INCREASED EXPRESSION OF STRESS-INDUCED GENES IN CHEMORESISTANT TUMOR CELLS

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A major problem in cancer chemotherapy is the emergence of drug-resistant cells. Chemotherapy-resistance is probably due to multiple mechanisms including altered uptake/excretion of drug, increased inactivation of drug, and altered host response such as increased DNA repair. As outlined in project number ZOI CM 06380-03 RO, we have isolated a variety of mammalian cDNA clones which code for transcripts specifically induced by DNA damage. We have initiated studies with a variety of human tumor cell lines which have been selected for resistance to cis-Pt diamminedichloride (DDP), nitrogen mustard (HN2), or other alkylating agents. Our initial studies have involved determining the level of different stress-induced transcripts in these chemoresistant tumor cell lines compared to their parent cell lines with normal sensitivity. Several examples of over-expression of certain of our DDI transcripts in DDP and alkylating agent resistant cells have been found. For example, in the case of gadd33 RNA, this transcript was constitutively elevated in both DDP, melphalan, and HN2 resistant human tumor cell lines and also in a MNNG resistant Chinese hamster cell line. DDIA18 mRNA was found to be substantially elevated in certain chemoresistant human ovarian cell lines. These studies raise the important possibility that overexpression of certain DNA-damage-inducible genes may play a role in chemotherapy resistance.