Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation via Manipulation of the MDM2 Pathway
Abstract
Androgen deprivation (AD) is a common treatment for prostate cancer, yet the mechanisms of action are poorly understood. Radiotherapy (RT) is also often used in the treatment of localized disease and AD+RT in more high risk cases. Our results indicate that MDM2 is central to prostate cancer response to AD, RT, and AD+RT. Our data establish that by reducing the expression of MDM2 with an antisense oligonucleotide (AS-MDM2) the apoptotic response of LNCaP cells in vitro to AD, RT, and AD+RT is increased. The enhancements in apoptosis translated into gains in overall cell death (measured by clonogenic assay) . These interactions were reduced in LNCaP-MST cells that overexpressed MDM2. Preliminary findings in vivo indicate that AS-MDM2 sensitizes LNCaP cells to AD; the experiments are still in progress. We have also found that MDM2 overexpression was evident in 48% of a cohort of locally advanced men treated on Radiation Therapy Oncology Group protocol 86-10, correlated with Gleason score and was associated with a trend for increased distant metastasis. MDM2 is a promising target for enhancing prostate cancer response to AD, RT, and AD+RT, which could potentially impact men with virtually any stage of disease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2004
- Accession Number
- ADA426171
Entities
People
- Alan Pollack
Organizations
- Fox Chase Cancer Center