Macromolecular derivatives of N,N-di-(2-chloroethyl)-4-phenylene diamine mustard. 2. In vitro cytotoxicity and in vivo anticancer efficacy

Prodrugs of N,N-di-(2-chloroethyl)-4-phenylene diamine (PDM) based on solub le poly[N-5-(2-hydroxyethyl)-L-glutamine] (PHEG) have been evaluated as tum our-targeted drugs. These materials an designed to exploit the enhanced per meability of tumour vasculature, combining a passive tumour tropism with sy stemic liberation of free PDM. Modification of PDM by coupling via oligopep tide spacers onto a polymeric carrier significantly reduced its cytotoxicit y towards different cell types in vitro. On the other hand, incubation of t he cells with the PHEG-Gly-Phe-Ala-Leu-PDM conjugate in the presence of col lagenase IV led to the release of lethal amounts of free drug, resulting in higher cytotoxicity for this derivative. The PHEG-Gly-Phe-Ala-Leu-PDM conj ugate, which is rapidly degraded by lysosomal and tumour-associated enzymes also showed a decreased systemic toxicity in vivo and could be administere d at a dose of 8 mg PDM/kg body weight intravenously, compared with just 2 mg/kg for free PDM. Furthermore, this derivative also showed better antitum our activity against a C26 colorectal carcinoma tumour model, compared with no activity for the free drug. The results indicate that the PHEG-Gly-Phe- Ala-Leu-PDM conjugate is a promising candidate for cancer treatment. (C) 19 99 Elsevier Science B.V. All rights reserved.