Cytotoxic activity of 7-N-(2-((2-(-γ-L-glutamylamino)-ethyl)dithio)ethyl)-mitomycin C and metabolites in cell lines with different resistance patterns

Abstract

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.