title: An adjustable release rate linking strategy for cytotoxin-peptide conjugates.
abstract: Peptide hormones are often rapidly internalized after binding to and activation of their receptors which are sometimes over-expressed on tumor cells. Thus, peptide ligands are increasingly being utilized for specific tumor cell targeting and internalization of radioactive isotopes for tumor imaging and for specifically delivering and internalizing cytotoxic moieties. Here, we describe a new carbamate linker system containing a series of built-in nucleophile assisted releasing (BINAR) groups which enable the 'fine-tuning' of intracellular cleavage rates of free cytotoxic agents containing reactive OH groups. Release rates were found to fit well with the chemical model and several conjugates of camptothecin and one of combretastatin were shown to have potent cytotoxic effects on cultures of human neuroblastoma IMR-32 cells which over-express somatostatin receptors.
authors.affiliation: Peptide Research Laboratories, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA. fuselier@tulane.edu
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fuselier
authors.forename: Lichun
authors.initials: L
authors.lastname: Sun
authors.forename: S Nathaniel
authors.initials: SN
authors.lastname: Woltering
authors.forename: William A
authors.initials: WA
authors.lastname: Murphy
authors.forename: Natalya
authors.initials: N
authors.lastname: Vasilevich
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001632:Bibenzyls / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002166:Camptothecin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives; D013267:Stilbenes; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D002219:Carbamates; D003432:Cross-Linking Reagents; D010455:Peptides; D013267:Stilbenes; D013004:Somatostatin; C040105:combretastatin; D002166:Camptothecin