Combined treatment of Dunning R3327 rat prostatic tumor with the 5alpha-reductase inhibitor PNU 157706 and the antiandrogen bicalutamide

Cancer Chemother Pharmacol. 2000;45(1):31-7. doi: 10.1007/pl00006739.

Abstract

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.

Purpose: 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.

MeSH terms

  • Androgen Antagonists / administration & dosage*
  • Androstenes / administration & dosage*
  • Anilides / administration & dosage*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cholestenone 5 alpha-Reductase
  • Dihydrotestosterone / analysis
  • Enzyme Inhibitors / administration & dosage*
  • Male
  • Nitriles
  • Organ Size / drug effects
  • Oxidoreductases / antagonists & inhibitors*
  • Prostatic Neoplasms / drug therapy*
  • Rats
  • Testosterone / analysis
  • Tosyl Compounds

Substances

  • Androgen Antagonists
  • Androstenes
  • Anilides
  • Enzyme Inhibitors
  • Nitriles
  • PNU 157706
  • Tosyl Compounds
  • Dihydrotestosterone
  • Testosterone
  • bicalutamide
  • Oxidoreductases
  • Cholestenone 5 alpha-Reductase