Combined treatment of Dunning R3327 rat prostatic tumor with the 5alpha-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide.
PNU 157706 [N-(1,1,1,3,3,3-hexafluorophenyl-propyl)-3-oxo-4-aza- 5alpha-androst-1-ene-17beta-carboxamide], a novel, potent and selective dual 5alpha-reductase inhibitor, was reported to be effective in inhibiting the growth of established tumors in the Dunning R3327 rat prostatic carcinoma model.


OBJECTIVE
We investigated the efficacy of treatment with PNU 157706 in combination with the antiandrogen bicalutamide in this prostatic tumor model.


METHODS
Rats with tumor diameters of about 1 cm were treated orally 6 days a week for 9 weeks with PNU 157706 (10 mg/kg per day) alone or in combination with bicalutamide (0.2 and 1 mg kg per day). Animals were killed 24 h after the last treatment, and ventral prostates were removed for testosterone (T) and dihydrotestosterone (DHT) determination.


RESULTS
PNU 157706 reduced the growth of established tumors by 39%; bicalutamide proved ineffective at 0.2 mg/kg per day, but reduced tumor growth by 45% at a dose of 1 mg/kg per day. The combination of PNU 157706 with both doses of bicalutamide caused an additive tumor growth inhibition (50% and 64%). Castration resulted in marked tumor growth inhibition (72%). Ventral prostate weight was markedly reduced by PNU 157706 (78%) treatment and by bicalutamide (59% and 77%); combined treatment was as effective as castration. Prostatic DHT content was markedly reduced by PNU 157706 (88%), whereas prostatic T increased slightly (60%). Concomitant treatment with bicalutamide antagonized the T increase induced by PNU 157706 and did not modify the already remarkable suppression of DHT.


CONCLUSIONS
These data show that the inhibitory effect of PNU 157706 and bicalutamide on Dunning prostatic tumor growth is additive, thus suggesting a possible role of PNU 157706 in the therapy of advanced prostate cancer, in combination with antiandrogens, to provide an effective peripheral androgen ablation therapy with minimal side effects.
Zaccheo
T
T
Department of Pharmacology, Discovery Research Oncology, Pharmacia & Upjohn, Nerviano (MI), Italy. tiziana.zaccheo@eu.pnu.com
Giudici
D
D
Panzeri
A
A
di Salle
E
E
D000726:Androgen Antagonists / Q000008:administration & dosage*; D000736:Androstenes / Q000008:administration & dosage*; D000813:Anilides / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000032:analysis; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D008297:Male; D009570:Nitriles; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D013739:Testosterone / Q000032:analysis; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000736:Androstenes; D000813:Anilides; D004791:Enzyme Inhibitors; D009570:Nitriles; C112526:PNU 157706; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D013739:Testosterone; C053541:bicalutamide; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase