Growth hormone-releasing hormone antagonist MZ-4-71 inhibits in vivo proliferation of Caki-I renal adenocarcinoma

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Abstract
In view of evidence that growth hormone (GH) and insulin-like growth factors (IGF) may play a role in the development of renal cell carcinoma (RCC), we investigated the effects of growth hormone-releasing hormone (GH-RH) antagonist MZ-4-71 on the proliferation of the human renal adenocarcinoma cell line Caki-I in vitro and in vivo. Male nude mice bearing xenografts of human Caki-I RCC were treated for 4 weeks with MZ-4-71 injected s.c. twice daily at a dose of 20 μg per animal. Tumor growth, serum, liver, and tumor IGF levels and IGF-I receptor concentrations in Caki-I cell membranes were measured. After 4 weeks of therapy, the final volume of Caki-I tumors in nude mice treated with MZ-4-71 was significantly (P < 0.01) decreased to 52.6 ± 12.3 mm3 as compared with controls that measured 504.2 ± 104.1 mm3. Treatment with GH-RH antagonist also significantly reduced tumor weight, serum levels of GH and IGF-I, liver concentrations of IGF-I, and tumor levels of IGF-I and IGF-II. High-affinity binding sites for IGF-I were detected in the cell membranes of Caki-I tumors. IGF-I and IGF-II stimulated the proliferation of Caki-I cells in tissue cultures. Antagonist MZ-4-71 could inhibit in vitro growth of Caki-I cells, but only at high concentrations. Our findings demonstrate that GH-RH antagonist MZ-4-71 can significantly inhibit the growth of Caki-I RCC. MZ-4-71 may exert its suppressive effect on tumor growth through a reduction in GH release from the pituitary and the subsequent decrease in the production of IGF-I in the liver and IGF-I and II by the tumors. The efficacy of MZ-4-71 suggests that this compound could be considered for the therapy of recurrent or metastatic RCC.