Biomarkers of Oxidative Injury and Their Modulation in Prostate Tissue from Patients with Prostatic Tissue from Patients with Prostate Cancer
Abstract
The development of potent prevention strategies to diminish the threat of prostate cancer (PCa) are in order and remains the long-term goal of this project. One possible etiologic factor in the development of PCa, is cellular exposure to chronic oxidative stress. Chronic oxidative damage can lead to the accumulation of potentially promutagenic oxidized DNA bases such as 8-hydroxydeoxyguanosine (8-OHdG). The detoxifying enzyme GSTP1 is inactivated in nearly 100%) of PCa and is also frequently inactivated in prostatic intraepithelial neoplasia lesions. We have successfully developed a model system to determine the role of GSTP 1 protein in the response of human PCa to chronic oxidative stress We exposed the human PCa cell line LNCaP (no GSTPl protein expression) and subclones of LNCaP engineered to overexpress GSTP1, in vitro, to chrome oxidative stress inflicted by protracted low dose irradiation (LDR) and arseiac trioxide. These experiments reveal: a) LNCaP exhibits an% improved survival following exposure to LDR and arsenic trioxide compared to the GSTPl-overexpressing subclones and b) LNCaP accumulates greater amounts of X-OHdG following this oxidative damage than the GSTPl-overexpressing subclones. Together, these data solidify our preliminary results and implicate GSTP as a major regulator of oxidative DNA damage and suggest that its inactivation may provide a necessary step in the neoplastic process in prostate cancer. Importantly, we have recently learned that measurement of 8-OHdG and other oxidized DNA base adducts is more accurately performed by HPLC- MS-MS than by HPLC-ECD, a method we typically employ. Given this reality, we have purchased, accepted and calibrated a new HPLC-MS-MS (PE Biosystems) and developed a rigorous method for determination of 8-OHdG in DNA from biologic samples.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2001
- Accession Number
- ADA391158
Entities
People
- Theodore L. Deweese
Organizations
- Johns Hopkins University