Growth hormone-releasing hormone: An autocrine growth factor for small cell lung carcinoma

Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth o f various cancers in vivo. This effect is thought to be exerted through sup pression of the pituitary growth hormone-hepatic insulin-like growth factor I (IGF-I) axis and direct inhibition of autocrine/paracrine production of IGF-I and -II in tumors. However, other evidence points to a direct effect of GHRH antagonists on tumor growth that may not implicate IGFs, although a n involvement of GHRH in the proliferation of cancer cells has not yet been established. In the present study we investigated whether GHRH can functio n as an autocrine/paracrine growth factor in small cell lung carcinoma (SCL C). H-69 and H-510A SCLC lines cultured in vitro express mRNA for GHRH, whi ch apparently is translated into peptide GHRH and then secreted by the cell s, as shown by the detection of GHRH-like immunoreactivity in conditioned m edia from the cells cultured in vitro. In addition, the levels of GHRH-like immunoreactivity in serum from nude mice hearing H-69 xenografts were high er than in tumor-free mice. GHRH(1-29)NH2 stimulated the proliferation of H -69 and H-510A SCLCs in vitro, and GHRH antagonist JV-1-36 inhibited it. JV -1-36 administered s.c, into nude mice bearing xenografts of H-69 SCLC redu ced significantly (P < 0.05) tumor volume and weight, after 31 days of ther apy, as compared with controls. Collectively, our results suggest that GHRH can function as an autocrine growth factor in SCLCs, Treatment with antago nistic analogs of GHRH may offer a new approach to the treatment of SCLC an d other cancers.