title: Improved targeting of platinum chemotherapeutics. the antitumour activity of the HPMA copolymer platinum agent AP5280 in murine tumour models.
abstract: AP5280 is a novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound platinum (Pt) therapeutic designed to increase the therapeutic index relative to conventional, small-molecule platinum agents. The platinum-polymer construct accumulates in solid tumours on the basis of increased capillary permeability. The bound platinum moiety is present as an N,O-Pt chelate at the distal end of a tetrapeptide linker, glycine-phenylalanine-leucine-glycine, and the weight-average molecular weight (Mw) of the construct is 22 kDa. The antitumour activity and toxicity of AP5280 were assessed in the syngeneic murine B16F10 and Lewis lung tumour models, and in the human ovarian carcinoma 2008 and head and neck squamous carcinoma UMSCC10b xenograft models. The maximum tolerated dose (MTD) of AP5280 was 6-fold greater than that of carboplatin (CBDCA) in vivo. AP5280 was active in all four tumour models, and it displayed a higher therapeutic index than CBDCA in each of these tumour models. The antitumour effect of AP5280 given at 16% of its MTD was equivalent to that produced by a MTD of CBDCA. Thus, consistent with the design goal for this drug, and despite being less potent than CBDCA, AP5280 produced less systemic toxicity relative to its antitumour activity and thus has a greater therapeutic index. On the basis of the improved therapeutic index evidenced in these models, AP5280 has been advanced into clinical trials.
authors.affiliation: Department of Medicine and the Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0058, USA.
authors.forename: X
authors.initials: X
authors.lastname: Lin
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: J R
authors.initials: JR
authors.lastname: Rice
authors.forename: D R
authors.initials: DR
authors.lastname: Stewart
authors.forename: D P
authors.initials: DP
authors.lastname: Nowotnik
authors.forename: S B
authors.initials: SB
authors.lastname: Howell
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous; D014410:Tumor Stem Cell Assay
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; C438846:HPMA copolymer-platinate; D009944:Organoplatinum Compounds; D016190:Carboplatin