title: GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer.
abstract: Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 μM) combined with 5-FU (1.25 μM), irinotecan (1.25 μM) or cisplatin (1.25 μM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G 1 fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40-55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT-29, HCT-116 and HCT-15 xenografts to 56-85%. Our observations indicate that JMR-132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL, USA.
authors.forename: Ferenc G
authors.initials: FG
authors.lastname: Rick
authors.forename: Stephan
authors.initials: S
authors.lastname: Seitz
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Luca
authors.initials: L
authors.lastname: Szalontay
authors.forename: Awtar
authors.initials: A
authors.lastname: Krishan
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.forename: Andreas
authors.initials: A
authors.lastname: Stadlmayr
authors.forename: Stefan
authors.initials: S
authors.lastname: Buchholz
authors.forename: Norman L
authors.initials: NL
authors.lastname: Block
authors.forename: Florian
authors.initials: F
authors.lastname: Hohla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005472:Fluorouracil / Q000627:therapeutic use / Q000633:toxicity; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; C534070:GHRH(1-29)NH2, PhAcTyr(1)-Arg(2)-P(H)e(4-CL)(6)-Ala(8)-Tyr(Me)(10)-His(11)-Abu(15)-His(20)-Nle(27)-Arg(28)-HLCr(29)-; D000077146:Irinotecan; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin