oblimersen and Waldenstrom-Macroglobulinemia

The components of the apoptotic pathway are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis and confers resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy, and monoclonal antibodies. Oblimersen sodium (G3139, Genasense, Genta Inc, Berkeley Heights, NJ) is an antisense oligonucleotide compound designed to specifically bind to the first six codons of the human bcl-2 mRNA sequence, resulting in degradation of bcl-2 mRNA and subsequent decrease in Bcl-2 protein translation. Oblimersen is the first oligonucleotide to demonstrate proof of principle of an antisense effect in human tumors by the documented downregulation of the target Bcl-2 protein. A growing body of preclinical and clinical evidence suggests that oblimersen synergizes with many cytotoxic and biologic/immunotherapeutic agents against a variety of hematologic malignancies and solid tumors. Randomized clinical trials are currently underway to evaluate the efficacy and tolerability of oblimersen in combination with cytotoxic chemotherapy in chronic lymphocytic leukemia (CLL), multiple myeloma (MM), malignant melanoma, and non-small cell lung cancer. In addition, nonrandomized trials are underway to evaluate oblimersen in non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), and hormone-refractory prostate cancer. Preclinical data support the clinical evaluation of oblimersen in additional tumor types, including chronic myelogenous leukemia, and breast, small cell lung, gastric, colon, bladder (CML), and Merkel cell cancers. Enhancement of the efficacy of anticancer treatments with oblimersen Bcl-2 antisense therapy represents a promising new apoptosis-modulating strategy, and ongoing clinical trials will test this therapeutic approach.

Topics: Animals; Apoptosis; Clinical Trials as Topic; Down-Regulation; Gene Expression; Genes, bcl-2; Humans; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides; Waldenstrom Macroglobulinemia

Oblimersen sodium is an antisense oligonucleotide to the first 6 codons of the B-cell leukemia gene 2 (bcl-2) open reading frame. It prevents the expression of the bcl-2 gene product and leads to apoptosis in cells that express Bcl-2. bcl-2 is one of the major apoptosis regulatory gene families and is found in a variety of low-grade B-cell non-Hodgkin's lymphomas. The in vitro use of oblimersen in Waldenstrom's macroglobulinemia (WM) cell line results in enhanced toxicity when exposed to fludarabine, dexamethasone, or rituximab. Oblimersen should also enhance the cytotoxic effect of chemotherapy in WM. Presented herein are early data on the phase I portion of a phase I/II study of oblimersen in WM to identify the maximum tolerated dose and to evaluate response in patients with symptomatic WM.

Topics: Aged; Aged, 80 and over; Apoptosis; Female; Genes, bcl-2; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Oligonucleotides, Antisense; Thionucleotides; Treatment Outcome; Waldenstrom Macroglobulinemia

Bcl-2 is an attractive target for anticancer therapy in a number of malignancies, as its expression is associated with inhibition of the apoptotic program and resistance to traditional therapeutic agents. Bcl-2 antisense therapy with G3139 (oblimersen sodium; Genasense, Genta Inc, Berkeley Heights, NJ) is in clinical trials for a number of malignancies, including an ongoing trial in myeloma. In vitro G3139 has been shown to downregulate Bcl-2 in myeloma cells, sensitizing them to chemotherapeutic agents. We have undertaken a project to evaluate antisense inhibition strategies in Waldenstrom's macroglobulinemia (WM), and whether the Bcl-2 pathway may provide a therapeutic target in this disease. We have shown that Bcl-2 is expressed in WM cells in vitro and that downregulation of Bcl-2 may be achieved by treatment with G3139. Treatment of WM cells with G3139 is associated with increased cell death and shows potential synergy with chemotherapeutic agents active in WM. Bcl-2 downregulation via G3139 antisense treatment may have potential anticancer efficacy in WM and further studies to address its effects on clinical specimens are warranted, in anticipation of using this agent in WM clinical trials.

Topics: Antineoplastic Agents; bcl-X Protein; Blotting, Western; Cell Line; Cell Survival; Down-Regulation; Drug Synergism; Gene Expression; Genes, bcl-2; Humans; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides; Transfection; Waldenstrom Macroglobulinemia