Role of carbonate in the cytotoxicity of carboplatin
Role of carbonate in the cytotoxicity of carboplatin
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DOI：
10.1021/tx700058f
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Dabrowiak, James C.
中科院分区：
文献类型：
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作者：
Di Pasqua, Anthony J.;Goodisman, Jerry;Dabrowiak, James C.
卡铂，[铂(NH3)(2)(CBDCA-O，O‘)]，1，其中CBDCA是环丁烷-1，1-二羧酸盐，用于治疗卵巢癌、肺癌和其他类型的癌症。我们最近展示了(Di Pasqua et al.(2006)Chem.Toxicol资源。卡铂与碳酸盐在模拟治疗条件下反应生成碳酸卡铂，顺式[铂(NH3)(2)(O-CBDCA)(CO3)](2-)](2-)，2。我们用C-13和H-1核磁共振和紫外可见吸收光谱表明，在不同条件下在碳酸盐缓冲液中老化的含有卡铂的溶液含有1，2和其他化合物。然后，我们证明了碳酸盐中老化的卡铂产生的化合物对人类神经母细胞瘤(SK-N-SH)、近端肾小管(HK-2)和Namalwa-Luc Burkitt淋巴瘤(BL)细胞的毒性比单独使用卡铂更大。此外，延长老化时间会增加铂溶液的细胞毒性，这是通过增加细胞死亡来衡量的。虽然HK-2细胞在接触碳酸盐形式的药物后存活损失很大，但在所研究的三种细胞系中，它们的IC50值最高，因此HK-2细胞对培养基中碳酸盐形式的毒性作用的抵抗力最强。这与在治疗中观察到的卡铂的低肾毒性是一致的。用电感耦合等离子体质谱(ICPMS)测得正常Jurkat细胞(NJ)和顺铂耐药Jurkat细胞(RJ)的摄取速率分别为Pth(-1)细胞(-1)的16.6+/-4.2和12.3+/-4.8amol。然而，当这些细胞暴露于碳酸盐介质中老化的卡铂时，正常Jurkat细胞以14.5+/-4.1amol的速率结合/摄取铂h(-1)细胞(-1)，而耐药细胞强烈结合/摄取Pth(-1)细胞(-1)的5.1+/-3.3amol。总而言之，这些研究表明，卡铂碳酸盐物种可能在细胞毒性和卡铂被细胞摄取方面发挥主要作用。
Carboplatin, [Pt(NH3)(2)(CBDCA-O,O')], 1, where CBDCA is cyclobutane-1,1-dicarboxylate, is used against ovarian, lung, and other types of cancer. We recently showed (Di Pasqua et al. (2006) Chem. Res. Toxicol. 19, 139-149) that carboplatin reacts with carbonate under conditions that simulate therapy to produce carbonato carboplatin, cis-[Pt(NH3)(2)(O-CBDCA)(CO3)](2-), 2. We use C-13 and H-1 NMR and UV-visible absorption spectroscopy to show that solutions containing carboplatin that have been aged in carbonate buffer under various conditions contain 1, 2, and other compounds. We then show that aging carboplatin in carbonate produces compounds that are more toxic to human neuroblastoma (SK-N-SH), proximal renal tubule (HK-2) and Namalwa-luc Burkitt's lymphoma (BL) cells than carboplatin alone. Moreover, increasing the aging time increases the cytotoxicity of the platinum solutions as measured by the increase in cell death. Although HK-2 cells experience a large loss in survival upon exposure to carbonato forms of the drug, they have the highest values of IC50 of the three cell lines studied, so that HK-2 cells remain the most resistant to the toxic effects of the carbonato forms in the culture medium. This is consistent with the well-known low renal toxicity observed for carboplatin in therapy. The uptake rates for normal Jurkat cells (NJ) and cisplatin-resistant Jurkat cells (RJ), measured by inductively coupled plasma mass spectrometry (ICP-MS), are 16.6 +/- 4.2 and 12.3 +/- 4.8 amol of Pt h(-1) cell(-1), respectively, when exposed to carboplatin alone. However, when these cells are exposed to carboplatin that has been aged in carbonate media, normal Jurkat cells strongly bind/take up Pt at a rate of 14.5 +/- 4.1 amol of Pt h(-1) cell(-1), while resistant cells strongly bind/take up 5.1 +/- 3.3 amol of Pt h(-1) cell(-1). Collectively, these studies show that carboplatin carbonato species may play a major role in the cytotoxicity and uptake of carboplatin by cells.