Molecular Targeting of Apoptotic Pathways

Sunday, October 16, 2005 10:15 AM-12:00 PM Room No. 603
Chair(s): Milas, Luka

(SY005) Radiation enhancement using an antisense Bcl-2 strategy.

Mason, Kathy*,1, 1 Experimental Radiation Oncology/Division of Radiation Oncology, Houston, TX, USA

ABSTRACT- Dysregulated apoptosis with increased expression of anti-apoptotic molecules of the Bcl-2 family or loss of pro-apoptotic molecules such as Bax is a common occurrence in cancer thought to contribute to tumorigenesis and malignant progression. Ample evidence shows that imbalance in the ratio of anti- and pro-apoptotic Bcl-2 family members can skew cellular responses toward survival and render tumor cells resistant to a variety of death stimuli, including radiation. Bcl-2 blocks cell death induced by anti-cancer agents by preventing cellular damage from being efficiently translated into cell death (apoptosis). The manipulation of these genes and their signaling pathways offers the possibility of therapeutic intervention by a number of strategies, one of which is Bcl-2 antisense. In vitro and in vivo studies demonstrated that a phosphorothioate oligonucleotide complementary to the first 18 nucleotides of the Bcl-2 coding sequence (G3139, oblimersen sodium, Genasense) effectively down-regulates Bcl-2, and renders tumor cells more responsive to a variety of chemotherapeutic drugs. This treatment strategy has now been tested in combination with ionizing radiation. Recent pre-clinical in vitro studies have provided compelling evidence that G3139 can also sensitize a variety of human tumor cell lines to radiation and this approach has now been extended to in vivo studies. Using human tumor xenografts of known Bcl-2 status, it has been shown that only Bcl-2 positive tumors showed an increased response to radiotherapy when treated with G3139. Radiation enhancement factors on the order of 1.6 to 2.0 have been achieved. When fully developed, this treatment strategy specifically targeting the apoptotic pathway has potential to improve the efficacy of conventional cancer treatment modalities including both chemotherapy and radiotherapy. Supported by Aventis.

Key words: Bcl-2, antisense, radiation, apoptosis

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2005 RRS