Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation via Manipulation of the MDM2 Pathway
Annual rept. 1 Apr 2003-31 Mar 2004
FOX CHASE CANCER CENTER PHILADELPHIA PA
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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 ADRT in more high risk cases. Our results indicate that MDM2 is central to prostate cancer response to AD, RT, and ADRT. 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 ADRT 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 ADRT, which could potentially impact men with virtually any stage of disease.
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