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      Oblimersen for the treatment of patients with chronic lymphocytic leukemia

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          Abstract

          Among adults in Western countries, chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia. CLL primarily affects the elderly and may be associated with multiple comorbidities. A cure has not been identified, and new treatment options are needed. Expression of Bcl-2 protein is associated with the pathogenesis of CLL and chemotherapy resistance. Oblimersen, a Bcl-2 antisense phosphorothioate oligonucleotide, is being evaluated in patients with CLL and other cancers; trials through Phase III have been completed. In the setting of relapsed/refractory CLL, single-agent oblimersen demonstrates modest activity, whereas the addition of oblimersen to fludarabine/cyclophosphamide significantly improves the rate of complete and nodular partial responses; moreover, these responses are durable and associated with clinical benefit. Oblimersen is more efficacious in relapsed rather than refractory patients. The side effect profile of oblimersen, alone or in combination with standard chemotherapy, is favorable compared with currently available chemotherapies. In the first cycle, an infusion reaction with or without tumor lysis syndrome is uncommon, and transient thrombocytopenia is observed. Catheter-related complications are associated with the need for continuous intravenous infusion of oblimersen over several days; other routes of administration are under clinical investigation. Oblimersen is a promising therapeutic approach for patients with relapsed CLL and should be further evaluated in the front-line setting.

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          Most cited references 64

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          Cancer statistics, 2007.

          Each year, the American Cancer Society (ACS) estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. This report considers incidence data through 2003 and mortality data through 2004. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,444,920 new cancer cases and 559,650 deaths for cancers are projected to occur in the United States in 2007. Notable trends in cancer incidence and mortality rates include stabilization of the age-standardized, delay-adjusted incidence rates for all cancers combined in men from 1995 through 2003; a continuing increase in the incidence rate by 0.3% per year in women; and a 13.6% total decrease in age-standardized cancer death rates among men and women combined between 1991 and 2004. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. While the absolute number of cancer deaths decreased for the second consecutive year in the United States (by more than 3,000 from 2003 to 2004) and much progress has been made in reducing mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.
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            BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis.

            Critical issues in apoptosis include the importance of caspases versus organelle dysfunction, dominance of anti- versus proapoptotic BCL-2 members, and whether commitment occurs upstream or downstream of mitochondria. Here, we show cells deficient for the downstream effectors Apaf-1, Caspase-9, or Caspase-3 display only transient protection from "BH3 domain-only" molecules and die a caspase-independent death by mitochondrial dysfunction. Cells with an upstream defect, lacking "multidomain" BAX, BAK demonstrate long-term resistance to all BH3 domain-only members, including BAD, BIM, and NOXA. Comparison of wild-type versus mutant BCL-2, BCL-X(L) indicates these antiapoptotics sequester BH3 domain-only molecules in stable mitochondrial complexes, preventing the activation of BAX, BAK. Thus, in mammals, BH3 domain-only molecules activate multidomain proapoptotic members to trigger a mitochondrial pathway, which both releases cytochrome c to activate caspases and initiates caspase-independent mitochondrial dysfunction.
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              National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment.

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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                October 2007
                October 2007
                : 3
                : 5
                : 855-870
                Affiliations
                Georgetown University Hospital, The Lombardi Comprehensive Cancer Center Washington, DC, USA
                Author notes
                Correspondence: Bruce D Cheson Professor of Medicine, Head of Hematology, Georgetown University Hospital, Lombardi Comprehensive Cancer Center, 3800 Reservoir Road, NW, Washington, DC 20007, USA Tel +1 202 444 7932 Fax +1 202 444 1229 Email bdc4@ 123456georgetown.edu
                Article
                2376092
                18473009
                © 2007 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                chronic lymphocytic leukemia, genasense®, oblimersen, g3139, bcl-2 antisense

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