Antagonists of growth hormone-releasing hormone (GH-RH) enhance tumour growth inhibition induced by androgen deprivation in human MDA-Pca-2b prostate cancers.
In the present study, we investigated whether the growth hormone-releasing hormone (GH-RH) antagonist JV-1-38 could enhance the effects of androgen deprivation produced by the anti-androgen Flutamide and luteinising hormone-releasing hormone (LH-RH) agonist Decapeptyl in an experimental model of human androgen-sensitive MDA PCa 2b prostate carcinoma implanted subcutaneously (s.c.) into nude mice. We also evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) the effects of combined treatment on the mRNA expression for prostate-specific antigen (PSA) and measured serum PSA levels. In experiment 1, GH-RH antagonist JV-1-38 greatly inhibited tumour growth in combination with Decapeptyl, but was ineffective when given alone. Thus, combined therapy with JV-1-38 at 20 microg/day and Decapeptyl microcapsules releasing 12.5 microg/day for 29 days inhibited significantly (P<0.01) MDA PCa 2b tumour growth by 65%, compared with controls. Combined treatment also significantly (P<0.05) decreased serum PSA levels by 52% and reduced tumour weight by 54% vs. controls. In experiment 2, GH-RH antagonist JV-1-38 at 20 microg/day likewise showed powerful growth inhibitory effects when combined with Flutamide (25 mg/kg/day) for 21 days. Combined treatment with JV-1-38 and slow-release pellets of Flutamide significantly (P<0.001) inhibited tumour growth by 61% versus controls, and was significantly (P<0.05) more effective than Flutamide or JV-1-38 alone. Combination therapy also reduced significantly (P<0.001) tumour weight and serum PSA levels by 59 and 47%, respectively. The mRNA expression for PSA in MDA PCa 2b tumours was not changed by JV-1-38, Decapeptyl and Flutamide alone or in their respective combinations. Our findings suggest that GH-RH antagonists could enhance the tumour inhibitory effects of androgen deprivation for the primary therapy of patients with advanced prostate carcinoma.
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Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, 1601 Perdido St, New Orleans, LA 70112-1262, USA.
Schally
A V
AV
Stangelberger
A
A
Groot
K
K
Varga
J L
JL
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D002455:Cell Division; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005485:Flutamide / Q000627:therapeutic use*; D013007:Growth Hormone-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D017329:Triptorelin Pamoate / Q000627:therapeutic use*
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; C411623:JV 1-38; D017329:Triptorelin Pamoate; D005485:Flutamide; D013007:Growth Hormone-Releasing Hormone