Androgen manipulation alters oxidative DNA adduct levels in androgen-sensitive prostate cancer cells grown in vitro and in vivo.

Abstract

Intracellular reactive oxygen species (ROS) may cause oxidative DNA damage, resulting in the formation of adducts such as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and the cyclic pyrimidopurinone N-1, N(2) malondialdehyde-2'-deoxyguanosine (M(1)dG). These adducts have been associated with carcinogenesis, genomic instability and clonal evolution. We tested two hypotheses in human prostate cancer cells grown in vitro and in a xenograft model: (1) treatment of androgen-sensitive cells with DHT increases levels of oxidative DNA adduct levels; (2) flutamide, a competitive androgen receptor antagonist, prevents DHT-induced changes. Levels of M(1)dG and 8-oxo-dG adducts were determined by immunoslot blot and liquid chromatography-tandem mass spectrometry. M(1)dG and 8-oxo-dG levels were significantly higher than control levels in LNCaP cells exposed to supra-physiological concentrations (25-100 nM) of DHT (both P<0.05 by ANOVA). Flutamide pre-treatment completely prevented this increase. In the xenograft model, tumour levels of M(1)dG were decreased by 46% (P=0.001 by Mann-Whitney Test) in flutamide-treated animals compared to controls. The changes demonstrated suggest that oxidative DNA adducts may serve as biomarkers of the efficacy of androgen manipulation in chemoprevention trials.

• Authors: Sanjeev Pathak, Rajinder Singh, Richard D Verschoyle, Peter Greaves, Peter B Farmer, William P Steward, J Kilian Mellon, Andreas J Gescher, Ricky A Sharma
• Journal: Cancer letters (Cancer Lett) Vol. 261 Issue 1 Pg. 74-83 (Mar 08 2008) ISSN: 0304-3835 [Print] Ireland
• PMID: 18096312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• DNA Adducts
• Reactive Oxygen Species
• Dihydrotestosterone
• Flutamide

Topics

• Androgens (pharmacology)
• Animals
• Cell Line, Tumor
• DNA Adducts (metabolism)
• DNA Damage
• Dihydrotestosterone (pharmacology)
• Flutamide (pharmacology)
• Humans
• Male
• Mice
• Neoplasm Transplantation
• Neoplasms, Hormone-Dependent (metabolism)
• Prostatic Neoplasms (metabolism)
• Reactive Oxygen Species (metabolism)