Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone

J. Pinski, Andrew V Schally, K. Groot, G. Halmos, K. Szepeshazi, M. Zarandi, P. Armatis

Research output: Contribution to journalArticle

87 Citations (Scopus)

Abstract

Background: Insulin-like growth factor I (IGF-I) may be involved in the proliferation of human osteosarcomas. Most of the IGF-I found in blood is produced in the liver, where transcription of the IGF-I gene is regulated by growth hormone (GH). Recently, we synthesized various potent antagonists of GH-releasing hormone (GH-RH), including [Ibu0, D-Arg2, Phe(4-Cl)6, Abu15, Nle27]hGH-RH(1-28)Agm, which is also called MZ-4-71. Purpose: We investigated the effects of this antagonist on the growth of the human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro. Methods: Nude male mice bearing SK-ES-1 and MNNG/HOS tumors were treated for 4 and 3 weeks, respectively, with MZ-4-71 administered from osmotic minipumps at a dose of 40 μg per animal per day. Tumor volume, tumor weight, and levels of receptors for IGF-I were determined. IGF-I levels in serum, tumor, and liver tissue were measured by radioimmunoassay. In other experiments, tumor-bearing nude mice were treated subcutaneously for 3 weeks with the GH-RH agonist hGH-RH(129)NH2 or with MZ- 4-71 for 13 days at doses of 50 μg per animal per day. Effects of MZ-4-71, hGH-RH(1-29)NH2, and human GH (hGH) on cell proliferation and on the production of IGF-I and cyclic adenosine monophosphate were also evaluated in SK-ES-1 and MNNG/HOS cells in vitro. Results: The growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited by MZ-4-71, as measured by a reduction in tumor volume and weight (all P values <.05). MZ- 4-71 treatment of either SK-ES-1 or MNNG/HOS tumor-bearing animals decreased tumor tissue IGF-I levels. The growth of MNNG/HOS xenografts was stimulated by hGH-RH(1-29)NH2 (P<.01). IGF-I levels in serum of tumor-bearing nude mice treated subcutaneously for 13 days with MZ-4-71 were decreased (both P values <.01). High-affinity binding sites for IGF-I were demonstrated on cell membranes of SK-ES-1 and MNNG/HOS tumors. In cell cultures of both osteosarcomas, IGF-I production was stimulated by 25 ng/mL hGH but was not changed by 10 ng/mL hGH-RH(1-29)NH2 or 5 μM MZ-4-71. Incorporation of [3H]thymidine into DNA in SK-ES-1 (but not MNNG/HOS) cells was increased by 25 ng/mL IGF-I (P<.01). The proliferation rate of the two cell lines was not affected by 5-50 ng/mL hGH-RH(129)NH2 or 1-80 ng/mL hGH but was suppressed by 10-6-10-5 M MZ-4-71. Conclusions: Our findings demonstrate that the GH-RH antagonist MZ-4-71 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.

Original languageEnglish
Pages (from-to)1787-1794
Number of pages8
JournalJournal of the National Cancer Institute
Volume87
Issue number23
StatePublished - Jan 1 1995
Externally publishedYes

Fingerprint

Growth Hormone
Growth Hormone-Releasing Hormone
Methylnitronitrosoguanidine
Insulin
Growth Factors
Hormones
Osteosarcoma
Insulin-Like Growth Factor I
Tumors
Tumor
Bearings (structural)
Growth
Nude Mice
Mouse
Tumor Burden
Neoplasms
Cell
Animals
Proliferation
Liver

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Radiology Nuclear Medicine and imaging

Cite this

Pinski, J., Schally, A. V., Groot, K., Halmos, G., Szepeshazi, K., Zarandi, M., & Armatis, P. (1995). Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. Journal of the National Cancer Institute, 87(23), 1787-1794.

Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. / Pinski, J.; Schally, Andrew V; Groot, K.; Halmos, G.; Szepeshazi, K.; Zarandi, M.; Armatis, P.

In: Journal of the National Cancer Institute, Vol. 87, No. 23, 01.01.1995, p. 1787-1794.

Research output: Contribution to journalArticle

Pinski, J, Schally, AV, Groot, K, Halmos, G, Szepeshazi, K, Zarandi, M & Armatis, P 1995, 'Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone', Journal of the National Cancer Institute, vol. 87, no. 23, pp. 1787-1794.
Pinski, J. ; Schally, Andrew V ; Groot, K. ; Halmos, G. ; Szepeshazi, K. ; Zarandi, M. ; Armatis, P. / Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. In: Journal of the National Cancer Institute. 1995 ; Vol. 87, No. 23. pp. 1787-1794.
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TY - JOUR

T1 - Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone

AU - Pinski, J.

AU - Schally, Andrew V

AU - Groot, K.

AU - Halmos, G.

AU - Szepeshazi, K.

AU - Zarandi, M.

AU - Armatis, P.

