Harrison, Mark; (1998) Studies on novel human DNA damage sensitive cell lines. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ionizing radiation and chemotherapy are standard non-surgical treatments in the management of cancer. Certain human syndromes, such as ataxia-telangiectasia, are associated with an increased normal tissue sensitivity to ionizing radiation. Characteristic pre-treatment features diagnostic of these syndromes allow identification of such individuals. There remains, however, a group of patients who show untoward sensitivity to conventional doses of radiotherapy and chemotherapy without any pre-treatment phenotype. Such individuals have been identified here and cell lines established from peripheral B lymphocytes. Five lymphoblastoid cell lines have been studied in depth. In vitro sensitivity to DNA damaging agents was examined using a radiolabeled hypoxanthine incorporation assay (J.E. Cleaver and G.H. Thomas, 1988; P. Goss and P.G. Parsons, 1977). All cell lines show an in vitro sensitivity to ionizing radiation. Each cell line also showed a unique pattern of cross-sensitivity to other DNA damaging agents, indicating different underlying molecular defects. Furthermore, cytogenetic analyses revealed that all cell lines showed some degree of inherent genomic instability. Potential defects in DNA repair and DNA damage signal transduction were assessed using a combination of functional assays and western blotting analyses of key enzyme components. One of the cell lines showed a potential defect in the DNA double-strand break repair pathway. Another cell line showed impaired cell cycle arrest following irradiation. The five cell lines thus represent different molecular defects that result in a common phenotype of hypersensitivity to ionizing radiation and chemotherapeutic agents.

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