US EPA

5430877 

Technical Report 

Molecular Mechanism of the Supra-Additive Response of Prostate Cancer to Androgen Ablation and Radiotherapy 

Pollack, A 

1999 

GRA and I 

e 2 

The main objectives of the proposal are to measure the molecular changes induced by androgen ablation and radiotherapy, to relate these changes to the supra-additive apoptotic response of androgen ablation plus radiation, and to use these data to develop a gene therapy strategy. Prostate cancer is the most common cancer in men, yet our understanding of the interaction of androgen ablation and radiation at the molecular level is severely lacking. The proposed project will define the role of the key proteins in the apoptotic pathway, p53, bax, and bcl-2. Considerable progress has been made on two fronts: first, characterization of pretreatment biomarker levels in human prostate cancers and second, the development of a gene therapy strategy using adenoviral-p53 and adenoviral E2F. In the latter studies, these vectors have been found to sensitize both LNCaP and PC3 cells to radiation, and preliminary data with Ad5- p53 suggest an added benefit when androgen ablation is added. Some delays have been encountered in measurement of biomarker level changes in LNCaP cells cultured in androgen deprived medium. The problems with the system have been resolved and this analysis is now underway. The immediate significance of these studies is that two gene therapy strategies have been developed and a clinical trial written to test the feasibility, morbidity and efficacy of this approach. The significance of the androgen ablation mechanism/biomarker studies will be manifest at the end of next year.