Therapy-induced carboplatin-DNA adduct levels in human ovarian tumours in relation to assessment of adduct measurement in mouse tissues
Therapy-induced carboplatin-DNA adduct levels in human ovarian tumours in relation to assessment of adduct measurement in mouse tissues
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DOI：
10.1016/j.bcp.2011.10.005
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发表时间：
2012-01-01
影响因子：
5.8
通讯作者：
Tilby, Michael J.
中科院分区：
文献类型：
--
作者：
Jarvis, Ian W. H.;Meczes, Emma L.;Tilby, Michael J.
尽管人们对铂类药物DNA加合物与细胞过程相互作用的分子机制了解越来越多，但肿瘤中加合物形成与临床反应之间的关系仍不清楚。我们已经在卵巢癌患者治疗后的活检中确定了卡铂- dna加合物的水平。使用实验动物评估组织样品中DNA加合物测量的可靠性。采用电感耦合等离子体质谱法（ICP-MS）测定铂- dna加合物水平，原子吸收光谱法（AAS）测定血浆药物浓度。测定暴露于铂类药物的Balb/c小鼠组织中加合物水平和血浆药代动力学。我们比较了携带人类神经母细胞瘤异种移植的nu/nu小鼠肿瘤组织和正常组织中的加合物水平。顺铂给药后30分钟，来自肾脏和肝脏的DNA加合物水平大约比脾脏或肿瘤高10倍和6倍。到60分钟时，肝脏和肾脏的水平明显下降，但脾脏和肿瘤没有下降。卡铂仅在肾脏中显示高加合物水平。肿瘤异种移植物中的加合物水平与体外类似药物暴露诱导的水平相当。在给药后6小时取出的临床样本中，肿瘤活检和外周血单个核细胞的加合物水平分别为1.9至4.3和0.2至3.6 nmol Pt/g DNA。这两个数据集之间没有明显的相关性。目前的结果表明，可靠的测量加合物在临床肿瘤是可行的。未来的研究结果应该能让我们更深入地了解耐药性。(C) 2011爱思唯尔公司版权所有。
Despite an increasing understanding of the molecular mechanisms by which platinum drug DNA adducts interact with cellular processes, the relationship between adduct formation in tumours and clinical response remains unclear. We have determined carboplatin-DNA adduct levels in biopsies removed from ovarian cancer patients following treatment. Reliability of DNA adduct measurements in tissues samples were assessed using experimental animals. Platinum-DNA adduct levels were measured using inductively coupled plasma mass spectrometry (ICP-MS) and plasma drug concentrations determined by atomic absorption spectrometry (AAS). Adduct levels in tissues and plasma pharmacokinetics were determined in Balb/c mice exposed to platinum drugs. Comparisons of adduct levels in tumour and normal tissue were made in nu/nu mice carrying human neuroblastoma xenografts. At 30 min post-cisplatin administration, adduct levels in DNA from kidney and liver were approximately 10- and 6-fold higher than spleen or tumour. By 60 min, levels in liver and kidney, but not spleen or tumour, had fallen considerably. Carboplatin showed high adduct levels only in kidney. Adduct levels in tumour xenografts were comparable to those induced in vitro with similar drug exposures. In clinical samples removed 6 h after drug administration, adduct levels ranged from 1.9 to 4.3 and 0.2 to 3.6 nmol Pt/g DNA for tumour biopsies and peripheral blood mononuclear cells, respectively. No correlation was apparent between these two data sets. The present results demonstrate that reliable measurements of adducts in clinical tumours are feasible. Future results should provide insight into drug resistance. (C) 2011 Elsevier Inc. All rights reserved.