Experimental and Clinical Therapeutics

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

(PP109) Pathophysiological effects of antibodies to IGF-1R and VEGFR-2 plus fractionated radiation in DU145 prostate carcinoma xenografts.

Fenton, Bruce*,1, Paoni, Scott1, 1 Department of Radiation Oncology, Rochester, NY, USA

ABSTRACT- Introduction: Several recent reports have demonstrated that the specific scheduling of antiangiogenic strategies with conventional therapy (chemotherapy or radiotherapy) can be critical to ultimate therapeutic response. Our previous studies have shown that alternative antiangiogenic strategies can produce quite opposite effects on tumor oxygenation and blood flow in murine mammary tumors. DC101 (ImClone Systems Inc.), an antiangiogenic monoclonal antibody against vascular endothelial growth factor receptor-2, resulted in substantial tumor hypoxia, while endostatin instead improved tumor oxygenation. The current experiments were designed to determine the pathophysiological effects of both single and combined treatments, using either antiangiogenic strategies or fractionated radiotherapy. Methods: DU145 human prostate xenograft tumors in mice were treated with either: a) saline, b) DC101, c) 15 x 2 Gy daily radiation fractions, d) A12 (ImClone Systems Inc.), an antibody to insulin growth factor receptor-1, or e) the combination of A12 and DC101. Tumor volumes were measured 3 times weekly for 3 wks. Using automated image processing techniques combined with immunohistochemical staining, total and perfused blood vessels were quantified, and tumor hypoxia was estimated by EF5 hypoxia marker uptake. Results: In comparison to controls, all treatment regimens produced substantial growth delay, with maximal response following the DC101 and the DC101/A12. Total and perfused vessel counts decreased significantly following both DC101 and the DC101/A12 combination, while overall tumor hypoxia increased only for the combination. Conclusions: In view of the reduced blood flow and/or increased hypoxia following DC101 and the DC101/A12 combination, radiotherapy would be predicted to be more effective when administered prior to the initiation of the antiangiogenic therapy. Ongoing studies are comparing the effects of alternative scheduling (antiangiogenics given pre-, post-, or concurrently with fractionated radiation) to gauge the importance of the accompanying pathophysiological alterations in potentiating combined treatment response. Supported by DOD Grant PC040737.

Key words: antiangiogenesis, hypoxia, combination therapy

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2005 RRS