A correlation of endocrine and anticancer effects of some antagonists of GHRH.
GHRH receptor antagonists inhibit growth and metastasis of a large number of experimental tumors expressing the pituitary GHRH receptor (pGHRH-R) and its major splice variant SV1. In this study, using Western blot, we demonstrated that DBTRG-05 and U-87MG human glioblastoma cell lines express pGHRH-R at levels 6-15 times higher than SV1. To reveal a correlation between the anticancer activity and the endocrine potency on inhibition of GH release, we compared the antitumor effect of GHRH antagonists JV-1-63 and MZJ-7-138 on growth of DBTRG-05 human glioblastomas grafted into athymic nude mice with their inhibitory potency on GH release. JV-1-63 strongly suppressed the stimulated GH secretion induced by clonidine in rats and inhibited the exogenous GHRH-induced GH surge by 88-99% in vivo and in vitro. MZJ-7-138 decreased the stimulated GH secretion by 58% in vitro and showed only a tendency to inhibit GH secretion in vivo. The strong inhibitor of GH release JV-1-63 reduced tumor growth of DBTRG-05 glioblastomas in nude mice by 46%, while the weak GH release suppressor MZJ-7-138 did not have an effect. Exposure of DBTRG-05 cells to the GHRH antagonists in vitro caused an upregulation of mRNA expression for pGHRH-R and a downregulation of SV1 expression, with JV-1-63 having significantly greater effects than MZJ-7-138. Our results demonstrate that a positive correlation exists between the endocrine potency and the antiproliferative efficacy of GHRH antagonists in tumors strongly expressing pGHRH-R.
Kovács
Magdolna
M
Department of Anatomy, University of Pécs, Medical School, 7624 Pécs, Hungary. magdolna.kovacs@aok.pte.hu
Schally
Andrew V
AV
Hohla
Florian
F
Rick
Ferenc G
FG
Pozsgai
Eva
E
Szalontay
Luca
L
Varga
József L
JL
Zarándi
Márta
M
D017398:Alternative Splicing; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy; D013006:Growth Hormone / Q000378:metabolism; D013007:Growth Hormone-Releasing Hormone / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D020033:Protein Isoforms; D011966:Receptors, LHRH; D013006:Growth Hormone; D013007:Growth Hormone-Releasing Hormone