and another.
"...The 14/18 chromosomal translocation, which characterizes approximately 80% to 90% of low-grade B-cell lymphomas, leads to the abnormal expression of bcl-2 protein.[13,14] Bcl-2 inhibits apoptosis, leading to the clonal accumulation of lymphoma cells over time and the eventual clinical diagnosis of low-grade lymphoma. Bcl-2 expression is also associated with poor prognosis.[13,14] For this reason, the targeting of bcl-2 gene or protein by immunotherapeutic means would be of much interest and potential.
Waters and colleagues[15] from the Institute of Child Health in London used an antisense approach, using G3139, an 18mer fully phosphorothiolated oligonucleotide complementary to the first 6 codons of bcl-2 mRNA. The molecule was previously shown to have dose-dependent antitumor activity in a SCID mouse xenograft model of lymphoma. A total of 21 patients with previously treated NHL received a 14-day subcutaneous infusion of G3139, at doses ranging from 4.6 to 195.8 mg/ m2/day. The maximum tolerated dose was 147.2 mg/m2/day (approximately 4 mg/kg/day), with dose-limiting toxicities consisting of thrombocytopenia, fever, and lethargy. Plasma levels shown to be efficacious in in vivo models were achieved in patients who received doses above 36.8 mg/m2/day.
Of 20 patients who are evaluable for response, 1 patient achieved complete remission (lasting 34+ months), 2 achieved a minor response, 9 had stable disease, and 9 had progressive disease. Systemic "B" symptoms improved in 6 of 10 patients, circulating lymphoma cells decreased in 7 of 12, and LDH declined after therapy in 4 patients. Bcl-2 protein, as measured by FACS in tumor tissue from 13 patients, was decreased in 5 patients after treatment. Unfortunately, insufficient pathologic material was available for bcl-2 testing in the 1 complete responder. This study is an important one, and serves as a proof of principle that this antisense approach against bcl-2 protein appears to have biologic activity against lymphoma. Additional study is clearly warranted..."
"...[13]Philip L, Simonian, Didier AM, et al: Bc1-2 and Bcl-XL can differentially block chemotherapy-induced cell death. Blood 1997;90:1208-1216.
[14]Ghia P, Boussiotis VA, Schultze JL, et al. Unbalanced expression of Bc1-2 family proteins in follicular lymphoma: contribution of CD40 signaling in promoting survival. Blood 1998;91:244-251.
[15]Waters JS, Webb A, Cunningham D, et al. Results of a Phase I clinical trial of bcl-2 antisense molecule G3139 (GENTA) in patients with non-Hodgkin's lymphoma. [Abstract 11]. American Society of Clinical Oncology 35th Annual Meeting, Atlanta, 1999, 18:4a..."
go to medscape.com, click on ASCO abstracts and search for genta.
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