title: Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers.
abstract: We investigated the efficacy of a powerful antagonist of bombesin/gastrin-releasing peptide (BN/GRP) RC-3940-II administered as a single agent or in combination with cytotoxic agents on the growth of HT-29, HCT-116 and HCT-15 human colon cancer in vitro and in vivo. GRP-receptor mRNA and protein were found in all three cell lines tested. Exposure of HT-29 cells to 10 μM RC-3940-II led to an increase in the number of cells blocked in S phase and G 2/M and cells with lower G(0)/G(1) DNA content. Similar changes on the cell cycle traverse of HT-29 cells could also be seen at lower concentrations of RC-3940-II (1 μM) after pretreatment with 100 nM GRP (14-27), indicating a dose-dependent mechanism of action based on the blockage of BN/GRP induced proliferation of tumor cells at lower concentrations. Daily in vivo treatment with BN/GRP antagonist RC-3940-II decreased the volume of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice by 25 to 67% (p < 0.005). Combined treatment with RC-3940-II and chemotherapeutic agents 5-FU and irinotecan resulted in a synergistic tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts by 43% to 78%. In HT-29 and HCT-116 xenografts the inhibition for the combinations of RC-3940-II and irinotecan vs. single substances (p < 0.05) was significantly greater. These findings support the use of RC-3940-II as an anticancer agent and may help to design clinical trials using RC-3940-II in combinations with cytotoxic agents.
authors: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, Miami, FL, USA.
authors: Ferenc G
authors: FG
authors: Rick
authors: Stefan
authors: S
authors: Buchholz
authors: Andrew V
authors: AV
authors: Schally
authors: Luca
authors: L
authors: Szalontay
authors: Awtar
authors: A
authors: Krishan
authors: Christian
authors: C
authors: Datz
authors: Andreas
authors: A
authors: Stadlmayr
authors: Elmar
authors: E
authors: Aigner
authors: Roberto
authors: R
authors: Perez
authors: Stephan
authors: S
authors: Seitz
authors: Norman L
authors: NL
authors: Block
authors: Florian
authors: F
authors: Hohla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001839:Bombesin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D019886:Gastrin-Releasing Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D018004:Receptors, Bombesin; C107120:bombesin receptor subtype 3; C096400:bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-; D000077146:Irinotecan; D019886:Gastrin-Releasing Peptide; D001839:Bombesin; D005472:Fluorouracil; D002166:Camptothecin