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


OBJECTIVE
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 micrograms 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(1-29)NH2 or with MZ-4-71 for 13 days at doses of 50 micrograms 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 microM 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(1-29)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.
D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006727:Hormone Antagonists / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000096:biosynthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D011817:Rabbits; D017526:Receptor, IGF Type 1 / Q000032:analysis; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D006727:Hormone Antagonists; C095215:MZ 4-71; D007334:Insulin-Like Growth Factor I; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone; D000242:Cyclic AMP; D017526:Receptor, IGF Type 1; D013936:Thymidine