Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers

Ferenc G. Rick, Stefan Buchholz, Andrew V. Schally, Luca Szalontay, Awtar K. Ganju-Krishan, Christian Datz, Andreas Stadlmayr, Elmar Aigner, Roberto Perez, Stephan Seitz, Norman L. Block, Florian Hohla

Research output: Contribution to journalArticle

17 Scopus citations

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 G2/M and cells with lower G0/G1 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.

Original languageEnglish (US)
Pages (from-to)2518-2525
Number of pages8
JournalCell Cycle
Volume11
Issue number13
DOIs
StatePublished - Jul 1 2012

Keywords

  • 5-FU
  • BN/GRP antagonist
  • Colon cancer
  • Cytotoxic agents
  • Irinotecan
  • RC-3940-II
  • Targeted therapy

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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