Cellular interaction and in vitro antitumor activity of lipophilic mitomycin C prodrugs.

Abstract

Cellular interaction and in vitro antitumor activities of lipophilic prodrugs of mitomycin C (MMC) were studied in order to clarify their mode of action. Five lipophilic derivatives with various lipophilic promoieties (benzylcarbonyl, benzyloxycarbonyl, pentyloxycarbonyl, nonyloxycarbonyl, and cholesteryloxycarbonyl groups) were tested. All the derivatives except for cholesteryloxycarbonyl MMC were converted to MMC in the supernatant of tumor cell homogenate.Lipophilic derivatives, especially nonyloxycarbonyl MMC and cholesteryloxycarbonyl MMC, associated with Ehrlich ascites carcinoma (EAC) cells more readily than MMC. While the association percentage remained almost constant during the course of incubation at 4 °C, it increased with incubation period at 37 °C, suggesting metabolic consumption of lipophilic derivatives in the tumor cells. Association percentages of derivatives at 4 °C were closely correlated to their partition coefficients between chloroform and water. The apparent distribution ratio of benzyloxycarbonyl MMC between EAC cells and the incubation medium also correlated with their volume ratio. These results suggested that lipophilic derivatives were incorporated into tumor cells through partition equilibrium between lipid components of tumor cells and the medium.In vitro antitumor activities of lipophilic MMC derivatives were studied using EAC and L1210 leukemia cell culture. In the continuous exposure experiment, lipophilic derivatives which were converted to MMC in tumor cells showed equal or somewhat lower growth inhibitory activity as compared with MMC. In the case of 1 h or 5 min exposure, nonyloxycarbonyl MMC was more active than MMC, indicating that the growth-inhibitory effects of lipophilic derivatives are closely related to both cellular interaction and conversion rate to MMC.