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Antitumor Activity of 7-N-{{2-{[2-(-L-Glutamylamino)ethyl]dithio}ethyl}}-mitomycin C

Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka [M. M., T. A., H. O., M. A., E. K., M. O., K. G., M. Ko., H. A., M. Ka.]; Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Tokyo [Y. S., Y. K., A. S.]; Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo [T. T.]; and Institute of Applied Microbiology, University of Tokyo, Yayoi, Bunkyo, Tokyo [T. T.], Japan

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-(-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.

¹ To whom requests for reprints should be addressed, at Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shimotogari 1188, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411, Japan.

Received 6/29/90. Accepted 10/ 4/90.