title: Antitumor effects of radioiodinated antisense oligonuclide mediated by VIP receptor.
abstract: A 15-mer phosphorothioate antisense oligonuclide (ASON) complementary to the translation start region of the C-myc oncogene mRNA was radioiodinated to enhance its antitumor activity, and vasoactive intestinal peptide bound covalently polylysine (VIP-polylysine) was used as a carrier to deliver the oligonucleotide into VIP receptor-positive tumor cells. The antitumor activity of radioiodinated ASON conjugated to VIP-polylysine(VIP-131I-ASON) was investigated in athymic mice bearing HT29 tumor xenografts in comparison with unconjugated radioiodinated ASON(131I-ASON), unlabelled ASON (VIP-ASON) and scrambled oligonucleotide (VIP-131I-MON) conjugated to VIP-polylysine. Conjugation 125I-ASON to VIP-polylysine resulted in a 5.6-fold decrease in the plasma clearance and a 3.4-fold increase in tumor uptake of the radiopharmaceutical. Athymic mice bearing HT29 tumor xenografts were treated with 4 weekly doses of VIP-131I-ASON and the antitumor effects were assessed by use of the slope of the tumor growth curve. VIP-131I-ASON exhibited strong antitumor effects against HT29 xenografts, decreasing tumor growth rate 9.67-, 7.90-fold more effectively than 131I-ASON and VIP-ASON at equivalent doses of ASON. Conversely, 131I-ASON, VIP-ASON or VIP-131I-MON caused no significant effect compared with the normal saline. These data indicated that use of a VIP-polylysine carrier greatly increased HT29 tumor uptake of ASON and treatment with the VIP-131I-ASON complexes resulted in tumor growth delay in human colon cancer xenograft.
authors.affiliation: Department of Nuclear Medicine, West China Hospital of Sichuan University, Sichuan Province, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Ou
authors.forename: Tianzhi
authors.initials: T
authors.lastname: Tan
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.forename: Yunchun
authors.initials: Y
authors.lastname: Li
authors.forename: Julian
authors.initials: J
authors.lastname: Li
authors.forename: Anren
authors.initials: A
authors.lastname: Kuang
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000628:therapy*; D016259:Genes, myc / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D007457:Iodine Radioisotopes / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011107:Polylysine / Q000378:metabolism* / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013873:Thionucleotides / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D007457:Iodine Radioisotopes; D016376:Oligonucleotides, Antisense; D019275:Radiopharmaceuticals; D013873:Thionucleotides; D011107:Polylysine; D014660:Vasoactive Intestinal Peptide