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: 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
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 13 Pg. 2518-25 (Jul 01 2012) ISSN: 1551-4005 [Electronic] United States
• PMID: 22751419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Peptide Fragments
• Receptors, Bombesin
• bombesin receptor subtype 3
• bombesin(6-14), Hca(6)-Leu(13)-psi(CH2N)-Tac(14)-
• Irinotecan
• Gastrin-Releasing Peptide
• Bombesin
• Fluorouracil
• Camptothecin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Bombesin (analogs & derivatives, antagonists & inhibitors, metabolism, pharmacology, therapeutic use)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, metabolism, pathology)
• Drug Synergism
• Drug Therapy, Combination
• Fluorouracil (pharmacology, therapeutic use)
• Gastrin-Releasing Peptide (antagonists & inhibitors, metabolism, pharmacology)
• HCT116 Cells
• HT29 Cells
• Humans
• Irinotecan
• Male
• Mice
• Mice, Nude
• Peptide Fragments (pharmacology, therapeutic use)
• Receptors, Bombesin (genetics, metabolism)
• Transplantation, Heterologous