研究吉西他滨耐药性的诊断性微剂量给药方法。
Diagnostic Microdosing Approach to Study Gemcitabine Resistance.
作者信息
Scharadin Tiffany M, Zhang Hongyong, Zimmermann Maike, Wang Sisi, Malfatti Michael A, Cimino George D, Turteltaub Kenneth, de Vere White Ralph, Pan Chong-Xian, Henderson Paul T
机构信息
Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis , Sacramento, California 95817, United States.
Accelerated Medical Diagnostics Incorporated , Berkeley, California 95618, United States.
出版信息
Chem Res Toxicol. 2016 Nov 21;29(11):1843-1848. doi: 10.1021/acs.chemrestox.6b00247. Epub 2016 Oct 10.
Gemcitabine metabolites cause the termination of DNA replication and induction of apoptosis. We determined whether subtherapeutic "microdoses" of gemcitabine are incorporated into DNA at levels that correlate to drug cytotoxicity. A pair of nearly isogenic bladder cancer cell lines differing in resistance to several chemotherapy drugs were treated with various concentrations of C-labeled gemcitabine for 4-24 h. Drug incorporation into DNA was determined by accelerator mass spectrometry. A mechanistic analysis determined that RRM2, a DNA synthesis protein and a known resistance factor, substantially mediated gemcitabine toxicity. These results support gemcitabine levels in DNA as a potential biomarker of drug cytotoxicity.
吉西他滨代谢产物可导致DNA复制终止并诱导细胞凋亡。我们确定了亚治疗剂量的“微剂量”吉西他滨是否以与药物细胞毒性相关的水平掺入DNA。用不同浓度的碳标记吉西他滨处理一对对几种化疗药物耐药性不同的近等基因膀胱癌细胞系4 - 24小时。通过加速器质谱法测定药物掺入DNA的情况。一项机制分析确定，DNA合成蛋白RRM2（一种已知的耐药因子）在很大程度上介导了吉西他滨的毒性。这些结果支持DNA中的吉西他滨水平作为药物细胞毒性的潜在生物标志物。
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