Antagonists of growth hormone-releasing hormone inhibit the proliferation of experimental non-small cell lung carcinoma.

Abstract

Recent studies show that antagonists of growth hormone-releasing hormone (GH-RH) inhibit proliferation of various cancers indirectly through blockage of the endocrine GH-insulin-like growth factor (IGF) I axis and directly by an action on tumor cells involving the suppression of autocrine/paracrine IGF-I, IGF-II, or GH-RH. The effectiveness of therapy with GH-RH antagonist JV-1-38 and its mechanisms of action were investigated in NCI-H838 non-small cell lung carcinoma (NSCLC) xenografted s.c. into nude mice and in vitro. Treatment with GH-RH antagonist JV-1-38 significantly (P < 0.05-0.001) inhibited tumor growth as demonstrated by a 58% decrease in final tumor volume, 54% reduction in tumor weight, and the extension of tumor-doubling time from 8.5 +/- 1.38 to 12 +/- 1.07 days as compared with controls. Using ligand competition assays with (125)I-labeled GH-RH antagonist JV-1-42, specific high-affinity binding sites for GH-RH were found on tumor membranes. Reverse transcription-PCR revealed the expression of mRNA for GH-RH and splice variant 1 (SV(1)) of GH-RH receptor in H838 tumors. Reverse transcription-PCR analysis also demonstrated that H838 tumors express IGF-I and IGF-I receptors. Tumoral concentration of IGF-I and its mRNA expression were significantly decreased by 25% (P = 0.05) and 65% (P < 0.001), respectively, in animals receiving JV-1-38, whereas serum IGF-I levels remained unchanged. In vitro studies showed that H838 cells secreted GH-RH and IGF-I into the medium. The growth of tumor cells in vitro was stimulated by IGF-I and inhibited by GH-RH antagonist JV-1-38 and a GH-RH antiserum. Our results extend the findings on the involvement of IGF-I in NSCLC and suggest that GH-RH may be an autocrine growth factor for H838 NSCLC. The antitumorigenic action of GH-RH antagonists could be partly direct and mediated by SV(1) of tumoral GH-RH receptors. The finding of GH-RH and SV(1) of GH-RH receptors in NSCLC provides a new approach to the treatment of this malignancy based on the use of antagonistic analogues of GH-RH.

• Authors: Zoltan Szereday, Andrew V Schally, Jozsef L Varga, Celia A Kanashiro, Francine Hebert, Patricia Armatis, Kate Groot, Karoly Szepeshazi, Gabor Halmos, Rebeca Busto
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 22 Pg. 7913-9 (Nov 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14633721 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• JV 1-38
• RNA, Messenger
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II
• Sermorelin
• Growth Hormone-Releasing Hormone

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Animals
• Cell Division (drug effects)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Growth Hormone-Releasing Hormone (analogs & derivatives, antagonists & inhibitors, metabolism, pharmacology)
• Humans
• Insulin-Like Growth Factor I (genetics, metabolism, pharmacology)
• Insulin-Like Growth Factor II (genetics, metabolism)
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mice
• Middle Aged
• RNA, Messenger (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sermorelin (pharmacology)
• Xenograft Model Antitumor Assays