A significant problem in the use of radiation and chemotherapy drugs is the development of resistance to these agents by recurrent and metastatic tumors. A number of mechanisms have been proposed for chemotherapy and radiation resistance. Previous studies have suggested that resistant cancer cells are more tolerant of DNA damage than sensitive cells. Overexpression of the multiple drug resistance gene P-glycoprotein, which acts as a drug efflux pump, has been implicated in drug resistance. The glutathione-S-X gene has also been shown to be involved in drug resistance. The increased expression of a number of proto-oncogenes, including AP-1, c-myc and ras, has been associated with chemotherapy resistance. Given the number of reported radi-ation and chemotherapy resistance genes in cancer, we took a global gene expression approach to examine differences between sensitive and resistant cells and their response to different types of DNA damage. We demonstrated increased numbers of responsive genes in sensitive normal epidermal keratinocytes compared to resistant squamous cell carcinoma cells, regardless of the type of DNA damage. Our results also show new genes that may be responsible for chemotherapy resistance in cancer cells, and differences in how sensitive and resistant cells respond to specific types of DNA damage.

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