Abstract 1379: Impact of tumor blood flow modulation on sensitivity of 9L gliosarcoma xenografts to the bioreductive drug, AQ4N

Abstract

Abstract The bioreductive drug AQ4N is reduced enzymatically under hypoxic conditions to yield AQ4, a cytotoxic metabolite and topoisomerase II inhibitor. This study tests the hypothesis that the two electron reductase DT-diaphorase (NQO1) contributes to AQ4N reduction and that modulation of tumor hypoxia increases AQ4N activity in vivo. A panel of human and rodent tumor cells was assayed for AQ4N sensitivity under normoxic and hypoxic conditions (0.1% O2 for 24 hr), followed by 3 days culture under normoxia without drug. 9L rat gliosarcoma and H460 lung carcinoma, but not 10 other tumor cell lines, exhibited substantially higher (≥ 8 fold) AQ4N sensitivity under hypoxic culture conditions. Investigation of the impact of the DT-diaphorase inhibitors dicumarol and flavone-8-acetic acid on AQ4N cytotoxicity and examination of the cell line dependence of DT-diaphorase protein expression indicated that this enzyme does not contribute to AQ4N cytotoxicity. Next, we investigated whether AQ4N chemosensitivity could be increased by modulating tumor hypoxia in s.c. 9L and H460 tumors implanted in immunodeficient mice. In mice treated with the vasodilator hydralazine, tumor hypoxia was significantly increased in 9L, but not H460 tumors, as determined by pimonidazole staining. Hydralazine also decreased tumor perfusion to a greater extent in 9L tumors than H460 tumors, as judged by uptake of Hoechst 33342. However, hydralazine-induced 9L tumor hypoxia did not increase AQ4N mediated tumor growth delay, in either scid or nude mouse models. Furthermore, combination of AQ4N treatment with inhibition of VEGF receptor-dependent angiogenesis, which increases tumor hypoxia in 9L xenografts, did not augment anti-tumor activity beyond that of VEGF receptor inhibition alone. These findings suggest that the enhancement of AQ4N cytotoxicity in these tumors requires a level of tumor hypoxia that is more extensive or prolonged that can be achieved using these vasodilators and anti-angiogenic agents. Supported in part by NIH grant CA49248 (to D.J.W.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1379.