HER2 Support Group Forums - View Single Post - Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

Rich66 · 08-15-2009, 04:01 PM

Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.

Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
The ATP-binding cassette (ABC) transporters (ABC-T) actively efflux structurally and mechanistically unrelated anticancer drugs from cells. As a consequence, they can confer multidrug resistance (MDR) to cancer cells. ABC-T are also reported to be phenotypic markers and functional regulators of cancer stem/initiating cells (CSC) and believed to be associated with tumor initiation, progression, and relapse. Dofequidar fumarate, an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both. Phase III clinical trials suggested that dofequidar had efficacy in patients who had not received prior therapy. Here we show that dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction. Estimation of ABC-T expression revealed that ABCG2/breast cancer resistance protein (BCRP) mRNA level, but not the ABCB1/P-gp or ABCC1/MDR-associated protein 1 mRNA level, in all the tested SP cells was higher than that in non-SP cells. The in vitro vesicle transporter assay clarified that dofequidar had the ability to suppress ABCG2/BCRP function. Dofequidar treatment sensitized SP cells to anticancer agents in vitro. We compared the antitumor efficacy of irinotecan (CPT-11) alone with that of CPT-11 plus dofequidar in xenografted SP cells. Although xenografted SP tumors showed resistance to CPT-11, treatment with CPT-11 plus dofequidar greatly reduced the SP-derived tumor growth in vivo. Our results suggest the possibility of selective eradication of CSC by inhibiting ABCG2/BCRP. (Cancer Sci 2009).
PMID: 19673889 [PubMed - as supplied by publisher]

The mentioned previous study:
http://jco.ascopubs.org/cgi/content/abstract/25/4/411

Results ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF,a 24.6% relative improvement and 10.5% absolute increase (P= .077). There was a trend for prolonged progression-free survival(PFS; median 241 days for CAF v 366 days for dofequidar + CAF;P = .145). In retrospectively defined subgroups, significantimprovement in PFS in favor of dofequidar was observed in patientswho were premenopausal, had no prior therapy, and were stageIV at diagnosis with an intact primary tumor. Except for neutropeniaand leukopenia, there was no statistically significant excessof grade 3/4 adverse events compared with CAF. Treatment withdofequidar did not affect the plasma concentration of doxorubicin.
Conclusion Dofequidar + CAF was well tolerated and is suggested to haveefficacy in patients who had not received prior therapy.
published online ahead of print at www.jco.org on December 18,2006.
Supported by Schering AG, Berlin, Germany.
Presented in part at the 29th European Society for Medical OncologyCongress, Vienna, Austria, October 29–November 2, 2004,and the 27th San Antonio Breast Cancer Conference, San Antonio,TX, December 8-11, 2004.

08-15-2009, 04:01 PM	#34
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Ce Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export. Katayama R, Koike S, Sato S, Sugimoto Y, Tsuruo T, Fujita N. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. The ATP-binding cassette (ABC) transporters (ABC-T) actively efflux structurally and mechanistically unrelated anticancer drugs from cells. As a consequence, they can confer multidrug resistance (MDR) to cancer cells. ABC-T are also reported to be phenotypic markers and functional regulators of cancer stem/initiating cells (CSC) and believed to be associated with tumor initiation, progression, and relapse. Dofequidar fumarate, an orally active quinoline compound, has been reported to overcome MDR by inhibiting ABCB1/P-gp, ABCC1/MDR-associated protein 1, or both. Phase III clinical trials suggested that dofequidar had efficacy in patients who had not received prior therapy. Here we show that dofequidar inhibits the efflux of chemotherapeutic drugs and increases the sensitivity to anticancer drugs in CSC-like side population (SP) cells isolated from various cancer cell lines. Dofequidar treatment greatly reduced the cell number in the SP fraction. Estimation of ABC-T expression revealed that ABCG2/breast cancer resistance protein (BCRP) mRNA level, but not the ABCB1/P-gp or ABCC1/MDR-associated protein 1 mRNA level, in all the tested SP cells was higher than that in non-SP cells. The in vitro vesicle transporter assay clarified that dofequidar had the ability to suppress ABCG2/BCRP function. Dofequidar treatment sensitized SP cells to anticancer agents in vitro. We compared the antitumor efficacy of irinotecan (CPT-11) alone with that of CPT-11 plus dofequidar in xenografted SP cells. Although xenografted SP tumors showed resistance to CPT-11, treatment with CPT-11 plus dofequidar greatly reduced the SP-derived tumor growth in vivo. Our results suggest the possibility of selective eradication of CSC by inhibiting ABCG2/BCRP. (Cancer Sci 2009). PMID: 19673889 [PubMed - as supplied by publisher] The mentioned previous study: http://jco.ascopubs.org/cgi/content/abstract/25/4/411 Results ORR was 42.6% for CAF compared with 53.1% for dofequidar + CAF,a 24.6% relative improvement and 10.5% absolute increase (P= .077). There was a trend for prolonged progression-free survival(PFS; median 241 days for CAF v 366 days for dofequidar + CAF;P = .145). In retrospectively defined subgroups, significantimprovement in PFS in favor of dofequidar was observed in patientswho were premenopausal, had no prior therapy, and were stageIV at diagnosis with an intact primary tumor. Except for neutropeniaand leukopenia, there was no statistically significant excessof grade 3/4 adverse events compared with CAF. Treatment withdofequidar did not affect the plasma concentration of doxorubicin. Conclusion Dofequidar + CAF was well tolerated and is suggested to haveefficacy in patients who had not received prior therapy. published online ahead of print at www.jco.org on December 18,2006. Supported by Schering AG, Berlin, Germany. Presented in part at the 29th European Society for Medical OncologyCongress, Vienna, Austria, October 29–November 2, 2004,and the 27th San Antonio Breast Cancer Conference, San Antonio,TX, December 8-11, 2004.