stage of tumor growth producing about 80% tumor weight inhibition (TWI), with tumor regression being maintained for 1 month. Finally, the antitumor effect resulted in a significant increase (70%) in mice survival.

Conclusions: These data indicate that the combined targeting of genes involved in uncontrolled proliferation and evasion of apoptosis renders HRPC responsive to chemotherapy making this treatment a promising antineoplastic strategy.