Author: Mark E Artz, Jiyeon Park, Lori Rice, Mohammad Saki, Sanjeev Shukla, Michael Vieceli ðĻâðŽ
Affiliation: University of Florida Health Proton Therapy Institute, Department of Radiation Oncology, University of Florida College of Medicine, UF Health Proton Therapy Institute, Department of Urology, University of Florida College of Medicine ð
Purpose: To investigate how varying levels of DNA repair mutations affect the LET sensitivity of prostate cancer cells.
Methods: The prostate cancer cell lines Du145 (low DNA repair mutations), PC3 (moderate mutations), and LNCaP (high mutations) were cultured and seeded in petri dishes for in vitro irradiation. AP/PA pencil beam scanning proton beams were used to create 2, 3, 4, and 5 keV/Ξm uniform LET-optimized fields with uniform dose to the bottom of the petri dish planning target volume; AP/PA 6x x-rays with uniform dose were used as a reference. Plan-specific quality assurance was performed for each field. The clonogenic assay was performed 12-14 days after irradiation to calculate surviving fractions and fit linear-quadratic cell survival curves. PC3 was also irradiated with single-layer (>5 Gy/s) and spread-out Bragg peak (SOBP) (0.04 Gy/s proximal at 2 keV/Ξm, 0.23 Gy/s distal at 4 keV/Ξm) fields to test if LET-dependence could be confounded by a dose-rate effect (i.e., high LET at the distal edge in SOBP fields is confounded with less overlapping layers resulting in higher average dose rates).
Results: The overall relative radiosensitivity between cells lines showed a strong correlation with increased levels of DNA repair mutations, with Du145 showing low sensitivity, PC3 moderate sensitivity, and LNCaP high sensitivity. DNA repair mutations were also correlated with LET sensitivity, with PC3 showing unequivocal LET-dependence and LNCaP showing statistically significant differences between x-rays and protons, both with RBEs up to 1.3; Du145 showed no LET-dependence. While higher dose-rate single-layer PC3 survival was lower than for lower dose-rate SOBP, both showed clear LET-dependence.
Conclusion: DNA repair mutations were correlated with overall radiosensitivity as the strongest effect and LET sensitivity as a secondary effect. RBE-enhancement was more strongly correlated with LET than dose-rate, although some differences in RBE and overall survival were seen between dose-rates.