Antitumorigenic actions of growth hormone-releasing hormone antagonists.

I a recent issue of PNAS, Kiaris et al. (1) reported that JV-1-36, a growth hormone-releasing hormone (GHRH) receptor antagonist, dramatically suppresses the proliferation of human small lung cell carcinoma cell lines grown in athymic nude mice and in culture. The antitumorigenic action of JV-1-36 is consistent with previous reports from the same laboratory demonstrating the effectiveness of this and other GHRH antagonists in suppressing both in vivo and in vitro proliferation of a wide variety of transformed human cell lines, including those derived from colorectal, pancreatic, renal, glial, bone, prostate, breast, and ovarian cancers (summarized in Table 1 and reviewed in ref. 2). GHRH-antagonists bind to GHRH receptors located on pituitary somatotropes, thereby blocking the hypothalamic GHRH-mediated activation of the intracellular cAMP signal transduction pathway; a requirement for optimum GH synthesis and release (summarized in Fig. 1 and reviewed in ref. 3). A decline in circulating GH levels leads to the reduction in IGF-I production from the liver, the primary contributor to circulating IGF-I concentrations (Fig. 1; ref. 4). The suppressive effects of GHRH antagonists on the GHyIGF-I axis have been demonstrated in normal rats, in transgenic mice expressing the human GHRH transgene, and in nude mice bearing human tumor xenografts (2). The use of GHRH antagonists to suppress the GHyIGF-I axis as a potential anticancer therapy evolved from a plethora of reports demonstrating that most normal and transformed tumor cell lines express receptors for IGF-I and proliferate in response to supplemental IGF-I treatment (for review, see ref. 5). In addition, GH directly stimulates IGF-I production in cell lines derived from osteosarcomas (6). Therefore, it could be reasoned that reducing liver or tumor production of IGF-I by inhibiting pituitary GH production would slow tumor growth. In support of this hypothesis, Pollak and coworkers (7, 8) found that the metastatic behavior of murine osteosarcoma and fibrosarcoma cell lines in vivo was decreased by hypophysectomy and restored by GH replacement. In addition, somatostatin, which also suppresses the GHy IGF-I axis, can decrease tumor growth in nude mice bearing a human pancreatic cell line that does not express somatostatin receptors (9). Finally, a positive correlation between serum IGF-I concentra-