Androgen-regulated gastrin-releasing peptide receptor expression in androgen-dependent human prostate tumor xenografts.
Human prostate cancer (PC) overexpresses the gastrin-releasing peptide receptor (GRPR). Radiolabeled GRPR-targeting analogs of bombesin (BN) have successfully been introduced as potential tracers for visualization and treatment of GRPR-overexpressing tumors. A previous study showed GRPR-mediated binding of radiolabeled BN analogs in androgen-dependent but not in androgen-independent xenografts representing the more advanced stages of PC. We have further investigated the effect of androgen modulation on GRPR-expression in three androgen-dependent human PC-bearing xenografts: PC295, PC310 and PC82 using the androgen-independent PC3-model as a reference. Effects of androgen regulation on GRPR expression were initially studied on tumors obtained from our biorepository of xenograft tissues performing reverse transcriptase polymerase chain reaction (RT-PCR) and autoradiography ((125)I-universal-BN). A prospective biodistribution study ((111)In-MP2653) and subsequent autoradiography ((125)I-GRP and (111)In-MP2248) was than performed in castrated and testosterone resupplemented tumor-bearing mice. For all androgen-dependent xenografts, tumor uptake and binding decreased drastically after 7 days of castration. Resupplementation of testosterone to castrated animals restored GRPR expression extensively. Similar findings were concluded from the initial autoradiography and RT-PCR studies. Results from RT-PCR, for which human specific primers are used, indicate that variations in GRPR expression can be ascribed to mRNA downregulation and not to castration-induced reduction in the epithelial fraction of the xenograft tumor tissue. In conclusion, expression of human GRPR in androgen-dependent PC xenografts is reduced by androgen ablation and is reversed by restoring the hormonal status of the animals. This knowledge suggests that hormonal therapy may affect GRPR expression in PC tissue making GRPR-based imaging and therapy especially suitable for non-hormonally treated PC patients.
Schroeder
Rogier P J
RP
Department of Nuclear Medicine, Erasmus MC, Dr. Molenwaterplein 50, Rotterdam, The Netherlands. r.schroeder@erasmusmc.nl
de Visser
Monique
M
van Weerden
Wytske M
WM
de Ridder
Corrina M A
CM
Reneman
Suzanne
S
Melis
Marleen
M
Breeman
Wout A P
WA
Krenning
Eric P
EP
de Jong
Marion
M
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001839:Bombesin / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D002369:Castration; D019886:Gastrin-Releasing Peptide / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007205:Indium Radioisotopes; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D018004:Receptors, Bombesin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000008:administration & dosage; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D007205:Indium Radioisotopes; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; D013739:Testosterone; D019886:Gastrin-Releasing Peptide; D001839:Bombesin