Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

• Published in: The Prostate 2019-03, Vol.79 (4), p.340-351
• Main Authors: Miyake, Makito, Tanaka, Nobumichi, Hori, Shunta, Ohnishi, Sayuri, Takahashi, Hiroo, Fujii, Tomomi, Owari, Takuya, Ohnishi, Kenta, Iida, Kota, Morizawa, Yosuke, Gotoh, Daisuke, Itami, Yoshitaka, Nakai, Yasushi, Inoue, Takeshi, Anai, Satoshi, Torimoto, Kazumasa, Aoki, Katsuya, Fujimoto, Kiyohide
• Format: Article
• Language: English
• Subjects: 5‐aminolevulinic acid; adverse event; Aminolevulinic acid; Antitumor activity; Bladder; Cancer therapies; Chemokines; DNA damage; Epithelium; Fibrosis; Inflammasomes; Macrophages; Mitochondria; Mucosa; Myc protein; Polymerase chain reaction; Prostate cancer; Radiation protection; Radiation therapy; radioprotection; radiotherapy; Rectum; Ribonucleic acid; RNA; Toxicity; Tumors; Urinary bladder; Urothelium
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.23740

Background Normal tissue damage caused by radiotherapy remains the largest dose‐limiting factor in radiotherapy for cancer. Therefore, the aim of this study was to investigate 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 prostate cancer (PCa) model. Methods To evaluate the radiosensitizing effect of ALA in vitro, clonogenic survival assays were performed in DU145, PC3, and MyC‐CaP cell lines. To evaluate the effect of ALA in vivo a single dose (25 Gy) of radiation with or without ALA was given to healthy mice. Next, a syngenic PCa model of MyC‐CaP cells in FVB mice was created, and multiple doses (12 Gy total) of radiation were administered to the mouse pelvic area with or without ALA administration. Resected tumors, recta, and urinary bladders were immunostained with antibodies against Ki‐67, γ‐H2AX, CD204, and uroplakin‐III. Total RNA levels in recta and urinary bladders were analyzed via RT2 Profiler polymerase chain reaction (PCR) arrays related to “Stress & Toxicity PathwayFinder,” “Mitochondria,” and “Inflammasomes.” Results The addition of in vitro single or in vivo repeated administration of exogenous ALA acted as a radiosensitizer for PCa cells. Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2 macrophages. Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding. The higher dose (300 mg/kg/day) of ALA exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Out of the 252 genes tested, 35 (13.4%) were detected as relevant genes which may be involved in the radioprotective role of ALA administration. These included interleukin‐1a (IL‐1a), IL‐1b, IL‐12, chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL3, and NLRP3. Conclusions Our study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiation therapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa.