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

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

Fingerprint

Gastrin-Releasing Peptide
Cytotoxins
Colonic Neoplasms
irinotecan
Growth
Bombesin
HT29 Cells
Heterografts
Nude Mice
Neoplasms
Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-bombesin(6-14)
S Phase
Fluorouracil
Antineoplastic Agents
Cell Cycle
Cell Count
Cell Proliferation
Clinical Trials
Cell Line
Messenger RNA

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

Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers. / Rick, Ferenc G.; Buchholz, Stefan; Schally, Andrew V; Szalontay, Luca; Krishan, Awtar; Datz, Christian; Stadlmayr, Andreas; Aigner, Elmar; Perez, Roberto; Seitz, Stephan; Block, Norman L; Hohla, Florian.

In: Cell Cycle, Vol. 11, No. 13, 01.07.2012, p. 2518-2525.

Research output: Contribution to journalArticle

Rick, FG, Buchholz, S, Schally, AV, Szalontay, L, Krishan, A, Datz, C, Stadlmayr, A, Aigner, E, Perez, R, Seitz, S, Block, NL & Hohla, F 2012, 'Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers', Cell Cycle, vol. 11, no. 13, pp. 2518-2525. https://doi.org/10.4161/cc.20900
Rick, Ferenc G. ; Buchholz, Stefan ; Schally, Andrew V ; Szalontay, Luca ; Krishan, Awtar ; Datz, Christian ; Stadlmayr, Andreas ; Aigner, Elmar ; Perez, Roberto ; Seitz, Stephan ; Block, Norman L ; Hohla, Florian. / Combination of gastrin-releasing peptide antagonist with cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers. In: Cell Cycle. 2012 ; Vol. 11, No. 13. pp. 2518-2525.
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AU - Stadlmayr, Andreas

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