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Purpose: Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH-; intravenous administration achieving mM plasma concentrations) selectively enhances H2O2-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH- could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues.Methods and Materials: Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor β immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene.Results: KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019.Conclusions: We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues. [ABSTRACT FROM AUTHOR]

Purpose: To systematically review scientific literature on the use of intensity-modulated brachytherapy (IMBT), including static and dynamic shielding approaches, to enhance therapeutic ratio. Studies were evaluated for technique, disease site, dosimetry, applicators, dosimetric calculations, and planning algorithms. Comparisons with standard-of-care brachytherapy techniques, alternative IMBT methods, or both were performed for dose-to-target volumes, organs at risk (OARs), and treatment planning or delivery times.Methods and Materials: Inclusion criteria were any peer-reviewed journal articles on IMBT published from January 1, 1980, to January 1, 2019, on PubMed, Google Scholar, Cochrane Library, and EBSCO databases. Two independent investigators reviewed each article for inclusion and exclusion criteria and scope. Data collected on each study included technique, source or shield material, disease site, n of study (n = number of simulated plans/treated patients), dose-to-target/OARs, and planning or delivery times. This review adhered to the Preferred Reporting Items for Systemic reviews and Meta Analyses (PRISMA).Results: Database queries yielded 1734 results, which were reduced to 436 after exclusion criteria and 78 peer-reviewed journal articles after evaluation of scope. Studies per disease site were 31 for cervical; 16 for rectal; 10 for oculocutaneous; 7 for breast; 6 for prostate; and 8 for other, multiple, or no specific disease site. Eighteen studies demonstrated a significant decrease in dose to OARs (5.1%-68.2%), 11 improved treatment planning or delivery times (7.6%-99.7%), and 6 increased target coverage (18.6%-71.6%) relative to standard-of-care or alternative IMBT technique. IMBT consistently decreased dose to OAR compared with the standard of care at the cost of increased planning or delivery times. Innovations in dose calculation or planning algorithms and applicators were capable of ameliorating prolonged treatment intervals.Conclusions: IMBT techniques improved the therapeutic ratio by reducing OAR doses, facilitating dose escalation, or both. Static-shielding techniques are clinically available as a result of the advent of commercially available heterogeneity-corrected dose-calculation algorithms, whereas dynamic-shielding techniques are still preclinical. [ABSTRACT FROM AUTHOR]