title: Camptothecin-somatostatin conjugates inhibit the growth of small cell lung cancer cells.
abstract: The effects of camptothecin-somatostatin (CPT-SS) conjugates were investigated on small cell lung cancer (SCLC) cells. CPT was coupled to a SS agonist (SSA), c(Cys-Phe-DTrp-Lys-Thr-Cys)Thr-NH2 using the built in nucleophile assisted-releasing group (L1) N-methyl-aminoethyl-Gly-Dser-Nle-Dtyr-Dser or (L2) aminoethyl-Gly-Dser-Nle-Dtyr-Dser. The resulting CPT-L1-SSA and CPT-L2-SSA inhibited the specific binding of [125I-Tyr11]SS to NCI-H69 cell membranes with IC50 values of 0.2 and 2.1 nM, respectively. [125I]CPT-L1-SSA was internalized by SCLC cells at 37 degrees C but not at 4 degrees C. CPT-L1-SSA and CPT-L2-SSA inhibited in a dose-dependent manner the increase in adenylylcyclase activity caused by 25 microM forskolin. In vitro, 0.3 microM CPT-L1-SSA half-maximally inhibited the clonal growth of SCLC cells and 1 microM CPT-L1-SSA strongly inhibited 3H-thymidine incorporation into DNA and trypan-blue exclusion. These results suggest that CPT conjugated peptides such as CPT-L1-SSA may prove useful for exploring the efficacy of receptor-directed cytotoxicity to inhibit the proliferation of SCLC cells.
authors.affiliation: DHHS, NIH, NCI Office of the Director, CCR, 31 Center Drive, Bethesda, MD 20892, USA. moodyt@mail.nih.gov
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: Joseph
authors.initials: J
authors.lastname: Fuselier
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
authors.forename: Samuel
authors.initials: S
authors.lastname: Mantey
authors.forename: Tapas
authors.initials: T
authors.lastname: Pradhan
authors.forename: Tomoo
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Robert T
authors.initials: RT
authors.lastname: Jensen
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C060347:lanreotide; D005576:Colforsin; D013004:Somatostatin; D000262:Adenylyl Cyclases; D002166:Camptothecin