期刊
BMC CANCER
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12885-016-2071-1
关键词
Breast cancer; Topoisomerase I; Irinotecan; SN-38; Resistance; ABCG2/BCRP
类别
资金
- IMK foundation
- Danish National Research Foundation [26-331-86-2]
- Sino-Danish Breast Cancer Research Centre
- Race Against Breast Cancer
- Danish Center for Translational Breast Cancer Research
- John and Birthe Meyer Foundation
- Netherlands Genomics Initiative (NGI)/the Netherlands Organization for Scientific Research
- The Danish Cancer Society [R70-A4581] Funding Source: researchfish
Background: Studies in taxane and/or anthracycline refractory metastatic breast cancer (mBC) patients have shown approximately 30 % response rates to irinotecan. Hence, a significant number of patients will experience irinotecan-induced side effects without obtaining any benefit. The aim of this study was to lay the groundwork for development of predictive biomarkers for irinotecan treatment in BC. Methods: We established BC cell lines with acquired or de novo resistance to SN-38, by exposing the human BC cell lines MCF 7 and MDA MB 231 to either stepwise increasing concentrations over 6 months or an initial high dose of SN-38 (the active metabolite of irinotecan), respectively. The resistant cell lines were analyzed for cross-resistance to other anti-cancer drugs, global gene expression, growth rates, TOP1 and TOP2A gene copy numbers and protein expression, and inhibition of the breast cancer resistance protein (ABCG2/BCRP) drug efflux pump. Results: We found that the resistant cell lines showed 7-100 fold increased resistance to SN-38 but remained sensitive to docetaxel and the non-camptothecin Top1 inhibitor LMP400. The resistant cell lines were characterized by Top1 down-regulation, changed isoelectric points of Top1 and reduced growth rates. The gene and protein expression of ABCG2/BCRP was up-regulated in the resistant sub-lines and functional assays revealed BCRP as a key mediator of SN-38 resistance. Conclusions: Based on our preclinical results, we suggest analyzing the predictive value of the BCRP in breast cancer patients scheduled for irinotecan treatment. Moreover, LMP400 should be tested in a clinical setting in breast cancer patients with resistance to irinotecan.
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