We investigated the
hypoxia-dependent cytotoxicity of
AQ4N (
banoxantrone) using a panel of 13
cancer cell lines and studied its relationship to the expression of the
quinone reductase DT-diaphorase (NQO1), which is widely found in
cancer cells. We also investigated pharmacologic treatments that increase tumor hypoxia in vivo and their impact on
AQ4N chemosensitivity in a solid
tumor xenograft model.
AQ4N showed ≥ 8-fold higher cytotoxicity under
hypoxia than normoxia in cultures of 9L rat
gliosarcoma and H460 human
non-small-cell lung carcinoma cells but not for 11 other human
cancer cell lines.
DT-diaphorase protein levels and
AQ4N chemosensitivity were poorly correlated across the
cancer cell line panel, and
AQ4N chemosensitivity was not affected by
DT-diaphorase inhibitors. The
vasodilator hydralazine decreased
tumor perfusion and increased tumor hypoxia in 9L
tumor xenografts, and to a lesser extent in H460
tumor xenografts. However,
hydralazine did not increase AQ4N-dependent antitumor activity. Combination of
AQ4N with the
angiogenesis inhibitor axitinib, which increases 9L tumor hypoxia, transiently increased antitumor activity but with an increase in host toxicity. These findings indicate that the capacity to bioactivate
AQ4N is not dependent on
DT-diaphorase and is not widespread in cultured
cancer cell lines. Moreover, the activation of
AQ4N cytotoxicity in vivo requires tumor hypoxia that is more extensive or prolonged than can readily be achieved by vasodilation or by antiangiogenic
drug treatment.