Abstract
Pharmacologic ascorbate enhances the therapeutic index of ATM-inhibitor based chemoradiation for colorectal cancer
Journal of clinical oncology, Vol.39(15_suppl), pp.3609-3609
05/20/2021
DOI: 10.1200/JCO.2021.39.15_suppl.3609
Abstract
3609
Background: Ataxia telangectasia mutated protein (ATM) is one of the key sensors of DNA damage and specific inhibitors of ATM are potent radiosensitizers. However, their clinical utility with radiation (RT) is limited because they lack tissue specificity and increase normal tissue injury. Pharmacologic (high dose) ascorbate (P-AscH
-
) selectively increases oxidative stress in tumors while functioning as a donor antioxidant and reducing RT damage in normal tissues. We hypothesized that P-AscH
-
could enhance the therapeutic index of ATM-inhibitor based chemoradiation (CRT) for colorectal cancer (CRC) by simultaneously enhancing efficacy and reducing RT bowel injury. Methods: Human HCT116, SW480, and HT29 and murine CT26 and MC38 CRC models were used. Clonogenic survival was assessed following single-fraction RT (2-8 Gy) +/- P-AscH
-
(5 pM/cell) +/- veliparib (PARP), VE821 (ATR), or KU60019 (ATM). Catalase expression was induced using HCT116 cells expressing a doxycycline inducible catalase transgene. DNA double strand breaks (DSBs) were quantified using neutral comet assays 0-24 hours post RT. Cell cycle phases were assessed using flow cytometry. ATM and pATM localization were assessed using IF. Jejunal toxicity was assessed using IHC in fixed tissues following single fraction (10 Gy) whole abdominal RT in c57blj/6 mice. Tumor growth delay was assessed following RT (5 Gy x 3) +/- drug treatment in unilateral flank tumors. Results: Veliparib, VE821, and KU60019 were potent radiosensitizers in HCT116, SW480, HT29, MC38, and CT26 CRC tumor models and P-AscH
-
further reduced clonogenic survival with DRIs in all lines except for HT29. In contrast, P-AscH
-
enhanced survival of cultured HUVEC and FHs-74 cells exposed to RT. Enhanced cell kill with P-AscH
-
is H
2
0
2
mediated as it is completely attenuated by inducible catalase expression. P-AscH
-
significantly increased the number of DNA DSBs in tumors after RT in vitro. Despite the increase in DNA DSBs, P-AscH
-
significantly decreased nuclear localization of activated P-ATM after RT and significantly decreased the fraction of cells in G2/M phases of the cell cycle. In vivo, RT + P-AscH
-
+ KU60019 induced more tumor growth delay/clearance than all other combinations in unilateral MC38 or HCT116 flank tumors. Finally, P-AscH
-
significantly reduced loss of jejunal crypt cell density, epithelial architecture, and markers of lipid and protein oxidation following whole abdominal RT. Conclusions: P-AscH
-
selectively enhances the efficacy of ATM-based CRT in CRC tumor models while simultaneously decreasing RT-mediated small bowel toxicity. In tumors, P-AscH
-
enhances DNA DSBs by stimulating an H
2
0
2
flux and prevents activation of DNA repair pathways and cell cycle checkpoints by inhibiting RT-induced activation of ATM. Selective radioprotectors like P-AscH
-
could facilitate the clinical translation ATM inhibitors as radiosensitizers.
Details
- Title: Subtitle
- Pharmacologic ascorbate enhances the therapeutic index of ATM-inhibitor based chemoradiation for colorectal cancer
- Creators
- Cameron Callaghan - University of IowaIbrahim Abukhiran - University of IowaRichard VanRheeden - UIHC Stead Family Department of Pediatrics, Division of Medical Genetics and Genomics, Iowa City, IA;Michael Petronek - UIHC Free Radical and Radiation Biology, Iowa City, IA;Kranti Mapuskar - UIHC Free Radical and Radiation Biology, Iowa City, IA;Md Yousuf Ali - UIHC Free Radical and Radiation Biology, Iowa City, IAAmanda Kalen - UIHC Free Radical and Radiation Biology, Iowa City, IA;Samuel Rodman - Department of Orthopedics and Rehabilitation, Iowa City, IA;Steven Neema Seyedin - University of IowaJoseph J. Cullen - University of IowaMitchell Coleman - Department of Orthopedics and Rehabilitation, Iowa City, IA;John Michael Buatti - University of IowaPrabhat Goswami - UIHC Free Radical and Radiation Biology, Iowa City, IA;Bryan G. Allen - University of IowaDouglas Spitz - UIHC Free Radical and Radiation Biology, Iowa City, IA;Joseph Michael Caster - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Journal of clinical oncology, Vol.39(15_suppl), pp.3609-3609
- DOI
- 10.1200/JCO.2021.39.15_suppl.3609
- ISSN
- 0732-183X
- eISSN
- 1527-7755
- Grant note
- name: RSNA Resident seed grant #RR1914
- Language
- English
- Date published
- 05/20/2021
- Academic Unit
- Orthopedics and Rehabilitation; Neurosurgery; Surgery; Otolaryngology; Radiation Oncology; Pathology; Fraternal Order of Eagles Diabetes Research Center; Iowa Neuroscience Institute
- Record Identifier
- 9984314293702771
Metrics
9 Record Views