Enhancement of the antitumor effect of flavone acetic acid by the bioreductive cytotoxic drug SR 4233 in a murine carcinoma.

Flavone acetic acid (FAA, NSC 347512) is a new anticancer drug currently undergoing clinical investigation. Although the precise mechanism for its broad spectrum of activity against transplanted murine solid tumors is unknown, it has been reported that FAA reduces tumor blood flow and produces hemorrhagic necrosis. We have confirmed this finding with the murine transplanted carcinoma SCCVII: 200 mg/kg FAA reduced tumor blood flow to 20-30% of normal for 1-2 days as determined by rubidium 86 extraction. In an attempt to exploit the tumor hypoxia produced by FAA, we have combined it with the novel bioreductive drug SR 4233, a benzotriazine dioxide with high selective toxicity for hypoxic cells. Marked enhancement of the antitumor effect of FAA (200 mg/kg) was observed when it was combined with SR 4233 (0.1 and 0.2 mmol/kg). This was seen using tumor cell survival, regrowth delay, and histological endpoints, with the best results obtained when the two agents were injected simultaneously. These data suggest that targeting bioreductive cytotoxic agents to tumors by producing tumor hypoxia may be a valid way of increasing the tumor cell killing of these agents.