Inhibition of Growth of Human Osteosarcomas by Antagonists of Growth Hormone-Releasing Hormone

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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-CI)6, Abu15, Nle27]hGH-RH(l-28)Agm, which is also called MZ-4–71. Purpose: We investigated the effects of this antagonist on the growth of the human osteosar-coma 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 mini-pumps 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 subcutaneous!y for 3 weeks with the GH-RH agonist hGH-RH(l-29)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(l-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 <.O5). 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 sub-cutaneously for 13 days with MZ-4–71 were decreased (both P values <.O1). 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(l-29)NH2 or 5 μM MZ-4–71. Incorporation of [3H]thy-midine 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(l-29)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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