Morimoto M, Ashizawa T, Ohno H, Azuma M, Kobayashi E, Okabe M, Gomi K, Kono M, Saitoh Y, Kanda Y
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Cancer Res. 1991 Jan 1;51(1):110-5.
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.
通过对新型丝裂霉素C（MMC）衍生物的广泛研究，发现几种在N-7位带有二硫键的化合物对小鼠肉瘤180实体瘤显示出优于MMC的活性。其中，7-N-[[2-[[2-(γ-L-谷氨酰胺基)乙基]二硫基]乙基]]-丝裂霉素C（KW-2149）被选用于进一步评估其在小鼠体内的抗肿瘤活性和毒性。KW-2149在提高腹腔接种P388白血病、M5076肉瘤和B16黑色素瘤小鼠的存活率方面表现出优于MMC的活性。静脉注射KW-2149在抑制皮下接种的P388白血病、M5076肉瘤和结肠26腺癌的生长以及提高静脉接种P388白血病和M5076肉瘤小鼠的存活率方面也表现出优异的活性。此外，KW-2149显著延长了对MMC耐药的P388白血病和L1210白血病小鼠的寿命。KW-2149和MMC均抑制接种于裸鼠体内的人肿瘤的生长。KW-2149在人肺癌Lu-65和Lu-99、膀胱癌T24和表皮样癌A431中的活性尤为突出。KW-2149在外周血白细胞数量减少方面与MMC相当，且KW-2149诱导的血小板减少症较轻且恢复迅速。KW-2149对23种人肿瘤细胞系的体外抗癌谱与MMC相似。然而，KW-2149抑制细胞系生长的浓度比MMC低10至100倍，并对MMC不敏感的肿瘤细胞系显示出有效的细胞毒性。这些细胞系包括肺表皮样癌Calu-1、胃癌MKN-28、结肠腺癌DLD-1、结肠腺癌LoVo、膀胱癌HT-1197、肉瘤G-292和黑色素瘤SK-MEL-28细胞。这些结果表明，KW-2149作为一种新型抗癌药物具有引人关注的特性，值得进一步开发。
