ABSTRACT
The pharmacokinetics and therapeutic effects of macromolecular prodrugs of mitomycin C (MMC), MMC-dextran conjugates (MMC-D) were studied after intratumoural injection in rats bearing Walker 256 carcinosarcoma. As the first step, the intratumoural disposition characteristics of these drugs were delineated in perfusion experiments employing a tissue-isolated tumour preparation. While MMC immediately disappeared from the tumour preparation following direct intratumoural injection, cationic and anionic MMC-D were retained in the tumour longer, demonstrating that the intratumoural clearance of MMC can be greatly retarded by dextran conjugation. The effect was more pronounced in the case of the cationic conjugate. Venous outflow data in the perfusion experiments were analyzed based on a compartment model in which the tumour tissue was assumed to consist of two compartments, one well- and the other poorly-perfused. The pharmacokinetic analysis revealed that macromolecular conjugation reduced elimination of MMC from the poorly-perfused region rather than well-perfused region. Simulation of conjugated and free MMC levels in the tissue using the calculated parameters clearly showed that intratumoural injection of MMC-D, especially the cationic form, can maintain a certain level of active free MMC in the tissue for a much longer time period. The long retention of cationic MMC-D in tumour after intratumoural injection was also confirmed by an in vivo pharmacokinetic study and whole body autoradiography in rats bearing subcutaneous Walker 256 carcinosarcoma. In addition, superior antitumour activity of cationic MMC-D was observed against subcutaneous tumours after intratumoural injection. Together with the finding that MMC is selectively toxic to hypoxic tumour cells at low concentrations, these pharmacokinetic studies strongly support the therapeutic efficacy of the macromolecular prodrugs.
