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Bcl-2 Antisense Enhances Docetaxel in Refractory Disease

Bcl-2 Antisense Enhances Docetaxel in Refractory Disease

ANAHEIM, California—An investigational antisense oligonucleotide directed against bcl-2 appears to help overcome the resistance of
hormone-refractory prostate cancer to 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

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