ANAHEIM, CaliforniaAn investigational antisense oligonucleotide directed against bcl-2 appears to help overcome the resistance of hormone-refractory prostate cancer to docetaxel(Drug information on docetaxel) (Taxotere). The combination of bcl-2 antisense (G3139, Genasense) and docetaxel, therefore, may prove to be effective in this type of cancer, researchers from the University of Texas Health Science Center, San Antonio, said at the American Urological Society annual meeting (abstract 690).
The bcl-2 protein is part of a larger family of proteins that regulates apoptosis and prevents cell death. The expression of the bcl-2 protein is increased in both number and intensity in prostate cancers that are hormone insensitive, compared with hormone-sensitive tumors.
In experimental models of radiation and hormone therapy, the bcl-2 protein confers resistance to apoptosis. It was hypothesized, therefore, that the protein might confer resistance to both androgen ablation therapy and chemotherapy in a prostate cancer model.
Anthony W. Tolcher, MD, associate director of clinical research at the CTRC Institute for Drug Development, reported that in a xenograft mouse model of prostate cancer, G3139 did, indeed, enhance the antitumor activity of docetaxel. "In this model, 7 of 10 mice were actually cured with the combination vs docetaxel alone, in which 3 of 10 mice were cured," Dr. Tolcher said.
They then conducted a phase I-II study of 20 patients (18 evaluable) with hormone-refractory prostate cancer. Eight had prior chemotherapy (which included prior taxanes in several cases). The patients received G3139 (5 to 7 mg/kg/d) as a continuous IV infusion for 5 days by portable pump, followed by docetaxel (60 to 75 mg/m²) given over 1 hour, with cycles repeated every 3 weeks. The optimal dose was determined to be G3139 7 mg/kg/d and docetaxel 75 mg/m².
Generally, the treatment was very well tolerated. Hematologic toxicity occurred in only one patient. Several patients experienced diuresis, and a few developed the typical docetaxel effects (alopecia, nail bed changes, and peripheral neuropathy). Several patients developed low-grade fever during G3139 infusion.
Downregulation of bcl-2 Protein