In this study the activity of
KW-2149 and two of its metabolites,
M-16 and M-18, was measured against cell lines with different types of resistance. The influence of these metabolites and of the exposure time on the cytotoxic efficacy of
KW-2149 was investigated. Against the human ovarian
carcinoma cell lines, AOvC and A2780,
KW-2149 was more active than
mitomycin C (MMC), with an IC50 of, respectively, 3.4 nM and 9.82 microM for
KW-2149 and 18.2 nM and 67.71 microM for MMC. Activity of M-18 was significant against both cell lines and was comparable with that of
KW-2149. Against an MMC-resistant cell line, AOvCMMC, the resistance factor (RF) for
KW-2149 was 3.1 versus 8.0 for MMC. Tested against a
cisplatin-resistant cell line, AOvCCDDP,
KW-2149 had a RF of 7.7 versus 2.4 for MMC. Increasing the exposure time from 1 to 8 h decreased the RF for
KW-2149 from 7.7 to 3.0. In an MDR mediated resistant cell line, A2780mdr+, prolongation of exposure time increased RF for
KW-2149 and MMC but decreased RF for M-18 from 7.0 at 1 h to 5.3 at 8 h. Tested against a rat colon
carcinoma cell line CC531,
KW-2149 and M-18 again demonstrated superior or equal activity compared with MMC, IC50 being, respectively, 0.6, 2.1 and 2.6. Here again M-18 showed an aberrant sensitivity pattern, as its activity decreased with mdr-1 expression in contrast to the other
mitomycins. Our data confirm the activity of
KW-2149 as an agent with equal or superior activity as compared with MMC. It is concluded that the metabolite M-18 can contribute to the activity of
KW-2149. Efficacy of both
KW-2149 and its metabolites increases with increasing exposure times. The increments of exposure time appeared even as a means to overcome resistance in some instances.