Multidrug resistance in ovarian cancer

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 gammaglutamyl 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.Cancer 602075-2080, 1987.HEMOTHERAPY has continued to have an increas-C ingly important role in the effective treatment of gynecologic malignancies, in particular, ovarian cancer. Cisplatin-based combination chemotherapy regimens produce complete remissions in 60-80% of patients with advanced-stage (FIG0 Stages I11 and IV) ovarian cancer. ' Many of these patients remain continuously disease free. However, a significant fraction of patients with advanced ovarian cancer will not achieve a complete response to therapy or will relapse from a complete remission. The development of acquired resistance to individual antineoplastic drugs in ovarian cancer is frequently associated with a broad cross-resistance to structurally dissimilar drugs, resulting in only a 6% to 10% response rate to salvage chemotherapy. The identification of the

Down-regulation of Ras-related Protein Rab 5C-dependent Endocytosis and Glycolysis in Cisplatin-resistant Ovarian Cancer Cell Lines

“…Earlier studies have found that multiple factors are linked to drug resistance in human ovarian cancer including reduced intracellular drug accumulation, intracellular cisplatin inactivation, and increased DNA repair (4). Reduced cellular drug accumulation is mediated by the copper transporter-1 responsible for the influx of cisplatin (5-9) and MDR1, which encodes an integral membrane protein named P-glycoprotein for the active efflux of platinum drugs.…”

Induction ofMRP5 andSMRP mRNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin

“…[1][2][3] Adriamycin resistance often may also result from overexpression of P-glycoprotein encoded by the MDR-1 gene. 4,5 However, the increased expression of Pglycoprotein and MDR-1 does not always contribute to clinical resistance, at least in lung cancer patients.…”

Disruption of P‐glycoprotein anticancer drug efflux activity by a small recombinant single‐chain Fv antibody fragment targeted to an extracellular epitope

“…The amount of MDR1 RNA as well as the amount of Pgp protein present in the target cell lines studied here correlate well with the level of MDR. 25,26 The inhibitory activity of the A2 scFv antibody on MDR cell lines correlates favorably with the level of Pgp overexpression, while the scFv molecule does not exhibit toxic effects on the parental, drug-sensitive cell lines.…”