Abstract
Variations in the radiosensitivity of tumor cells within and between tumors impact tumor response to radiation, including the dose required to achieve permanent local tumor control. The increased expression of DNA-PKcs, a key component of a major DNA damage repair pathway in tumors treated by radiation, suggests that DNA-PKcs-dependent repair is likely a cause of tumor cell radioresistance. This study evaluates the relative biological effect of spread-out Bragg-peak protons in DNA-PKcs-deficient cells and the same cells transfected with a functional DNA-PKcs gene. A cloned radiation-sensitive DNA-PKcs-deficient tumor line and its DNA-PKcs-transfected resistant counterpart were used in this study. The presence of functional DNA-PKcs was evaluated by DNA-PKcs autophosphorylation. Cells to be proton irradiated or x-irradiated were obtained from the same single cell suspension and dilution series to maximize precision. Cells were concurrently exposed to 6-MV x-rays or mid 137-MeV spread-out Bragg peak protons and cultured for colony formation. The surviving fraction data were well fit by the linear-quadratic model for each of 8 survival curves. The results suggest that the relative biological effectiveness of mid spread-out Bragg peak protons is approximately 6% higher in DNA-PKcs-mediated resistant tumor cells than in their DNA-PKcs-deficient and radiation-sensitive counterpart. DNA-PKcs-dependent repair of radiation damage is less capable of repairing mid spread-out Bragg peak proton lesions than photon-induced lesions, suggesting protons may be more efficient at sterilizing DNA-PKcs-expressing cells that are enriched in tumors treated by conventional fractionated dose x-irradiation.
Highlights
The radiosensitivity of tumor cells varies between as well as within tumors and significantly impacts tumor response to radiation, including the dose required to achieve permanent local control [1,2,3,4,5,6,7,8,9]
The results indicate that DNA damage induced by protons is less amenable to DNA-PKcs–dependent repair than damage induced by x-rays, a result that is not inconsistent with studies showing that homologous recombination-defective cells (NHEJ competent) exhibited an increased proton relative biological effectiveness (RBE) [24, 25]
The RBE of the wild-type and Nonhomologous end-joining (NHEJ)-deficient cells did not significantly differ, the results are not incompatible with the RBE difference observed in the present study
Summary
The radiosensitivity of tumor cells varies between as well as within tumors and significantly impacts tumor response to radiation, including the dose required to achieve permanent local control [1,2,3,4,5,6,7,8,9]. The factor or factors governing tumor cell sensitivity, while not fully understood, likely modulate the induction and/or repair of radiation-induced DNA damage and especially DNA double-strand-breaks. Nonhomologous end-joining (NHEJ) is the principal repair pathway of radiation-induced DNA double-strand breaks. It is Proton RBE of tumor cells of interest that clinical studies have reported an increased expression of a key component of NHEJ, that is, DNAPKcs, in tumors that fail conventional fractionated dose x-ray treatment [10,11,12,13]. In studies using wild-type and DNA-PKcs–deficient or DNAPKcs–inhibited cells (or other key constituents of NHEJ), a significant proton RBE difference between sensitive and resistant cells has generally not been observed [15, 16, 24, 25]
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