title: Macromolecular derivatives of N,N-di-(2-chloroethyl)-4-phenylene diamine mustard. 2. In vitro cytotoxicity and in vivo anticancer efficacy.
abstract: Prodrugs of N,N-di-(2-chloroethyl)-4-phenylene diamine (PDM) based on soluble poly[N5-(2-hydroxyethyl)-l-glutamine] (PHEG) have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with systemic liberation of free PDM. Modification of PDM by coupling via oligopeptide spacers onto a polymeric carrier significantly reduced its cytotoxicity towards different cell types in vitro. On the other hand, incubation of the cells with the PHEG-Gly-Phe-Ala-Leu-PDM conjugate in the presence of collagenase 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 conjugate, which is rapidly degraded by lysosomal and tumour-associated enzymes also showed a decreased systemic toxicity in vivo and could be administered 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 antitumour 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.
authors.affiliation: Department of Organic Chemistry, Polymer Materials Research Group, University of Gent, Krijgslaan 281 S4-bis, B-9000 Gent, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Soyez
authors.forename: L W
authors.initials: LW
authors.lastname: Seymour
authors.forename: E
authors.initials: E
authors.lastname: Schacht
mesh_terms: D000816:Aniline Mustard / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival; D017364:Collagenases / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D011355:Prodrugs; D014407:Tumor Cells, Cultured