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

Authors

  • Ryszard Braczkowski M.D., Ph.D.,

    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
    Current affiliation:
    1. Department of Medicine, Medical University of Silesia, Katowice, Poland.
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  • Andrew V. Schally M.D., Ph.D.,

    Corresponding author
    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
    • Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112-1262
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    • Fax: (504) 566-1625

  • Artur Plonowski M.D., Ph.D.,

    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Jozsef L. Varga Ph.D.,

    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Kate Groot Ph.D.,

    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
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  • Magdalena Krupa B.S.,

    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
    2. Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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  • Patricia Armatis M.S.

    1. Endocrine, Polypeptide, and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana
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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. Cancer 2002;95:1735–45. © 2002 American Cancer Society.

DOI 10.1002/cncr.10865

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