5、6-dimethylxanthenone-4-acetic酸(DMXAA):一个新的癌症治疗的生物反应修饰符。

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周,Kestell P,公元前Baguley,帕克斯顿JW

5、6-dimethylxanthenone-4-acetic酸(DMXAA):一个新的癌症治疗的生物反应修饰符。

新药投资。2002年8月,20 (3):281 - 95。

PubMed ID

12201491 (在PubMed

]

文摘

临床实验的抗癌药物5、6-dimethylxanthenone-4-acetic酸(DMXAA)是由奥克兰癌症协会研究中心(ACSRC)。它最近完成了第一阶段试验在新西兰和英国癌症研究的方向运动的I / II期临床试验。生物反应修饰符,DMXAA的药理学和毒理学特性非常不同于大多数传统的化疗药物。诱导细胞因子(特别是肿瘤坏死因子(tnf)、5 -羟色胺和一氧化氮(NO)), anti-vascular和抗血管生成效应被认为是主要的作用机理基于体外和动物实验。在第一阶段研究的癌症患者,DMXAA也表现出不同的生物效应,包括tnf诱导、5 -羟色胺和不符合这些影响在体外和动物实验。临床前研究表明,DMXAA有更强的抗肿瘤活性相比flavone-8-acetic酸(FAA)。与联邦航空局没有显示在癌症患者抗肿瘤活性,DMXAA(22毫克/公斤的静脉输液超过20分钟)导致部分响应在一个转移性宫颈鳞状细胞癌患者在研究的第一阶段65名癌症患者进入新西兰。最大耐受剂量(MTD)的老鼠,兔子,老鼠和人类是30,99年、330年和99年分别毫克/公斤。DMXAA dose-limiting毒性的癌症患者包括急性可逆震颤、认知障碍、视觉障碍、呼吸困难和焦虑。血浆蛋白结合和分配的血细胞DMXAA依赖物种和药物浓度。 DMXAA is extensively metabolised, mainly by glucuronidation of its acetic acid side chain and 6-methylhydroxylation, giving rise to DMXAA acyl glucuronide (DMXAA-G), and 6-hydroxymethyl-5-methylxanthenone-4-acetic acid (6-OH-MXAA), which are excreted into bile and urine. DMXAA-G has been shown to be chemically reactive, undergoing hydrolysis, intramolecular migration and covalent binding. Studies have indicated that DMXAA glucuronidation is catalysed by uridine diphosphate glucuronosyltransferases (UGT1A9 and UGT2B7), and 6-methylhydroxylation by cytochrome P450 (CYP1A2). Non-linear plasma pharmacokinetics of DMXAA has been observed in animals and patients, presumably due to saturation of the elimination process and plasma protein binding. Species differences in DMXAA plasma pharmacokinetics have been observed, with the rabbit having the greatest plasma clearance, followed by the human, rat and mouse. In vivo disposition studies in these species did not provide an explanation for the differences in MTD. Co-administration of DMXAA with other drugs has been shown to result in enhanced anti-tumour activity and alterations in pharmacokinetics, as reported for the combination of DMXAA with melphalan, thalidomide, cyproheptadine, and the bioreductive agent tirapazamine, in mouse models. Species-dependent DMXAA-thalidomide pharmacokinetic interactions have been observed. Co-administration of thalidomide significantly increased the plasma area of the plasma concentration-time curve (AUC) of DMXAA in mice, but had no effect on DMXAA's pharmacokinetics in the rat. It appears that the pharmacological and toxicological properties of DMXAA as a new biological response modifier are unlikely to be predicted based on preclinical studies. Similar to many biological response modifiers, DMXAA alone did not show striking anti-tumour activity in patients. However, preclinical studies of DMXAA-drug combinations indicate that DMXAA may have a potential role in cancer treatment when co-administered with other drugs. Further studies are required to explore the molecular targets of DMXAA and mechanisms for the interactions with other drugs co-administered during combination treatment, which may allow for the optimisation of DMXAA-based chemotherapy.

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药物酶

药物	酶	类	生物	药理作用	行动
Vadimezan	细胞色素P450 1 a2	蛋白质	人类	未知的	底物	细节
Vadimezan	UDP-glucuronosyltransferase 1 - 9	蛋白质	人类	未知的	底物	细节
Vadimezan	UDP-glucuronosyltransferase 2 b7	蛋白质	人类	未知的	底物	细节