oblimersen and Multiple-Myeloma

Bcl-2 is an apoptosis regulating protein, overexpression of which is associated with chemotherapy resistant disease, aggressive clinical course, and poor survival in patients with B-cell lymphoproliferative disorders. Overexpression of Bcl-2 protein results in an aberrant intrinsic apoptotic pathway that confers a protective effect on malignant cells against a death signal (e.g., chemotherapy or radiotherapy). Downregulation of this oncoprotein, thus, represents a possible new way to target clinically aggressive disease. Preclinical studies have shown that this oncoprotein can be effectively decreased by Bcl-2 antisense in malignant lymphoid cells and can reverse chemotherapy resistance, as well as enhance the anti-apoptotic potential of both chemotherapeutic and biologic agents. Ongoing clinical trials are exploring the role of Bcl-2 downregulation with oblimersen (Bcl-2 antisense) in patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma. Early results from these studies are promising and support the proof of the principle. As these studies are completed and mature data emerges, the role of Bcl-2 antisense therapy in the treatment of B-cell malignancies will become clearer.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Leukemia; Lymphoma, B-Cell; Multiple Myeloma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; Thionucleotides

Most malignant plasma cells overexpress Bcl-2, which contributes to resistance against apoptosis induced by dexamethasone and other anticancer agents. Oblimersen sodium (Genasense, previously known as G3139), an antisense oligonucleotide that specifically binds to bcl-2 messenger RNA, decreases production of Bcl-2 protein in both human myeloma cell lines, as well as in ex vivo purified myeloma cells, and enhances the cytotoxicity of dexamethasone and doxorubicin. Combining oblimersen with other anticancer agents represents a therapy-enhancing strategy to reverse the multidrug resistance seen in multiple myeloma (MM). Phase II trials are evaluating the potential role of oblimersen in reversing resistance to standard therapies. Preliminary results from these trials in patients with refractory or relapsed MM indicate that the combination of oblimersen with dexamethasone/thalidomide (Thalomid) or vincristine/doxorubicin/dexamethasone is active and well tolerated and that oblimersen may help overcome chemotherapy resistance and restore sensitivity to MM cells. A randomized phase III clinical trial comparing dexamethasone plus oblimersen with dexamethasone alone in patients with relapsed or refractory myeloma has completed enrollment, with results expected to be available in 2004. Future studies will focus on the role of oblimersen in combination with novel biologic agents such as bortezomib (Velcade).

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dexamethasone; Doxorubicin; Humans; Multiple Myeloma; Oligonucleotides, Antisense; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides; Treatment Outcome

An increasing number of unique active new chemotherapeutic and biologic agents are currently available for clinical research studies. Nucleoside analogs in development for non-Hodgkin's lymphoma (NHL) include clofarabine, troxacitabine, and bendamustine, a hybrid of an alkylating nitrogen mustard group and a purine-like benzimidazole, with demonstrated activity in NHL. Drugs directed at the cell cycle include flavopiridol and UCN-01. The proteasome plays a pivotal role in cellular protein regulation and activation of NFkappaB, which maintains cell viability through the transcription of inhibitors of apoptosis. PS-341 is a specific, selective inhibitor of the 26S proteasome which induces apoptosis and has activity in cell types characterized by overexpression of Bcl-2. Response rates of 50%, including complete remissions, have been reported using this agent in patients with refractory multiple myeloma. Studies are ongoing in NHL and chronic lymphocytic leukemia. G3139, an antisense oligonucleotide, has shown promise in early studies. Rituximab has revolutionized the treatment of NHL. However, other active antibodies are now available, including alemtuzumab, epratuzumab, and Hu1D10. The radioimmunoconjugates (90)Y-ibritumomab tiuxetan and (131)I-tositumomab may also play an important role in the management of NHL. Future therapeutic strategies should involve rational combinations of new chemotherapy drugs, biologic agents, and antisense compounds to increase the cure rate in patients with lymphoma.

Topics: Adenine Nucleotides; Alemtuzumab; Alkaloids; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antibodies, Neoplasm; Antineoplastic Agents; Apoptosis; Arabinonucleosides; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cell Cycle; Cell Survival; Clofarabine; Cytosine; Dioxolanes; Flavonoids; Hematologic Neoplasms; Humans; Immunoconjugates; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoma, Non-Hodgkin; Multiple Myeloma; NF-kappa B; Nitrogen Mustard Compounds; Oligonucleotides, Antisense; Peptide Hydrolases; Piperidines; Protease Inhibitors; Proteasome Endopeptidase Complex; Pyrazines; Remission Induction; Rituximab; Staurosporine; Thionucleotides

