We are studying the biology of ovarian cancer, the mechanisms of antineoplastic drug resistance in ovarian cancer, and the pharmacologic reversal of the drug resistance. These studies have been aided by the development of unique model systems of ovarian cancer including 10 new ovarian cancer cell lines and an intraperitoneal model of human ovarian cancer with ascites, pulmonary metastasis, and death from intraabdominal carcinomatosis. In addition, we have developed drug resistant variant cell lines which are 6-100 times more resistant to chemotherapy than the sensitive parental cell line from which they were derived. Using these model systems we have demonstrated that resistance to melphalan and cisplatin is linked to elevations in cellular glutathione levels. We have also shown that buthionine sulfoximine (BSO), a synthetic amino acid which inhibits synthesis of glutathione, leads to a decrease in glutathione levels in vitro and in vivo and increases the cytotoxicity of melphalan. In addition, we have demonstrated that drug resistance to cisplatin in these model systems of ovarian cancer is also related to increased capacity for the cells to repair DNA damage. Aphidicolin, an inhibitor of the enzyme DNA polymerase increases the cytotoxicity of cisplatin in the resistant cell lines by blocking DNA repair. In addition, glutathione also facilitates the repair of platinum and DNA damage. The combination of aphidicolin and BSO leads to maximum depletion of repair capacity. The molecular basis for cisplatin resistance is being investigated with the goal of identifying and cloning the responsible gene. It has also been demonstrated that some human ovarian cancer cell lines have increased amplification/expression of the mdr-1 gene although all the cell lines examined thus far do not have any decrease in drug accumulation of

National Institute of Health (NIH)
Division of Cancer Treatment (NCI)
Intramural Research (Z01)
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Cancer Treatment
United States
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