Antitumor activity and toxicity in animals of N-7[2-(4-nitrophenyldithio) ethyl] mitomycin C (BMY-25067).
BMY-25067, N-7[2-(4-nitrophenyldithio)-ethyl] mitomycin C was selected from a number of disulfide derivatives of the highly active compound RR150, N-7(thioethyl) mitomycin C for further study. BMY-25067 had tumor inhibitory effects equivalent to mitomycin C (MMC) against ascitic P388 and L1210 leukemias and M109 lung carcinoma in mice with i.p. treatment. However, it demonstrated superior activity against B16 melanoma with a high percentage of cures when both tumors and drug were given i.p. Additionally, in separate tests against B16 melanoma implanted s.c. with treatment i.v., BMY-25067 was also consistently superior to MMC. This activity was observed when therapy was initiated either one day post-tumor implant or delayed until the ninth day post-tumor implant. Slight activity was seen against a line of L1210 partially resistant to MMC and none against a line of P388 completely resistant to MMC. Against s.c. M109, BMY-25067 inhibited tumor growth but did not prolong survival with the treatment schedule used. At their respective maximum non-lethal doses in mice, BMY-25067 was less neutropenic than MMC. This was confirmed in ferrets which were also examined for the compound's effects on platelets. BMY-25067 appeared to have much less effect on platelets than MMC; the nadir for BMY-25067 was 3.8 x 10(5) platelets/cmm compared to 7 x 10(4) platelets/cmm for MMC when the drugs were compared at a dose ratio of 2:1, BMY-25067:MMC (determined to represent their relative potencies). This initial evidence of superior antitumor effectiveness particularly to a solid tumor separated from site of treatment and reduced hematologic toxicity suggest that BMY-25067 may be a worthwhile candidate for clinical trial.
Bradner
W T
WT
Pharmaceutical Research and Development Division, Bristol-Myers Company, Syracuse, New York 13221-4755.
Rose
W C
WC
Schurig
J E
JE
Florczyk
A P
AP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D005260:Female; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016685:Mitomycin; D008937:Mitomycins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D008937:Mitomycins; D016685:Mitomycin; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C