Radiosensitization in prostate cancer: mechanisms and targets

Abstract

Prostate cancer is the second most commonly diagnosed cancer in American men over the age of 45 years and is the third most common cause of cancer related deaths in American men. In 2012 it is estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 men will succumb to prostate cancer. Currently, radiation therapy is one of the most common definitive treatment options for localized prostate cancer. However, significant number of patients undergoing radiation therapy will develop locally persistent/recurrent tumours. The varying response rates to radiation may be due to 1) tumor microenvironment, 2) tumor stage/grade, 3) modality used to deliver radiation, and 4) dose of radiation. Higher doses of radiation has not always proved to be effective and have been associated with increased morbidity. Compounds designed to enhance the killing effects of radiation, radiosensitizers, have been extensively investigated over the past decade. The development of radiosensitizing agents could improve survival, improve quality of life and reduce costs, thus benefiting both patients and healthcare systems. Herin, we shall review the role and mechanisms of various agents that can sensitize tumours, specifically prostate cancer.

Figure 1

Cellular Effects of Ionizing Radiation. Photons of radiation produce direct DNA damage, but it is less likely than indirect damage, where photons eject electrons from target biomolecules in the cytoplasm, creating multiple ionizations, especially in oxygen compounds and producing free radicals, which break DNA.

Figure 2

G2/M Arrest after Ionizing Radiation DNA Damage. Activation of ATM and ATR by DNA damage produces G2 arrest. Once DNA is repaired Cdc25c is inactivated which stimulates Cdc2 and enhances cell entry into mitosis by Cyclin B.