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Cellular Interaction and in Vitro Antitumor Activity of Mitomycin C-Dextran Conjugate¹

Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606 [S. M., A. Y., Y. T., M. H., H. S.], and Second Department of Surgery, Fukui Medical College, Fukui [N. T.], Japan

Cellular interaction and in vitro antitumor activity of a polymeric prodrug of mitomycin C (MMC), mitomycin C-dextran conjugate (MMC-D), were studied in relation to its physicochemical characteristics. MMC-D with cationic and anionic charges were examined. The cationic MMC-D was synthesized using a spacer, -aminocaproic acid and dextrans with molecular weights of 10,000, 70,000, or 500,000 [MMC(C6)D_cat]. The anionic MMC-D was synthesized using 6-bromohexanoic acid as a spacer and dextran with a molecular weight of 70,000 [MMC(C6)D_an].

Cellular adsorption was determined by measuring the concentration of the drug in the medium after incubation with three tumor cell lines, Ehrlich ascites carcinoma, L1210 leukemia, and AH66 ascites hepatoma cells. MMC(C6)D_cat was adsorbed more readily than MMC or MMC(C6)D_an on the tumor cell surface by an electrostatic force. The percentage of adsorption remained almost constant during the course of incubation and no significant difference was observed between the incubation at 4°C and that at 37°C. A corresponding increase in the amounts of MMC(C6)D_cat adsorbed on with higher molecular weights was noted, which conformed to Langmuir's adsorption isotherm.

In vitro antitumor activity was evaluated using L1210 and EAC cell culture systems and human tumor colony forming assay. MMC(C6)D_cat showed growth inhibition essentially equal to that of MMC in continuous drug exposure experiments. In a 1-h drug exposure experiment, MMC(C6)D_cat with a molecular weight of 70,000 or 500,000 was more active than MMC, and a good correlation was observed between the effects of MMC(C6)D_cat and the extent of cellular interaction.

These results show that cellular interaction played an important role in the manifestation of the antitumor effect of MMC-D and that these phenomena are governed by the physicochemical properties of macromolecular prodrugs, such as electric charge and molecular weight.

¹ Supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.

² To whom requests for reprints should be addressed.

Received 7/11/85. Revised 2/ 5/86. Accepted 5/19/86.

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