The impact of DNA double‐strand break repair pathways throughout the carbon ion spread‐out Bragg peak beam

• Published in: Cancer science Vol. 114; no. 12; pp. 4548 - 4557
• Main Authors: Buglewicz, Dylan J., Buglewicz, Jessica K. F., Hirakawa, Hirokazu, Kato, Takamitsu A., Liu, Cuihua, Fang, YaQun, Kusumoto, Tamon, Fujimori, Akira, Sai, Sei
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2023; John Wiley and Sons Inc
• Subjects: Animals; Bragg peak; Carbon; carbon ion radiotherapy; Cell culture; Cell survival; CHO Cells; Cricetinae; Cricetulus; Cytotoxicity; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA damage and repair; DNA End-Joining Repair; DNA Repair; Dosimetry; Double-strand break repair; gamma‐H2AX; Homologous recombination; Humans; Ion beams; Kinases; Mammalian cells; NHEJ; Non-homologous end joining; Original; Ovaries; Radiation therapy; Radiosensitivity; Tumor cells; Yeast; Bragg peak; HR; DNA damage and repair; NHEJ; carbon ion radiotherapy; gamma-H2AX
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15972

Following carbon ion beam irradiation in mammalian cells, such as used in carbon ion radiotherapy (CIRT), it has been suggested that the balance between whether nonhomologous end joining (NHEJ) or homologous recombination (HR) is utilized depends on the DNA double‐strand break (DSB) complexity. Here, we quantified DSB distribution and identified the importance of each DSB repair pathway at increasing depths within the carbon ion spread‐out Bragg peak (SOBP) beam range. Chinese hamster ovary (CHO) cell lines were irradiated in a single biological system capable of incorporating the full carbon ion SOBP beam range. Cytotoxicity and DSB distribution/repair kinetics were examined at increasing beam depths using cell survival as an endpoint and γ‐H2AX as a surrogate marker for DSBs. We observed that proximal SOBP had the highest number of total foci/cell and lowest survival, while distal SOBP had the most dense tracks. Both NHEJ‐ and HR‐deficient CHO cells portrayed an increase in radiosensitivity throughout the full carbon beam range, although NHEJ‐deficient cells were the most radiosensitive cell line from beam entrance up to proximal SOBP and demonstrated a dose‐dependent decrease in ability to repair DSBs. In contrast, HR‐deficient cells had the greatest ratio of survival fraction at entrance depth to the lowest survival fraction within the SOBP and demonstrated a linear energy transfer (LET)‐dependent decrease in ability to repair DSBs. Collectively, our results provide insight into treatment planning and potential targets to inhibit, as HR was a more beneficial pathway to inhibit than NHEJ to enhance the cell killing effect of CIRT in targeted tumor cells within the SOBP while maintaining limited unwanted damage to surrounding healthy cells. This is the first study to demonstrate that homologous recombination is the most beneficial pathway to inhibit over nonhomologous end joining to enhance the cell killing effect of carbon ion radiotherapy in the targeted tumor cells within the carbon ion spread‐out Bragg peak.