title: The development of VIP-ellipticine conjugates.
abstract: The mechanism by which vasoactive intestinal peptide (VIP)-ellipticine (E) conjugates are cytotoxic for human lung cancer cells was investigated. VIP-alanyl-leucyl-alanyl-leucyl-alanine (ALALA)-E and VIP-leucyl-alanyl-leucyl-alanine (LALA)-E inhibited (125)I-VIP binding to NCI-H1299 cells with an IC50 values of 0.5 and 0.1 microM, respectively. VIP-ALALA-E and VIP-LALA-E caused elevation of cAMP in NCI-H1299 cells with ED50 values of 0.7 and 0.1 microM. Radiolabeled VIP-LALA-E was internalized at 37 degrees C and delivered the cytotoxic E into NCI-H1299 cells. VIP-LALA-E inhibited the growth of NCI-H1299 cells in vitro. Three days after the addition of VIP-LALA-E to NCI-H1299 cells, cell viability decreased based on trypan blue exclusion and reduced 3H-thymidine uptake. These results suggest that VIP-E conjugates are internalized in lung cancer cells as a result of VPAC1 receptor-mediated endocytosis.
authors.affiliation: Department of Health and Human Services, NCI Office of the Director, CCR, Building 31, Room 3A34, 31 Center Drive, Bethesda, MD 20892, USA. moodyt@mail.nih.gov
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moody
authors.forename: Gregory
authors.initials: G
authors.lastname: Czerwinski
authors.forename: Nadia I
authors.initials: NI
authors.lastname: Tarasova
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Moody
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Michejda
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D004611:Ellipticines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004705:Endocytosis; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018005:Receptors, Vasoactive Intestinal Peptide / Q000819:agonists / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D013936:Thymidine / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C034192:ellipticine; D014660:Vasoactive Intestinal Peptide; D000242:Cyclic AMP; D013936:Thymidine