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Characteristics of Antitumor Activity of KW-2189, a Novel Water-soluble Derivative of Duocarmycin, against Murine and Human Tumors

Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shimotogari 1188, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411 [E. K., A. O., M. A., M. O., K. G., T. H.] and Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Asahi-machi 3-6-6, Machida-shi, Tokyo 194 [S. N., A. A., H. S.], Japan

Methyl(1S)-1-bromomethyl-7-methyl-5-[(4-methylpiperazinyl)-carbonyloxy]-3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-8-carboxylate 3 hydrobromide (KW-2189), a novel derivative of duocarmycin B₂, was selected for extensive evaluation based on its improved antitumor activity, water solubility, and stability in the culture medium, as compared with duocarmycin B₂. Although the in vitro cell growth-inhibitory activity of KW-2189 was less potent than that of duocarmycin B₂, it significantly inhibited the growth of five murine solid tumors including Colon 26 adenocarcinoma, Colon 38 adenocarcinoma, and B16 melanoma in vivo. KW-2189 was also effective against murine P388 leukemia and L1210 leukemia not only by local administration (i.p.-i.p. system), but also by systemic administration (i.p.-i.v. or i.v.-i.v. system). The most remarkable feature of KW-2189 was its efficacy against various human xenografts, which was observed in 14 tumors among 16 tested tumors including drug-insensitive tumors by single i.v. administration. Tumor regression was observed in mice bearing LC-6 lung, St-4 and St-40 stomach, Li-7 liver, PAN-2 pancreas, and MX-1 breast carcinomas. In many cases, the activities of KW-2189 were more than those of clinically active agents, mitomycin C, Adriamycin, cisplatin, and cyclophosphamide. Delayed lethal toxicity, which was reported in mice treated with CC-1065 whose structure was similar to KW-2189, was not observed in mice treated with KW-2189. KW-2189 inhibited DNA synthesis more significantly than RNA or protein synthesis, although DNA strand breaks were not observed. KW-2189 was activated by porcine liver esterase, mouse liver homogenate or Hep G2 homogenate, and DU-86-DNA adducts were detected in KW-2189-treated HeLa S₃ cells, suggesting that KW-2189 was converted to DU-86 in the cells. These results indicate that KW-2189 is an interesting candidate for further development as a novel antitumor agent.

¹ Present address: Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shimotogari 1188, Nagaizumi-cho, Sunto-gun, Shizuoka-ken 411, Japan.

² To whom requests for reprints should be addressed.

Received 11/ 4/93. Accepted 2/23/94.

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