Reducing Toxicity of Radiation Treatment of Advanced Prostate Cancer

Abstract

Abstract : Toxicity is a major impediment to effective radiation therapy of locally advanced prostate cancer. Work under this award focuses on the potential of a novel class of pharmacological radiation protectors (cysteine modifying agetns (CMAs) to reduce normal tissue toxicity of radiation therapy. During the third year of this award we continued to characterize effects of (the synthetic triterpenoid RTA 408 and the sesquiterpene lactone DMAPT that had emerged as a robust and selective radiation protectors of normal tissues. While radioprotective for normal tissues, both compounds also showed anti-tumor activity against four human prostate cancer cell lines grown as xenotransplants in mice. During the last year we have gained insights into the mechanism(s) of action underlying the opposite and beneficial effects of CMAs on normal and malignant tissues. A major effort focused on the effects these drugs on myeloid (bone marrow-derived) cells. This is based on our finding that inhibiting recruitment of myeloid cells obviates radiation protection of normal tissues by RTA 408. Others described that effects on myeloid cells also underlie tumor growth inhibition by synthetic triterpenoids. This circumstance raises the interesting perspective of a potential convergent phenotype in myeloid cells elicited by RTA 408 and related compounds. During the last funding period we carried out phenotypic and proteomic analyses to define how RTA408 and related compounds affect myeloid cell phenotypes. This work has revealed novel leads and pathways relevant to cytoprotection. These will be pursued to improve development of this class of drugs for the radioprotection indication and as anti-tumor agents.