FK317 - A NOVEL SUBSTITUTED DIHYDROBENZOXAZINE WITH POTENT ANTITUMOR-ACTIVITY WHICH DOES NOT INDUCE VASCULAR LEAK SYNDROME

Purpose: FK973, a substituted dihydrobenzoxazine, is an antitumor anti biotic which has shown high therapeutic efficacy in a phase I study, b ut its development has been abandoned because of the side effect of va scular leak syndrome (VLS) in the clinical study. This study was perfo rmed to investigate whether or not FK317, a new benzmethoxy derivative of FK973, retains the antitumor activity of FK973 without the side ef fect of VLS. Methods: VLS was evaluated by the volume of pleural effus ion in rats. Cytotoxic activities were determined by a tetrazolium-bas ed colorimetric assay (MTT assay) against murine (B16, P388) and human (HeLa S3, KB) tumor cell lines. Antitumor activities against murine a scitic leukemia (P388: L1210), murine solid tumors (reticulum cell sar coma M5076, Colon 38 carcinoma) and human xenografts (mammary carcinom a MX-1, lung carcinoma LX-1) were examined. Results: FK973 (1.8 mg/kg) given i.v. to rats induced pleural effusion,, one of the elements of VLS, 36 days after the first dosing, but did not 28 days after dosing. This model reflects clinical VLS delayed-type effusion with high prot ein concentrations. In contrast, FK317 (1.0-3.2 mg/kg) did not induce pleural effusion at all. FK317 had stronger cytotoxic effects against in vitro cultured B16, P388, HeLa S3 and KB tumor cell lines, and in i n vivo experiments, FK317 showed equivalent antitumor activity against P388, M5076 and MX-1, and more potent antitumor activity against L121 0, Colon 38 and LX-1 compared with FK973. Conclusion: These results su ggest that FK317 retains the antitumor activity of FE973 and does not induce VLS, and FK317 is a drug with high clinical potential for treat ing tumors in humans.