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Multidrug resistance in ovarian cancer
A Fojo1, T C Hamilton, R C Young
1Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20892.
Abstract:
The development of acquired resistance has limited the effectiveness of chemotherapy in the treatment of ovarian cancer. Experimental model systems were developed to study the mechanisms associated with primary resistance to chemotherapeutic agents and broad cross-resistance (multidrug resistance) which is characteristic of human ovarian cancer. Doxorubicin-resistant cell lines developed in vitro by exposure of a sensitive cell line to increasing concentrations of doxorubicin develop resistance on the basis of a decrease in drug accumulation and have increased expression of the mdr-1 gene. This gene encodes for a membrane glycoprotein and leads to a decreased drug accumulation in drug resistant cell lines. Cell lines established from patients refractory to doxorubicin-containing combinations, however, do not demonstrate a decrease in drug accumulation. Studies are in progress on the measurement of mdr-1 levels in tumors of patients undergoing treatment to determine whether agents, such as verapamil may be useful in the treatment of drug resistant gynecologic cancers. Human ovarian cancer cell lines from drug resistant patients also has been demonstrated to increase levels of glutathione. Lowering of glutathione levels with buthionine sulfoximine (BSO), which irreversibly inhibits the enzyme gamma-glutamyl cysteine synthetase, leads to a marked potentiation of the cytotoxicity of melphalan both in vitro and in vivo in a nude mouse model of human ovarian cancer. Based on those studies, BSO is undergoing toxicologic evaluation before initiation of clinical trials in drug resistant patients. Our studies demonstrate that drug resistance in human ovarian cancer is likely due to interaction of multiple factors. However, biochemical intervention in some of the key steps leading to drug resistance has been demonstrated experimentally feasible and indicates that pharmacologic reversal of drug resistance is a clinical possibility.
Insights
Acquired resistance limits ovarian cancer chemotherapy. Targeting drug accumulation and glutathione pathways shows promise for overcoming multidrug resistance and improving treatment outcomes.
Area of Science:
- Gynecologic Oncology
- Cancer Pharmacology
- Molecular Biology
Background:
- Acquired resistance significantly hinders chemotherapy effectiveness in ovarian cancer treatment.
- Multidrug resistance (MDR) is a common challenge in human ovarian cancer, limiting therapeutic options.
Purpose of the Study:
- To investigate mechanisms of primary and multidrug resistance in ovarian cancer.
- To explore strategies for overcoming drug resistance, including targeting mdr-1 gene expression and glutathione levels.
Main Methods:
- Developed in vitro experimental models of doxorubicin resistance.
- Analyzed drug accumulation, mdr-1 gene expression, and glutathione levels in resistant cell lines and patient samples.
- Evaluated the efficacy of buthionine sulfoximine (BSO) in potentiating melphalan cytotoxicity in preclinical models.
Main Results:
- In vitro doxorubicin-resistant cell lines showed decreased drug accumulation and increased mdr-1 gene expression.
- Ovarian cancer cell lines from resistant patients did not consistently show decreased drug accumulation but exhibited increased glutathione levels.
- Buthionine sulfoximine (BSO) significantly enhanced melphalan's cytotoxicity in vitro and in vivo.
Conclusions:
- Drug resistance in human ovarian cancer is multifactorial.
- Biochemical interventions targeting resistance mechanisms, such as glutathione depletion with BSO, are feasible and may reverse drug resistance.
- Pharmacologic reversal of drug resistance presents a potential clinical strategy for ovarian cancer treatment.