Presentation Authors: Makito Miyake*, Nobumichi Tanaka, Takuya Owari, Shunta Hori, Yosuke Morizawa, Yoshitaka Itami, Yasushi Nakai, Kiyohide Fujimoto, Nara, Japan
Introduction: Radiotherapy-induced normal tissue damage in rectum and bladder remains the largest dose-limiting factor for treatment of prostate cancer (PCa). 5-aminolevulinic acid (ALA) reportedly exerts a broad range of cytoprotective effects, for example, against cisplatin-induced nephrotoxicity. Here, we investigated the supplementary oral 5-aminolevulinic acid (ALA) to standard radiation therapy as a novel radioprotective approach that would not compromise the antitumor effect of radiation in normal rectal and bladder mucosa in a syngenic PCa model.
Methods: Myc-CaP cells were isolated from a c-myc transgenic FVB mouse with PCa. A syngenic PCa model of MyC-CaP cells was created by subcutaneous inoculation to the pelvic area. To evaluate the effect of ALA in vivo, multiple doses (12 Gy total) of radiation was delivered to the mouse pelvic area with or without 30 mg/kg/day of oral ALA for 28 days. Resected tumors, recta, and urinary bladders were subjected to immunostaining with Ki-67, Î³-H2AX, CD204, and uroplakin-III antibodies. Expression levels of mRNA in recta and urinary bladders were analyzed via RT2 Profiler qPCR arrays related to &[Prime]Stress & Toxicity PathwayFinder&[Prime], &[Prime]Mitochondria&[Prime], and &[Prime]Inflammasomes&[Prime].
Results: The repeated oral administration of ALA exerted as a radiosensitizer for PCa cells (Figure 1A). Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2-polarized macrophages (Figure 1B). Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding (Figure 1C). Out of the 252 genes tested, 35 (13.4%) were indentified as relevant genes which are involved in the radioprotective role of exogenous ALA. These genes included IL-1a, IL-1b, IL-12, CXCL1, CXCL3, and NLRP3.
Conclusions: The present study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiatiotherapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa.
Source of Funding: Fiscal Years 2015-2016 Nara Medical University Grant-in-Aid for Collaborative Research Projects