title: Development and activities of a new melphalan prodrug designed for tumor-selective activation.
abstract: The synthesis of C-Mel, a cephalosporin carbamate derivative of the clinically used alkylating agent melphalan, is described. C-Mel was designed as an anticancer nitrogen mustard prodrug that releases melphalan upon tumor-specific activation by targeted beta-lactamase (bL). The Km and kcat values for bL hydrolysis of C-Mel were 218 microM and 980 s(-1), respectively. In vitro cytotoxicity assays with 3677 human melanoma cells demonstrated that C-Mel was 40-fold less toxic than melphalan and was activated in an immunologically specific manner by L49-sFv-bL, a recombinant fusion protein that binds to the melanotransferrin antigen on melanomas and on some carcinomas. L49-sFv-bL in combination with C-Mel led to regressions and cures of established subcutaneous 3677 tumors in nude mice. The effects were significantly greater than those of melphalan, which did not result in any long-term regressions in this tumor model. The therapeutic effects were comparable to those obtained in mice treated with the previously described L49-sFv-bL/7-(4-carboxybutanamido)-cephalosporin mustard (CCM) combination. However, C-Mel may be more attractive than CCM for clinical development since the released drug is clinically approved.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Kerr
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: N O
authors.initials: NO
authors.lastname: Siemers
authors.forename: P D
authors.initials: PD
authors.lastname: Senter
authors.forename: V M
authors.initials: VM
authors.lastname: Vrudhula
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D018906:Antineoplastic Agents, Alkylating; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D008558:Melphalan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D011355:Prodrugs / Q000138:chemical synthesis*; D011993:Recombinant Fusion Proteins; D014407:Tumor Cells, Cultured; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D018906:Antineoplastic Agents, Alkylating; C112055:C-Mel; D002511:Cephalosporins; D000922:Immunotoxins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; D001618:beta-Lactamases; D008558:Melphalan