Summary
KW-2149, a new mitomycin C (MMC) derivative, inhibited the growth of murine P388 leukemia in vitro at 20-fold lower concentrations than those of MMC. KW-2149 was also effective in inhibiting the growth of MMC-resistant P388 (P388/MMC) cells. To elucidate these characteristics of KW-2149, its uptake and efflux were compared with those of MMC in MMC-sensitive and-resistant P388 cells. Both MMC and KW-2149 accumulated rapidly in P388 cells after incubation at the concentration of 0.47 and 0.024 μm, respectively, which were the IC50 values at 1-h exposure. Although this concentration of KW-2149 was 20 times lower than that of MMC, its intracellular concentration was little more than that of MMC, suggesting that KW-2149 accumulated in the cells quite efficiently. The accumulated KW-2149 in the cells after 1-h treatment remained for as long as 24 h after the incubation of the cells in drug-free medium, suggesting that most of the intracellular KW-2149 or MMC was bound to cellular components. The ratios of resistance of P388/MMC cells to MMC and KW-2149 were 34 and 8.8, respectively, at 1-h exposure, suggesting that P388/MMC cells were partially resistant to KW-2149 in vitro. P388/MMC cells also showed partial resistance to cisplatin, Adriamycin,m-AMSA, and etoposide. The accumulation of MMC in P388/MMC cells was lower than that in P388 cells, although the size of the former cells was almost equal to that of the latter. As a result, the amount of DNA-bound MMC was lower in P388/MMC cells than in P388 cells, suggesting its involvement in the mechanisms of MMC resistance in P388/MMC cells.
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Abbreviations
- m-AMSA:
-
4′-(9-acridinylamino)methanesulfon-m-aniside
- HPLC:
-
high-performance liquid chromatography
- IC50 :
-
concentration required for 50% growth inhibition
- MMC:
-
mitomycin C
- PFM:
-
porfiromycin
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Kobayashi, E., Okabe, M., Kono, M. et al. Comparison of uptake of mitomycin C and KW-2149 by murine P388 leukemia cells sensitive or resistant to mitomycin C. Cancer Chemother. Pharmacol. 32, 20–24 (1993). https://doi.org/10.1007/BF00685871
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DOI: https://doi.org/10.1007/BF00685871