FK317, a novel substituted dihydrobenzoxazine, exhibits potent antitumor activity against human tumor xenografts in nude mice

The antitumor effects of FK317, a novel substituted dihydrobenzoxazine, wer e evaluated using human tumor xenografts (small cell lung cancer, non-small cell lung cancer, stomach cancer, colon cancer, pancreatic cancer, breast cancer, cervical cancer and ovarian cancer). Tumor growth-inhibitory effect s and the effective dose-range of FK317 were much stronger and broader, res pectively, than those of reference drugs such as mitomycin C, adriamycin, c isplatin, taxol and irinotecan. Furthermore, the body weight decrease and m yelosuppression in FK317-treated mice were less than in the animals given a ny of the reference drugs. To explain this tumor selectivity, the distribut ion of FK317 was investigated after dosing tumor-bearing mice with the C-14 -labelled compound. The concentration of FK317 in tumor tissues was relativ ely low; and long tumor retention was not observed. However, thin-layer chr omatographic separation revealed that the radioactivity in the tumor reside d mainly in strongly cytotoxic metabolites, while that in other tissues res ided mainly in non-cytotoxic metabolites, These results suggest that FK317 shows strong antitumor activity without side effects, and one reason for th is is its specific metabolite pattern. FK317 is now undergoing phase I clin ical trials.