alexa Ex vivo reversal of chemoresistance by tariquidar (XR9576).
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Pharmacogenomics & Pharmacoproteomics

Author(s): Di Nicolantonio F, Knight LA, Glaysher S, Whitehouse PA, Mercer SJ,

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Abstract The expression of P-glycoprotein (P-gp) has been demonstrated to confer resistance to several anticancer drugs, including anthracyclines, taxanes and vinca alkaloids. Tariquidar is a novel inhibitor of P-gp that has been shown to reverse resistance to cytotoxic drugs in tumor cell lines and mouse xenografts. We have used an ATP-based chemosensitivity assay (ATP-TCA) to compare the activity of cytotoxic drugs in combination with tariquidar against a variety of solid tumors (n = 37). The expression of P-gp was determined in a subset of solid tumor samples by immunohistochemistry (n = 16). Resistance was seen in 20 of 37 (54\%) tumors tested with doxorubicin, in 27 of 34 (79\%) samples tested with paclitaxel and 17 of 31 (55\%) with vinorelbine. Tariquidar alone showed no activity over a wide range of concentrations up to 2 microM (n = 14). The median IC90s for doxorubicin, paclitaxel and vinorelbine, alone were 2.57, 27.4 and 15.5 microM. These decreased to 1.67 (p<0.0005), 20.6 (p<0.05) and 9.5 microM (p<0.001), respectively, in combination with tariquidar. Tariquidar also significantly decreased resistance in 14 of 20 (70\%), six of 27 (22\%) and six of 17 (35\%) samples tested with doxorubicin, paclitaxel and vinorelbine, respectively. Immunohistochemical staining for P-gp was positive in nine of 16 (56\%) samples and in all of these cases addition of tariquidar improved the activity of the cytotoxic. The results show that tariquidar is able to decrease resistance in a number of solid tumors resistant to cytotoxic drugs known to be P-gp substrates. These data support the introduction of tariquidar in combination with chemotherapy to clinical trials of patients expressing P-gp.
This article was published in Anticancer Drugs and referenced in Journal of Pharmacogenomics & Pharmacoproteomics

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