Ex vivo reversal of chemoresistance by tariquidar (XR9576)
Anti-Cancer Drugs, ISSN: 0959-4973, Vol: 15, Issue: 9, Page: 861-869
2004
- 22Citations
- 5Captures
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Metrics Details
- Citations22
- Citation Indexes22
- 22
- CrossRef19
- Captures5
- Readers5
Article Description
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 μM (n = 14). The median ICs for doxorubicin, paclitaxel and vinorelbine, alone were 2.57, 27.4 and 15.5 μM. These decreased to 1.67 (p < 0.0005), 20.6 (p < 0.05) and 9.5 μM (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. © 2004 Lippincott Williams & Wilkins.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=8344280376&origin=inward; http://dx.doi.org/10.1097/00001813-200410000-00006; http://www.ncbi.nlm.nih.gov/pubmed/15457126; http://journals.lww.com/00001813-200410000-00006; https://dx.doi.org/10.1097/00001813-200410000-00006; https://journals.lww.com/anti-cancerdrugs/Abstract/2004/10000/Ex_vivo_reversal_of_chemoresistance_by_tariquidar.6.aspx
Ovid Technologies (Wolters Kluwer Health)
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