Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP196) In vivo interaction of single dose radiation with G3139, a Bcl-2 antisense oligonucleotide.

Wiedenmann, Nicole*,1, 2, Neal, Robert1, Hunter, Nancy1, Raju, Uma1, Milas, Luka1, Mason, Kathy1, 1 Department of Experimental Radiation Oncology, Houston, TX, USA2 Department of Radiation Oncology, Munich, D, Germany

ABSTRACT- Bcl-2-overexpression has been found in many cancer types and has been associated with increased resistance to apoptotic stimuli such as radiation or chemotherapy. Bcl-2 antisense treatment combined with radiatiotherapy is a novel experimental approach to specifically counteract Bcl-2 mediated radiation resistance and to potentiate efficacy of treatment. The aim of this study was to investigate in vivo anti-tumor effects of a combined modality treatment scheme consisting of radiation and the Bcl-2 targeted antisense oligonucleotide G3139 (Oblimersen Sodium). Bcl-2 and Bax expression of two human colon carcinoma cell lines (SW-620 and HT-29) was assessed by Western blot analysis in vitro. Pronounced Bcl-2 expression was found in SW-620 but not in HT-29 cells, while Bax was equally expressed by both cell lines. To test for anti-tumor effects in vivo, both cell lines were grown as xenografts in nude mice. Treatment with G3139 (5mg/kg ip) was initiated when tumors grew to 6mm diameter and continued for 14 consecutive days. Tumors were irradiated with a single dose of 15 Gy after progression to 8mm in diameter. Treatment endpoint was time to grow from 8mm to12mm diameter. G3139 alone delayed tumor growth of the Bcl-2 negative tumor HT-29 for 2.8 days whereas a growth delay of 6.6 days was observed for the Bcl-2-overexpressing SW-620 tumor. G3139 combined with radiation clearly enhanced radioresponse of SW-620 tumors (EF=1.6), while it did not enhance radioresponse of HT-29 tumors (EF=1.0). To clarify the mechanisms underlying the anti-tumor efficacy of G3139, its reverse sequence analog, G3622, was also tested. Neither G3622 alone nor G3622 combined with radiation enhanced anti-tumor efficacy of the Sw-620 tumor. These findings suggest a nucleotide sequence-specific and Bcl-2 expression-dependent effect of G3139 for the cell lines examined. To further investigate the curative potential of G3139, a TCD50 assay was initiated using a range of single doses (20 to 60 Gy). A DMF will be calculated at 120 days (currently day 60). In conclusion, G3139 strongly potentiated the single dose radiation response of the Bcl-2 over-expressing SW-620 human colon cancer xenograft. These positive results warrant further investigation in combination with more clinically relevant dose fractionation schemes. ( Supported by Aventis )

Key words: g3139, oblimersen sodium, bcl-2

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2005 RRS