PY - 1995/1/1

Y1 - 1995/1/1

N2 - Background: Insulin-like growth factor I (IGF-I) may be involved in the proliferation of human osteosarcomas. Most of the IGF-I found in blood is produced in the liver, where transcription of the IGF-I gene is regulated by growth hormone (GH). Recently, we synthesized various potent antagonists of GH-releasing hormone (GH-RH), including [Ibu0, D-Arg2, Phe(4-Cl)6, Abu15, Nle27]hGH-RH(1-28)Agm, which is also called MZ-4-71. Purpose: We investigated the effects of this antagonist on the growth of the human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro. Methods: Nude male mice bearing SK-ES-1 and MNNG/HOS tumors were treated for 4 and 3 weeks, respectively, with MZ-4-71 administered from osmotic minipumps at a dose of 40 μg per animal per day. Tumor volume, tumor weight, and levels of receptors for IGF-I were determined. IGF-I levels in serum, tumor, and liver tissue were measured by radioimmunoassay. In other experiments, tumor-bearing nude mice were treated subcutaneously for 3 weeks with the GH-RH agonist hGH-RH(129)NH2 or with MZ- 4-71 for 13 days at doses of 50 μg per animal per day. Effects of MZ-4-71, hGH-RH(1-29)NH2, and human GH (hGH) on cell proliferation and on the production of IGF-I and cyclic adenosine monophosphate were also evaluated in SK-ES-1 and MNNG/HOS cells in vitro. Results: The growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited by MZ-4-71, as measured by a reduction in tumor volume and weight (all P values <.05). MZ- 4-71 treatment of either SK-ES-1 or MNNG/HOS tumor-bearing animals decreased tumor tissue IGF-I levels. The growth of MNNG/HOS xenografts was stimulated by hGH-RH(1-29)NH2 (P<.01). IGF-I levels in serum of tumor-bearing nude mice treated subcutaneously for 13 days with MZ-4-71 were decreased (both P values <.01). High-affinity binding sites for IGF-I were demonstrated on cell membranes of SK-ES-1 and MNNG/HOS tumors. In cell cultures of both osteosarcomas, IGF-I production was stimulated by 25 ng/mL hGH but was not changed by 10 ng/mL hGH-RH(1-29)NH2 or 5 μM MZ-4-71. Incorporation of [3H]thymidine into DNA in SK-ES-1 (but not MNNG/HOS) cells was increased by 25 ng/mL IGF-I (P<.01). The proliferation rate of the two cell lines was not affected by 5-50 ng/mL hGH-RH(129)NH2 or 1-80 ng/mL hGH but was suppressed by 10-6-10-5 M MZ-4-71. Conclusions: Our findings demonstrate that the GH-RH antagonist MZ-4-71 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.

AB - Background: Insulin-like growth factor I (IGF-I) may be involved in the proliferation of human osteosarcomas. Most of the IGF-I found in blood is produced in the liver, where transcription of the IGF-I gene is regulated by growth hormone (GH). Recently, we synthesized various potent antagonists of GH-releasing hormone (GH-RH), including [Ibu0, D-Arg2, Phe(4-Cl)6, Abu15, Nle27]hGH-RH(1-28)Agm, which is also called MZ-4-71. Purpose: We investigated the effects of this antagonist on the growth of the human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro. Methods: Nude male mice bearing SK-ES-1 and MNNG/HOS tumors were treated for 4 and 3 weeks, respectively, with MZ-4-71 administered from osmotic minipumps at a dose of 40 μg per animal per day. Tumor volume, tumor weight, and levels of receptors for IGF-I were determined. IGF-I levels in serum, tumor, and liver tissue were measured by radioimmunoassay. In other experiments, tumor-bearing nude mice were treated subcutaneously for 3 weeks with the GH-RH agonist hGH-RH(129)NH2 or with MZ- 4-71 for 13 days at doses of 50 μg per animal per day. Effects of MZ-4-71, hGH-RH(1-29)NH2, and human GH (hGH) on cell proliferation and on the production of IGF-I and cyclic adenosine monophosphate were also evaluated in SK-ES-1 and MNNG/HOS cells in vitro. Results: The growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited by MZ-4-71, as measured by a reduction in tumor volume and weight (all P values <.05). MZ- 4-71 treatment of either SK-ES-1 or MNNG/HOS tumor-bearing animals decreased tumor tissue IGF-I levels. The growth of MNNG/HOS xenografts was stimulated by hGH-RH(1-29)NH2 (P<.01). IGF-I levels in serum of tumor-bearing nude mice treated subcutaneously for 13 days with MZ-4-71 were decreased (both P values <.01). High-affinity binding sites for IGF-I were demonstrated on cell membranes of SK-ES-1 and MNNG/HOS tumors. In cell cultures of both osteosarcomas, IGF-I production was stimulated by 25 ng/mL hGH but was not changed by 10 ng/mL hGH-RH(1-29)NH2 or 5 μM MZ-4-71. Incorporation of [3H]thymidine into DNA in SK-ES-1 (but not MNNG/HOS) cells was increased by 25 ng/mL IGF-I (P<.01). The proliferation rate of the two cell lines was not affected by 5-50 ng/mL hGH-RH(129)NH2 or 1-80 ng/mL hGH but was suppressed by 10-6-10-5 M MZ-4-71. Conclusions: Our findings demonstrate that the GH-RH antagonist MZ-4-71 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.

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