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 Krishan, Christian Datz, Andreas Stadlmayr, Elmar Aigner, Roberto Perez, Stephan Seitz, Norman L. Block, Florian Hohla

Research output: Contribution to journalArticle

16 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

    Fingerprint

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

Cite this

Rick, F. G., Buchholz, S., Schally, A. V., Szalontay, L., Krishan, A., Datz, C., Stadlmayr, A., Aigner, E., Perez, R., Seitz, S., Block, N. L., & Hohla, F. (2012). Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers. Cell Cycle, 11(13), 2518-2525. https://doi.org/10.4161/cc.20900