Effective treatment of experimental human non-Hodgkin's lymphomas with antagonists of growth hormone-releasing hormone.

Antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit the growth of various cancers. We investigated the antitumour activity and the mechanism of action of GHRH antagonists in human non-Hodgkin's lymphomas (NHL). Nude mice bearing xenografts of RI and HI human NHL were treated with GHRH antagonists MZ-5-156 and MZ-J-7-138 at a dose of 40μg twice daily. The concentrations of serum IGF-1 and GHRH, bFGF, and VEGF in tumor tissue were measured by radioimmunoassays. Expression of GHRH and splice variant I of the GHRH receptor in both cell lines was examined by RT-PCR. The effects of MZ-5-156, MZ-J-7-138 and GHRH on cell proliferation were evaluated in vitro. Treatment with MZ-5-156 and MZ-J-7-138 significantly (P < 0.05) inhibited the growth of RI and HT tumors by 59.9-73.9%. High- affinity binding sites for GHRH and mRNA for GHRH and splice variant-I of the GHRH receptors were found on RI and HI tumors. RI and HT cells contained GHRH peptide, and their growth in vitro was significantly inhibited by both antagonists. IGF-l levels in serum of mice were significantly decreased by antagonist MZ-5- 156. Iherapy with GHRH antagonists also significantly reduced tumoral bFGF, whereas VEGF levels were not suppressed. Our findings suggest that GHRH antagonists inhibit the growth of RI and HI lymphomas by direct effects mediated by tumoral receptors for GHRH. GI-IRH antagonists could offer a new therapeutic modality for the management of advanced NHL. [ABSTRACT FROM AUTHOR]