Through the extensive investigation of new
mitomycin C (MMC) derivatives, several compounds with
disulfide at N-7 were found to show activities superior to MMC against murine
Sarcoma 180 solid
tumor. Among them, 7-N-[[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]]-
mitomycin C (KW-2149) was selected for further evaluation of antitumor activity and toxicity in mice.
KW-2149 exhibited activity superior to MMC in increasing survival of i.p. inoculated
P388 leukemia-, M5076
sarcoma-, and
B16 melanoma-bearing mice.
KW-2149 administered i.v. also exhibited superior activity in inhibiting the growth of s.c. inoculated
P388 leukemia, M5076
sarcoma, and colon 26
adenocarcinoma and in increasing survival of i.v. inoculated
P388 leukemia- and M5076
sarcoma-bearing mice. Furthermore,
KW-2149 remarkably increased the life span of MMC-resistant
P388 leukemia- and
L1210 leukemia-bearing mice.
KW-2149 and MMC inhibited the growth of human
tumors inoculated into nude mice. The activity of
KW-2149 was prominent in human lung
carcinoma Lu-65 and Lu-99, bladder
carcinoma T24, and
epidermoid carcinoma A431.
KW-2149 was comparable to MMC in decreasing the number of WBC in the peripheral blood, and the
thrombopenia induced by
KW-2149 was mild and recovery was rapid. The in vitro anticellular spectrum of
KW-2149 against 23 human tumor cell lines was similar to that of MMC. However,
KW-2149 inhibited the growth of the cell lines at concentrations of 10- to 100-fold lower than MMC and showed efficient cytotoxicity against MMC-insensitive tumor cell lines. These included lung
epidermoid carcinoma Calu-1, stomach
carcinoma MKN-28,
colon adenocarcinoma DLD-1,
colon adenocarcinoma LoVo, bladder
carcinoma HT-1197,
sarcoma G-292, and
melanoma SK-MEL-28 cells. These results indicate that
KW-2149 bears interesting characteristics as a new anticancer drug and warrants further development.