Upregulation of the Bcl-2 antiapoptotic protein is reported to be associated with aggressive clinical course in multiple myeloma. Oblimersen sodium is a bcl-2 antisense oligonucleotide complementary to the first six codons of the open-reading frame of bcl-2 mRNA that can decrease transcription of Bcl-2 protein and increase myeloma cell susceptibility to cytotoxic agents. In this phase III randomised trial, we investigated in patients with relapsed/refractory myeloma whether addition of oblimersen to dexamethasone improved clinical outcomes vs. dexamethasone alone. Two hundred and twenty-four patients were randomised to receive either oblimersen/dexamethasone (N = 110) or dexamethasone alone (N = 114). The primary endpoint was time to tumor progression (TTP). Final results of this study demonstrated no significant differences between the two groups in TTP or objective response rate. The oblimersen/dexamethasone regimen was generally well tolerated with fatigue, fever and nausea, the most common adverse events reported.

Topics: Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Administration Schedule; Fatigue; Female; Fever; Humans; Male; Middle Aged; Multiple Myeloma; Nausea; Oligonucleotides, Antisense; Thionucleotides; Treatment Outcome

Bcl-2 regulates the mitochondrial apoptosis pathway that promotes chemotherapy resistance. Bcl-2 antisense oligonucleotide, G3139, targets Bcl-2 mRNA.. G3139 was administered (3 to 7 mg/kg/d for 7 days) by continuous intravenous infusion. On day 4, patients started thalidomide (100 to 400 mg as tolerated) and dexamethasone (40 mg daily for 4 days) on 21-day cycles for three cycles. Stable and responding patients continued on 35-day cycles for 2 years.. Thirty-three patients (median age, 60 years; range, 28 to 76 years) received 220 cycles. Patients received a median of three prior regimens including thalidomide (n = 15) and stem-cell transplantation (n = 31). The regimen was well tolerated; the median number of cycles per patient was eight (range, one to 16+ cycles). Toxicities included reversible increase in creatinine, thrombocytopenia, neutropenia, fatigue, anorexia, constipation, fever, neuropathy, edema, electrolyte disturbances, and hyperglycemia. Fifty-five percent of patients had objective responses, including two complete responses (CRs), four near CRs (positive immunofixation), and 12 partial responses; six patients had minimal responses (MRs). Of patients who received prior thalidomide, seven had objective responses, and three had MRs. The median duration of response was 13 months, and estimated progression-free and overall survival times were 12 and 17.4 months, respectively. Responding patients had significant increase in polyclonal immunoglobulin M (P = .005), indicating innate immune system activation. Western blot analysis of Bcl-2 protein isolated from myeloma cells before and after G3139 demonstrated a decrease of Bcl-2 levels in three of seven patients compared with six of nine patients using reverse transcriptase polymerase chain reaction.. G3139, dexamethasone, and thalidomide are well tolerated and result in encouraging clinical responses in relapsed multiple myeloma patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Dexamethasone; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Multiple Myeloma; Oligonucleotides, Antisense; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; Stem Cell Transplantation; Survival Analysis; Thalidomide; Thionucleotides; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma; Oligonucleotides, Antisense; Thionucleotides; Treatment Outcome

An antisense oligodeoxynucleotide (ODN) complementary to the first six codons of the Bcl-2 mRNA, G3139 (oblimersen sodium; Genasense), has been shown to downregulate Bcl-2 and produce responses in a variety of malignancies including drug-resistant lymphoma. Incubation of ex vivo purified plasma cells from patients with multiple myeloma (MM) with carboxyfluorescein (FAM)-labeled antisense ODNs resulted in a time- and dose-dependent uptake in the cytoplasm and nucleus. No major differences in uptake of Bcl-2 antisense ODNs were observed among patients' samples. Incubation of purified myeloma plasma cells with G3139, but not solvent or reverse polarity control ODNs, resulted in a reduction (>75%) of Bcl-2 mRNA levels after 2 and 4 days, as measured by Real-Time PCR. Treatment with G3139 led to a sequence-specific reduction of Bcl-2 protein levels within 4 days of exposure in 10 out of 11 clinical samples from patients with chemosensitive and multidrug-resistant disease, without significant reduction of alpha-Actin, Bax, Bcl-XL, or Mcl-1 proteins. This resulted in a significantly enhanced sensitivity of the myeloma tumor cells to dexamethasone or doxorubicin-induced apoptosis. G3139 can consistently enter myeloma cells, downregulate the expression of Bcl-2, and enhance the efficacy of myeloma therapy. These data support further clinical evaluation of G3139 therapy in multiple myeloma.

Topics: Aged; Annexin A5; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Blotting, Western; Bone Marrow; Dexamethasone; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Oligonucleotides, Antisense; Plasma Cells; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Thionucleotides; Vincristine