Effect of the 5 alpha-reductase inhibitor PNU 156765, alone or in combination with flutamide, in the Dunning R3327 prostatic carcinoma model in rats.
The efficacy of treatment with the 5 alpha-reductase inhibitor PNU 156765 (FCE 28260) was investigated in the Dunning R3327 prostatic tumor in rats. The compound, given orally at the doses of 10 and 50 mg/kg/day, for 8 weeks, reduced the growth of established tumors by 49-50%, an effect similar to that of flutamide at 5 mg/kg/day (46% inhibition). In a further experiment, the combination of PNU 156765 10 mg/kg/day and flutamide 5 mg/kg/day resulted in greater inhibition than either treatment alone (70 vs. 20% in PNU-156765-treated and 51% in flutamide-treated groups). The effect of the combination was similar to that of castration (75% inhibition). Ventral prostate weight was more markedly reduced by PNU 156765 than by flutamide, and combined treatment was as effective as castration. Prostatic dihydrotestosterone content was markedly reduced by PNU 156765 while prostatic testosterone increased. Concomitant treatment with flutamide antagonized the testosterone increase induced by PNU 156765. These data indicate a role for 5 alpha-reductase inhibitors in the therapy of prostate cancer, in combination with antiandrogens, in order to achieve adequate androgen blockade with minimal side effects.
Department of Pharmacology, Pharmacia & Upjohn, Nerviano, Italy. tiziana.zaccheo@eu.pnu.com
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Zaccheo
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Giudici
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Panzeri
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di Salle
D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000502:physiology; D000736:Androstenes / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001378:Azasteroids / Q000494:pharmacology / Q000627:therapeutic use*; D042944:Cholestenone 5 alpha-Reductase; D013196:Dihydrotestosterone / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005485:Flutamide / Q000627:therapeutic use*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011467:Prostate / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D012669:Seminal Vesicles / Q000187:drug effects; D013739:Testosterone / Q000378:metabolism
C088574:(22RS-N-1,1,1-trifluoro-2-phenylprop-2-yl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carboxamide; D000726:Androgen Antagonists; D000728:Androgens; D000736:Androstenes; D001378:Azasteroids; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D013739:Testosterone; D005485:Flutamide; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase