Cisplatin and dimethyl sulfoxide react to form an adducted compound with reduced cytotoxicity and neurotoxicity
Cisplatin and dimethyl sulfoxide react to form an adducted compound with reduced cytotoxicity and neurotoxicity
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DOI：
10.1016/j.neuro.2008.02.010
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发表时间：
2008-05-01
期刊：
影响因子：
3.4
通讯作者：
Windebank, Anthony J.
中科院分区：
文献类型：
--
作者：
Fischer, Stephanie J.;Benson, Linda M.;Windebank, Anthony J.
目的：我们展示了顺铂在溶液中与二甲亚砜（DMSO）快速反应，并鉴定了所得化合物的结构和反应活性。方法：采用电喷雾电离质谱法（ESI-MS）和核磁共振（NMR）对DMSO与顺铂反应形成的化合物进行化学结构鉴定。我们研究了鉴定的化合物与DNA的反应性。通过对神经元和癌细胞的体外毒性研究以及对大鼠的体内毒性研究来确定所鉴定化合物的癌症化疗和毒性作用。结果：顺铂与DMSO快速结合形成DMSO加合物。所得到的化合物在体外和细胞中都降低了与双链DNA结合的能力。这种化合物在体外降低了对癌细胞和神经元的毒性。体内肾毒性研究表明，该内合物具有与顺铂不同的肾毒性和消除特性。结论：从这项工作中，我们得出结论，在DMSO中溶解顺铂会形成具有不同治疗和生物学特性的内合化合物。此外，未来的研究建议使用DMSO联合顺铂进行化疗治疗的患者必须重新考虑。由于反应的快速和性质，DMSO和顺铂不应联合用于患者治疗。(C) 2008爱思唯尔公司版权所有。
Purpose: We present work that demonstrates that cisplatin reacts rapidly with dimethyl sulfoxide (DMSO) in solution and identify the structure and reactivity of the resulting compound.Methods: Electrospray ionization-mass spectrometry (ESI-MS) and NMR were used to identify the chemical structure of compounds formed when DMSO reacts with cisplatin. We studied the reactivity of the identified compound with DNA. In vitro toxicity studies in neurons and cancer cells and in vivo toxicity studies in rats were used to determine both the cancer chemotherapeutic and toxic effects of the identified compound.Results: Cisplatin binds rapidly with DMSO to form a DMSO adduct. The resulting compound has reduced ability to bind to double-stranded DNA both in vitro and in cells. This compound has reduced toxicity for cancer cells and neurons in vitro. In vivo nephrotoxicity studies show that the adducted compound has different nephrotoxicity and elimination characteristics than cisplatin.Conclusions: From this work, we conclude that dissolving cisplatin in DMSO results in formation of an adducted compound with different therapeutic and biological characteristics. Furthermore, future studies which propose using DMSO in combination with cisplatin for chemotherapeutic treatment in patients must be reconsidered. Due to the rapidity and nature of the reaction, DMSO and cisplatin should not be combined for patient treatment. (C) 2008 Elsevier Inc. All rights reserved.