FK973, a new, substituted dihydrobenzoxazine (11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11- diazatetracyclo[7.4.1.0.0]tetra-deca-2,4,6-
trien-6,9-diyl diacetate), was obtained by chemical modification of a novel
antibiotic which was isolated from the fermentation products of Streptomyces sandaensis No. 6897.
FK973 had cytotoxic effects against in vitro cultured human and murine
tumor cells.
FK973 in doses of 0.032-5.6 mg/kg (i.p.) had stronger antitumor activities and higher chemotherapeutic ratio than
mitomycin C against such murine ascitic
tumors as P388 and
L1210 leukemia,
B16 melanoma, M5076
reticulum cell sarcoma of ovarian origin, Colon 26
carcinoma, Ehrlich
carcinoma, and MH134
hepatoma. In tests against murine and human solid
tumors implanted s.c. in normal mice and nude mice, respectively,
FK973 (i.v.) inhibited growth of murine
tumors (M5076
sarcoma, Colon 38
carcinoma,
B16 melanoma, and
Lewis lung carcinoma) by 66-100% and human
tumors (LX-1 lung, MX-1 mammary, and SC-6 stomach
carcinoma) by 84-99%. In studies with
drug-resistant
P388 leukemia,
FK973 was also effective against
vincristine-resistant P388, moderately effective against
mitomycin C (MMC)- and
adriamycin-resistant P388, and partially effective against
cyclophosphamide-resistant P388 cells in mice. Leukopenic effects of
FK973 and MMC in mice were comparable at doses which gave antitumor activity almost equally.
FK973 had no effect on the numbers of platelets and red blood cells, whereas MMC markedly decreased both.
FK973 decreased the numbers of colony forming units in spleen and in culture and the effect was less than that of MMC. Therefore,
FK973 may give weaker myelosuppression than MMC. The results suggest that
FK973 will be a beneficial
drug for the treatment of
cancer.