Antagonists of GHRH are being developed for the treatment of various
cancers. In this study we investigated in vivo and in vitro the effects of the GHRH antagonist
MZ-J-7-118 and its mechanism of action in HEC-1A human
endometrial cancer. Treatment of nude mice bearing HEC-1A xenografts with 10 mug/d
MZ-J-7-118 for 6 wk significantly inhibited the volume of HEC-1A
tumors by 43%,
tumor weight by 40% compared with controls and prolonged the
tumor doubling time from 18.7 +/- 1.4 to 25.4 +/- 3.8 d. Administration of 20 mug
MZ-J-7-118, sc, twice a day significantly (P < 0.05) decreased HEC-1A growth, as evidenced by a 57.9% decrease in
tumor volume, a 50.7% reduction in
tumor weight, and the extension of
tumor doubling time from 17.5 +/- 2.8 to 36.4 +/- 6.5 d.
Therapy with GHRH antagonists significantly decreased serum
IGF-I levels in experiment 1, and significantly increased tumoral
IGF-I levels in experiment 2 in treated mice. Levels of
IGF-II and
vascular endothelial growth factor-A in
tumors were not changed. Specific high affinity binding sites for GHRH were found on HEC-1A
tumor membranes using
ligand competition assays with (125)I-labeled GHRH antagonist JV-1-42.
MZ-J-7-118 displaced radiolabeled JV-1-42 with an IC(50) of 0.13 +/- 0.04 nm. The expression of
mRNA for GHRH and splice variants of the
GHRH receptor in HEC-1A
tumors was demonstrated by real-time RT-PCR analysis. HEC-1A cells cultured in vitro secreted GHRH into the medium. The GHRH antagonist
MZ-J-7-118 inhibited the growth of HEC-1A cells in vitro. Our results indicate that GHRH antagonists can reduce the growth of human
endometrial cancer and could be used as an alternative adjuvant
therapy for the management of
endometrial cancer.