PHARMACOKINETIC CHARACTERISTICS AND THERAPEUTIC EFFECTS OF MITOMYCIN-C DEXTRAN CONJUGATES AFTER INTRATUMORAL INJECTION

The pharmacokinetics and therapeutic effects of macromolecular prodrug s of mitomycin C (MMC), MMC-dextran conjugates (MMC-D) were studied af ter intratumoural injection in rats bearing Walker 256 carcinosarcoma. As the first step, the intratumoural disposition characteristics of t hese drugs were delineated in perfusion experiments employing a tissue -isolated tumour preparation. While MMC immediately disappeared from t he tumour preparation following direct intratumoural injection, cation ic and anionic MMC-D were retained in the tumour longer, demonstrating that the intratumoural clearance of MMC can be greatly retarded by de xtran conjugation. The effect was more pronounced in the case of the c ationic conjugate, Venous outflow data in the perfusion experiments we re analyzed based on a compartment model in which the tumour tissue wa s assumed to consist of two compartments, one well- and the other poor ly-perfused. The pharmacokinetic analysis revealed that macromolecular conjugation reduced elimination of MMC from the poorly-perfused regio n rather than well-perfused region, Simulation of conjugated and free MMC levels in the tissue using the calculated parameters clearly showe d that intratumoural injection of MMC-D, especially the cationic form, can maintain a certain level of active free MMC in the tissue for a m uch longer time period. The long retention of cationic MMC-D in tumour after intratumoural injection was also confirmed by an in vivo pharma cokinetic study and whole body autoradiography in rats bearing subcuta neous Walker 256 carcinosarcoma. In addition, superior antitumour acti vity of cationic MMC-D was observed against subcutaneous rumours after intratumoural injection. Together with the finding that MMC is select ively toxic to hypoxic tumour cells at low concentrations, these pharm acokinetic studies strongly support the therapeutic efficacy of the ma cromolecular prodrugs. (C) 1998 Elsevier Science B.V.