BMY-25282, 7-N-(dimethylamino methylene)mitomycin C, is one of a novel series of amidino
mitomycin derivatives. Some of these were discovered as intermediates in a synthetic program being conducted to find improved procedures for modifying the structure of
mitomycin C (MMC). Markedly superior in vivo antitumor effects have been observed with
BMY-25282 compared to MMC in initial tests against i.p.-implanted
P388 leukemia and
B16 melanoma. When administered i.v. to mice bearing s.c.
B16 melanoma,
BMY-25282 was also superior to MMC. The derivative was fully active against a line of
L1210 leukemia which was partially resistant to MMC treatment but had little or no activity against a line of L1210 fully resistant to MMC. It is also 2 to 4 times more potent than MMC based on a comparison of doses required to achieve optimum antitumor effects. The superior antitumor efficacy of
BMY-25282 over MMC against both i.p. and s.c.
B16 melanoma was maintained when the
drug was given in
pluronic acid formulation. Against P-388
leukemia, however, the efficacy of the drugs was equivalent when
BMY-25282 was administered in the
pluronic vehicle. In an in vitro clonogenic assay involving freshly explanted human
tumors,
BMY-25282 was consistently more potent in cytotoxic effects than MMC. With human
colorectal carcinoma samples,
BMY-25282 was 13.8 times more potent than MMC. The i.v. 50% lethal dose values of
BMY-25282 and MMC in C57BL/6 X DBA/2 F1 mice were 2.1 mg/kg and 8.6 mg/kg, respectively. Leukopenic effects of the drugs in mice were comparable at doses up to their respective 50% lethal dose values. Hematology studies in ferrets revealed a similar pattern of depression and recovery of lymphocytes, neutrophils, and platelets for
BMY-25282 and MMC; however, with
BMY-25282 there was earlier recovery of platelet counts.
BMY-25282 is being further developed toward possible clinical trial.