Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 ewing sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone: Effects on insulin-like growth factor II

Ryszard Braczkowski, Andrew V Schally, Artur Plonowski, Jozsef L. Varga, Kate Groot, Magdalena Krupa, Patricia Armatis

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. Antagonists of growth hormone-releasing hormone (GH-RH) can inhibit the proliferation of various tumors either indirectly through the suppression of the pituitary growth hormone/hepatic insulin-like growth factor I (IGF-I) axis and the lowering of serum IGF-I concentration or directly by reducing the levels of IGF-I and IGF-II and their mRNA expression in tumors and blocking the effect of autocrine GH-RH. In this study, the authors investigated the effects of the GH-RH antagonist JV-1-38 on MNNG/HOS human osteosarcoma and SK-ES-1 human Ewing sarcoma cell lines. METHODS. Male nude mice bearing subcutaneous xenografts of MNNG/HOS or SK-ES-1 tumors were treated subcutaneously with JV-1-38 at a dose of 20 μg twice daily for 4 weeks. The concentrations of IGF-I and IGF-II in serum and in tumor tissue were measured by radioimmunoassay. Tumor and liver levels of mRNA for IGF-I and IGF-II were determined by reverse transcriptase-polymerase chain reaction analysis. The effects of JV-1-38, IGF-I, and IGF-II on cell proliferation in vitro were evaluated. RESULTS. GH-RH antagonist significantly (P < 0.05) inhibited the tumor volume and tumor weight of MNNG/HOS and SK-ES-1 tumors by > 50% after 4 weeks and increased tumor doubling time. JV-1-38 lowered the serum IGF-I level, decreased the expression of mRNA for IGF-I in the liver, and significantly (P < 0.05-0.01) reduced the concentration of IGF-II and mRNA levels for IGF-II in both sarcomas. The concentration of IGF-I was lowered only in SK-ES-1 tumors. In vitro, the proliferation of SK-ES-1 and MNNG/HOS cells was inhibited by JV-1-38 and by antisera to IGF-I and IGF-II. CONCLUSIONS. The inhibition of MNNG/HOS osteosarcoma and SK-ES-1 Ewing sarcoma by GH-RH antagonists was linked to a suppression of IGF-II production in tumors. However, in SK-ES-1 tumors, the effects on IGF-I also may be involved.

Original languageEnglish
Pages (from-to)1735-1745
Number of pages11
JournalCancer
Volume95
Issue number8
DOIs
StatePublished - Oct 15 2002
Externally publishedYes

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Keywords

  • Ewing sarcoma
  • Growth hormone-releasing hormone antagonists
  • Insulin-like growth factor I
  • Insulin-like growth factor II
  • Osteosarcoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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