Solid tumors contain subpopulations of cells at various levels of hypoxia. Such cells have increased resistance to radiation and to drugs used in chemotherapy. In addition, the hypoxic environment has been associated with decreased stability of the genome, and provides an environment in which cancer cells have the potential to acquire additional mutations. Several clinical studies have associated response to therapy and survival of cancer patients with the fraction of hypoxic cells in the tumor. In the applicant's previous work he has shown that hypoxic cell resistance to cytotoxic drugs is associated with upregulation of several genes associated with drug resistance. Induction of gene expression has been found to result from enhanced transcription factor binding to the AP-1 site in the promoter region of a number of enzymes involved in detoxification.
The first aim i n this application is to continue to characterize the cis-acting elements that mediate the inductive response. The applicant and his collaborators have shown more specifically that the elevation of AP-1 activity is a consequence of both of the induction of c-jun transcription, and of its activation by phosphorylation. He has demonstrated selective effects of hypoxia on jun kinase (JNK). His second specific aim is to characterize this interaction more fully. A model for acquired resistance relies on the exposure of sensitive cells to increasing drug concentrations. He has developed a series of hypoxia-conditioned derivatives of HT29 colon carcinoma cells by repeated hypoxic exposure. These cells have altered growth characteristics, and respond differently to cytotoxic drugs. Using differential display, the applicant has identified a number of genes upregulated and downregulated in this series of cell lines. In this application the cells will be characterized further, and the novel transcripts will be isolated and their contribution to their resistant phenotype determined. It is expected that this work will yield novel targets for the reversal of hypoxic cell resistance in the clinic.
Showing the most recent 10 out of 32 publications
