The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir.
Recent reports have shown that androgen stimulation of androgen deprived prostate cancer cells leads to formation of double strand breaks (DSBs). Here, we exploit this finding and investigate the extent and timing of androgen induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR).
Androgen induced DNA damage was assessed by comet assays and γH2A. X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models.
We document that androgen treatment of androgen deprived prostate cancer cell lines resulted in a dose and time dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor (AR) and topoisomerase II beta (TOP2B) but not on cell cycle progression. In vitro models demonstrated a synergistic interaction between ionizing radiation and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice.
These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Feb 01 [Epub ahead of print]
Mohammad Hedayati, Michael C Haffner, Jonathan Coulter, Raju R Raval, Yonggang Zhang, Haoming Zhou, Omar Mian, Emma J Knight, Susan Dalrymple, John T Isaacs, Aileen Santos, Russell K Hales, Nina Razavi, William G Nelson, Srinivasan Yegnasubramanian, Theodore L DeWeese
Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine. , Oncology, The Johns Hopkins University School of Medicine. , Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine. , Department of Radiation Oncology, The Ohio State University Wexner Medical Center. , Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine. , Department of Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine. , Radiation Oncology and Molecular Radiation Sciences, The Johns Hopkins University School of Medicine. , Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine. , The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. , The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University. , Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine. , Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. , Radiation Oncology, Johns Hopkins University School of Medicine. , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. , Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine. , Radiation Oncology and Molecular Radation Sciences, Johns Hopkins University School of Medicine