首页> 外文会议>American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics >Quantitative HPLC-ESI-MS/MS Analysis of bis-N7-Guanine Cross-Links in White Blood Cells of Cancer Patients Receiving Cyclophosphamide Therapy
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Quantitative HPLC-ESI-MS/MS Analysis of bis-N7-Guanine Cross-Links in White Blood Cells of Cancer Patients Receiving Cyclophosphamide Therapy

机译:癌症患者白细胞中BIS-N7-鸟嘌呤交联的定量HPLC-ESI-MS / MS分析,接受环磷酰胺治疗的癌症患者

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Cyclophosphamide (CPA) is a common DNA alkylating agent used in many chemotherapy regimens, including bone marrow transfer conditioning protocols. CPA is metabolized by cytochrome P450 2B6 to yield 4-hydroxy-CPA, phosphoramide mustard, nornitrogen mustard (NOR), and acrolein. Formation of the DNA-DNA crosslinks, N,N-bis-[2-(7-guaninyl)ethyl] amine (G-NOR-G), through N-7 alkylation of guanine bases in DNA by NOR is considered the primary mechanism of action of CPA. However, few methods are available to quantify CPA-induced DNA lesions. The objective of the present work was to analyze the formation and repair of G-NOR-G adducts in white blood cells of cancer patients undergoing CPA therapy. Sensitive and specific capillary HPLC-ESI~(+)-MS/MS methodology was developed that enabled accurate quantification of G-NOR-G in blood of cancer patients at different times following IV administration of CPA. We found that G-NOR-G adduct numbers reach a maximum value 8 hours following drug treatment and are still detectable 24 h post treatment. These results suggest that interindividual differences in sensitivity towards CPA may result from variations in the rates of G-NOR-G cross-link formation and repair.
机译:环磷酰胺(CPA)是在许多化疗方案中使用的常见DNA烷化剂,包括骨髓转移调理方案。 CPA通过细胞色素P450 2B6代谢,得到4-羟基-CPA,磷酰胺芥末,甲醛芥菜(NOR)和丙烯醛。通过在DNA中的鸟嘌呤碱基碱基烷基化的DNA-DNA交联,N,N-BIS-[2-(7-胍基)乙基]胺(G-NOR-G)的形成,也不认为是主要机制CPA的行动。但是,很少有方法可以量化CPA诱导的DNA病变。本作目前的目的是分析癌症患者接受CPA治疗的白细胞中G-NOR-G加合物的形成和修复。开发了敏感性和特异性毛细管HPLC-ESI〜(+) - MS / MS方法,使能够在IV施用CPA施用后的不同时间的癌症患者的血液中的G-NOR-G的精确定量。我们发现G-NOR-G加合物数在药物处理后8小时达到最大值,并且仍然可检测到24小时后处理。这些结果表明,对CPA的敏感性的敏感性差异可能是由G-NOR-G交联形成和修复率的变化产生的。

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