Basic research for the gene therapy to the radioresistant tumors

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BACKGROUND: DNA double-strand breaks (DSB) are the major lethal lesions induced by ionizing radiation. The capability for DNA DSB repair is crucial for inherent radiosensitivity of tumor and normal cells. DNA-PKcs, Ku70, Ku85, XRCC4, and NBS1 play a critical role in DNA DSB repair.METHODS: As a basic research for the gene therapy to the radioresistant tumors, we immunohistochemically investigated the expression of DNA-PKcs, Ku70, Ku85, XRRCC4, and NBS1 in 134 specimens from various normal and tumor tissues with different radiosensitivity.RESULTS: Immunopositivity to Ku70, Ku85, DNA-PKcs, XRCC4 and NBS1 was found in all tumor tissues examined. The staining for Ku70, Ku85, DNA-PKcs was nuclear, but for XRCC4 and NBS1 it was nuclear and cytoplasmic. There were no apparent differences in the expression of these five proteins among cancerous tissues and the corresponding normal tissues. No apparent differences in nuclear staining intensity were detected in the expression of these five proteins among tumor tissues with different radiosensitivity, although non-Hodgkin's lymphoma (B or T cell) tended to show a lower expression than he others. The stromal cells generally expressed these five proteins at much lower frequency than either tumor or epithelial cells in both tumor and normal tissues.DISCUSSION: We did not observe the relationship between radiosensitivity and expression of the five proteins involved in repair of DNA DSB by NHEJ. The questions then arises as to why tumors with similar expressions of the five proteins have different intrinsic radiosensitivity? One possibility is that expression of those proteins does not necessarily reflect their function. Cells which have a similar expression of these proteins could have different efficacies in their function. To elucidate this problem, it is necessary to use antibodies which reflect the function of these five proteins. We are planning to find the substrates of specific sites of these substrates.