The role of DNA single- and double-strand breaks in cell killing by ionizing radiation.

Ionizing radiation produces many types of DNA lesions that have the potential of killing cells. The lethal lesion is probably an unrepaired or misrepaired double-strand break produced as part of a complex lesion. A variety of DNA damage assays have been applied in an effort to predict the sensitivity of cells to ionizing radiation. However, the relationships between initial DNA damage, rejoining of breaks and ultimate cell killing by radiation are not fully understood or predictable. While most repair-deficient cell lines can be identified based on slower strand break rejoining, controversy surrounds the ability of DNA damage assays to rank the radiosensitivity of tumor cells reliably in terms of results of clonogenic assays. Part of the difficulty may be that the most relevant lesions, those that are closely spaced locally or regionally, cannot be easily quantified. It is also possible that the DNA damage can be interpreted differently (in relation to repairability) depending on cell type and/or DNA damage assay. Repair itself does not always increase survival, and survival is the outcome of the actions of several pathways that can be both cell- and tissue-specific. Measurements of misrepair leading to chromosome damage and mutation have been helpful in ranking the radiosensitivity of cell lines, and may be a requirement for predictive assays. These concepts are illustrated with results from alkaline and neutral comet assays developed to detect single-strand breaks and double-strand breaks in individual cells.