Decrease in the level and mRNA expression of LH-RH and EGF receptors after treatment with LH-RH antagonist cetrorelix in DU-145 prostate tumor xenografts in nude mice.
Using radioligand binding, RT-PCR, and Southern blot analyses, we evaluated whether agonist [D-Trp6]LH-RH and antagonist Cetrorelix could affect the levels of receptors for LH-RH and EGF and expression of mRNA for these receptors in DU-145 human androgen-independent prostate cancers xenografted into nude mice. Radioligand binding studies showed the presence of specific high affinity receptors for LH-RH and EGF in DU-145 prostate tumors. Cetrorelix, but not [D-Trp6]LH-RH significantly inhibited tumor growth. The concentration of LH-RH receptors was reduced by 22% (p<0. 05) and 67% (p<0.01) after 4 weeks of treatment with [D-Trp6]LH-RH and Cetrorelix respectively. The concentration of EGF receptors fell by 48% (p<0.05) in the [D-Trp6]LH-RH group, whereas Cetrorelix led to a 66% reduction (p<0.01). The expression of LH-RH and EGF receptor mRNA was investigated by RT-PCR analysis followed by Southern blotting. Densitometric analysis of the developed bands showed that the antagonist Cetrorelix decreased the expression of LH-RH receptor mRNA by 55% (p<0.01) compared to control group while the 20% reduction after treatment with the LH-RH agonist was non-significant. Treatment with [D-Trp6]LH-RH and Cetrorelix also reduced the expression of EGF receptor mRNA by 35% and 68% respectively (both, p<0.01) compared to control group. In conclusion, these data demonstrate that growth inhibition of DU-145 prostate tumors induced by prolonged administration of LH-RH antagonist Cetrorelix is accompanied by a marked decrease in the concentration of LH-RH and EGF receptors as well as in their mRNA levels.
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Experimental Medicine, Tulane University School of Medicine, New Orleans, LA 70146, USA.
N
N
Lamharzi
G
G
Halmos
A
A
Jungwirth
A V
AV
Schally
D000818:Animals; D001665:Binding Sites; D015139:Blotting, Southern; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000378:metabolism; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism* / Q000648:ultrastructure; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism*; D011869:Radioligand Assay; D011966:Receptors, LHRH / Q000096:biosynthesis* / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D017329:Triptorelin Pamoate; D014407:Tumor Cells, Cultured
D006727:Hormone Antagonists; D012333:RNA, Messenger; D011966:Receptors, LHRH; D017329:Triptorelin Pamoate; D007987:Gonadotropin-Releasing Hormone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C062876:cetrorelix