SYNTHESIS AND EVALUATION OF MACROMOLECULAR PRODRUGS OF MITOMYCIN-C

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) prodrugs of the antitumou r antibiotic mitomycin C (MMC) were synthesised using peptidyl spacers , tri- and tetrapeptides, to link the drug to the macromolecular carri er. The relationship between the length and composition of the oligope ptide spacer and the rate of drug release was studied by incubation in buffers, serum and in the presence of enzymes (lysosomal enzymes and collagenase IV). It was observed that tetrapeptide-based conjugates ge nerally release MMC more effectively than tripeptide derivatives. Conj ugates having a terminal glycine in the spacer are less stable to hydr olysis than those with a terminal hydrophobic amino acid both in buffe r and in serum. The gly-phe-ala-leu conjugate released MMC very rapidl y in the presence of both lysosomal enzymes and collagenase IV. Biolog ical experiments indicate that PHEG-MMC conjugates act as prodrugs of MMC: cytotoxicity was observed after hydrolytic release of the active compound in vitro. In vivo studies of P388 solid tumour-bearing mice s uggest that conjugates which release MMC slowly may be more effective in inhibiting tumour growth and prolonging animal lifespan. Preliminar y in vivo bone marrow toxicity studies indicate that PHEG-MMC prodrugs are less myelosuppressive than free MMC.