Abstract
L1210 mouse leukemia cell lines resistant to mitomycin C (MMC) were established by repeated continuous exposure of parental L1210 leukemia cells to MMC in vitro. The established cell lines showed 13-fold or more resistance to MMC compared with the parental cell line. A macromolecular prodrug of MMC, MMC-dextran conjugate with cationic charge (MMC-Dcat.), and lipophilic MMC prodrugs were assessed for ability to circumvent the resistance of tumor cells against MMC. Association of MMC and its prodrugs with resistant cell lines was similar to that with the parental cell line. Higher cellular association of drugs was observed with increase of the molecular weight of MMC-D and with increase of the partition coefficient of lipophilic MMC prodrugs.In vitro antitumor activities of MMC prodrugs against resistant cell lines were evaluated by determining cell number after cultivation for 3 or 4 d with the agents. In the continuous exposure experiment, the degrees of resistance to most prodrugs were almost the same as that to MMC. On the other hand, MMC-Dcat. showed higher activity against parental L1210 cells but lower activity against resistant cells than MMC in the 1 h exposure experiment. In the case of lipophilic MMC prodrugs, nonyloxycarbonyl MMC showed higher activity against both parental and resistant cells compared with MMC. The degree of resistance to nonyloxycarbonyl MMC was one-fifth of that to MMC. Thus, it may be possible to attack the drug-resistance problem by means of the prodrug approach.
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