Sensitization of Prostate Cancer Cells to Androgen Deprivation and Radiation Via Manipulation of the MDM2 Pathway

摘要

MDM2 is a feedback regulator of p53. We found that MDM2 is central to the apoptotic response of prostate cancer cells to radiotherapy (RT), androgen deprivation (AD) and RT+AD. In vitro measurements in androgen sensitive and insensitive cells revealed that antisense- MDM2 (AS-MDM2) significantly enhanced apoptosis and overall cell death (clonogen survival) in response to all of these treatments. An orthotopic model using wild-type LNCaP cells injected into the prostates of nude mice corroborated the in vitro findings, particularly in terms of sensitization to AD. The mouse model involved determinations of growth inhibition through measurements of serum PSA and MRI-based tumor volume. Treatment with AS-MDM2+AD and AS-MDM2+AD+RT resulted in the greatest growth inhibition, compared to the other groups. We have also measured MDM2 expression using immunohistochemistry in men treated on Radiation Therapy Oncology Group trials 86-10 and 92-02. MDM2 overexpression was associated with a higher rate of distant metastasis and mortality, independent of conventional factors, treatment, Ki-67 and p53. We now have a method not only for identifying men at high risk of treatment failure, but also for selecting men who would have the greatest potential benefit from therapeutically targeting MDM2. Men in all prostate cancer risk groups should benefit.