Antagonists of growth hormone-releasing hormone inhibit the proliferation of experimental non-small cell lung carcinoma.
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.
Szereday
Zoltan
Z
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, 1601 Perdido Street, New Orleans, LA 70112, USA.
Schally
Andrew V
AV
Varga
Jozsef L
JL
Kanashiro
Celia A
CA
Hebert
Francine
F
Armatis
Patricia
P
Groot
Kate
K
Szepeshazi
Karoly
K
Halmos
Gabor
G
Busto
Rebeca
R
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017337:Sermorelin / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C411623:JV 1-38; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone