Potent antagonists of
growth hormone-releasing hormone (GHRH) have been developed for the treatment of disorders caused by excessive GHRH or
growth hormone (GH) production and for
therapy of
cancers. GHRH antagonists suppressed the release of GH and
insulin-like growth factor (
IGF)-I in transgenic mice overexpressing human (h) GHRH gene, an animal model of human
acromegaly. It was also shown in GH3 rat
pituitary tumor cells overexpressing the human pituitary
GHRH receptor (pGHRH-R) that GHRH antagonists can inhibit c-
AMP production and GH secretion through the human receptor. These observations indicate that GHRH antagonists could be used clinically in disorders characterized by excessive GHRH/GH secretion. Many recent studies demonstrate that GHRH antagonists can inhibit
tumor growth by several mechanisms. By indirect action through pGHRH-Rs these antagonists suppress circulating GH/
IGF-I level, which results in the inhibition of
cancers that depend on GH and/or
IGF-I as
growth factors. However, GHRH antagonists are also effective inhibitors of
tumor IGF-II production, which is a potent
mitogen but independent of GH. GHRH antagonists can inhibit
tumor cell proliferation by direct action on
tumor cell receptors, suppressing the
IGF-II and other
growth factor production of
tumor cells. In addition, various human
tumors and tumor cell lines secrete GHRH
peptide and respond to GHRH with proliferation. This finding suggests that GHRH functions as an autocrine
growth factor and that GHRH antagonists can block its effects on
tumor growth. Recently, we demonstrated the expression of hGHRH-R and its splice variants in various human
cancers. Antiproliferative action of GHRH antagonists on these
cancers indicates that the direct inhibitory effects of GHRH antagonists are mediated by tumoral
GHRH receptors.