The effect of new drug exposure versus a drug free interval on prior drug resistance in ovarian cancer

Abstract

Continuous exposure of ovarian tumours to a chemotherapy drug can result in the acquisition of drug resistance, which ultimately leads to chemotherapy failure and the death of a great majority of ovarian cancer patients. While previous studies suggest that withdrawal of the chemotherapy drug for a period of time (the drug-free interval) can result in restored clinical sensitivity to the drug, it is unclear whether exposure to a new drug of contrasting mechanism of action may accelerate restored sensitivity to the prior drug. In this study, we exposed a carboplatin-resistant ovarian tumour cell line (A2780CBN) to increasing concentrations of docetaxel (A2780CBNDXL cells) or we permitted the cells to grow in the absence of drug for an identical number of drug passages (A2780CBNCC cells). Similarly, we exposed a docetaxel-resistant ovarian tumour cell line (A2780DXL) to increasing concentrations of carboplatin (A2780DXLCBN cells) or we permitted the cells to growth in the absence of drug for an identical period (A2780DXLCC cells). By measuring the sensitivity of the above cell lines to either carboplatin or docetaxel, the aim of my thesis studies was to compare the effects of a drug-free interval or the acquisition of new drug resistance on prior drug resistance in vitro. The results showed that the prior carboplatin resistance was not significantly altered by the acquisition of docetaxel resistance or by withdrawal of carboplatin. However, prior docetaxel resistance was greatly reduced by selection for carboplatin resistance or by prolonged docetaxel withdrawal. Microarray analysis suggests that the loss of docetaxel resistance may be related to down-regulated expression of the ABCB1 and ABCB4 genes, which encode multidrug transporters. It may also relate to up-regulation of CYP1B1 gene expression, which encodes cytochrome P450, a phase I enzyme involved in taxane metabolism. The microarray analysis data also suggests that the newly established carboplatin resistance in A2780DXLCBN cells may be related to the expression of genes that promote cell survival by protecting cells from apoptotic death.