Methyl(1S)-1-bromomethyl-7-methyl-5-[(4-methylpiperazinyl)-carb onyloxy]- 3-[(5,6,7-trimethoxy-2-indolyl)-carbonyl]-1,2-dihydro-3H-pyrolo[3, 2-e] indole-8-carboxylate 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.