Effective treatment of experimental human non-Hodgkin's lymphomas with antagonists of growth hormone-releasing hormone.
Antagonists of growth hormone-releasing hormone (GHRH) were shown to inhibit the growth of various cancers. We investigated the antitumor activity and the mechanism of action of GHRH antagonists in human non-Hodgkin's lymphomas (NHL). Nude mice bearing xenografts of RL and HT human NHL were treated with GHRH antagonists MZ-5-156 and MZ-J-7-138 at a dose of 40 microg twice daily. The concentrations of serum IGF-1 and GHRH, bFGF, and VEGF in tumor tissue were measured by radioimmunoassays. Expression of GHRH and splice variant 1 of the GHRH receptor in both cell lines was examined by RT-PCR. The effects of MZ-5-156, MZ-J-7-138 and GHRH on cell proliferation were evaluated in vitro. Treatment with MZ-5-156 and MZ-J-7-138 significantly (P < 0.05) inhibited the growth of RL and HT tumors by 59.9-73.9%. High-affinity binding sites for GHRH and mRNA for GHRH and splice variant-1 of the GHRH receptors were found on RL and HT tumors. RL and HT cells contained GHRH peptide, and their growth in vitro was significantly inhibited by both antagonists. IGF-I levels in serum of mice were significantly decreased by antagonist MZ-5-156. Therapy with GHRH antagonists also significantly reduced tumoral bFGF, whereas VEGF levels were not suppressed. Our findings suggest that GHRH antagonists inhibit the growth of RL and HT lymphomas by direct effects mediated by tumoral receptors for GHRH. GHRH antagonists could offer a new therapeutic modality for the management of advanced NHL.
Keller
Gunhild
G
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
Schally
Andrew V
AV
Groot
Kate
K
Toller
Gabor L
GL
Havt
Alexandre
A
Köster
Frank
F
Armatis
Patricia
P
Halmos
Gabor
G
Zarandi
Marta
M
Varga
Jozsef L
JL
Engel
Jörg B
JB
D000818:Animals; D045744:Cell Line, Tumor; D017931:DNA Primers; D004305:Dose-Response Relationship, Drug; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000097:blood; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011863:Radioimmunoassay; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017337:Sermorelin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D017931:DNA Primers; C106656:MZ 5-156; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D005346:Fibroblast Growth Factors; D007334:Insulin-Like Growth Factor I; D017337:Sermorelin; D013007:Growth Hormone-Releasing Hormone