The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice.
The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF receptor-1 knockout mice.
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DOI：
10.1038/sj.bjc.6600479
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发表时间：
2002-08-12
影响因子：
8.8
通讯作者：
Baguley, BC
中科院分区：
文献类型：
--
作者：
Zhao, L;Ching, LM;Kestell, P;Baguley, BC
新型抗血管抗癌药物5，6-二甲基黄原酮-4-乙酸已完成I期临床试验。其对小鼠的作用包括诱导肿瘤坏死因子、释放5-羟色胺、抑制肿瘤血流、诱导肿瘤出血性坏死和消退。我们使用肿瘤坏死因子受体-1基因定向破坏的小鼠作为结肠癌38的受体，以确定肿瘤坏死因子信号在5，6-二甲基黄原酮-4-醋酸作用中的作用。在肿瘤坏死因子受体-1−/−和野生型小鼠体内，5，6-二甲基黄原酮-4-乙酸的药代动力学以及诱导血浆和组织肿瘤坏死因子的程度相似。然而，肿瘤坏死因子受体-1−/−小鼠的5，6-二甲基黄原酮-4-醋酸的最大耐受量(>；100 mg kg−1)显著高于野生型小鼠(27.5 mg kg−1)。5，6-二甲基黄原酮-4-醋酸(25 mg kg−1)对肿瘤坏死因子受体-1−/−小鼠的抗肿瘤作用明显减弱。然而，对肿瘤坏死因子受体-1−/−小鼠的毒性降低表明，在较高剂量(50 mg kg−1)下，5，6-二甲基黄原酮-4-乙酸对野生型小鼠的疗效与较低剂量(25 mg kg−1)相当。5，6-二甲基黄原酮-4-醋酸诱导的血浆5-羟基吲哚乙酸的升高，在结肠癌38号荷瘤小鼠中大于非荷瘤的肿瘤坏死因子受体-1−/−小鼠，但在每种情况下的反应都小于野生型小鼠。结果表明，肿瘤坏死因子在介导5，6-二甲基黄原酮-4-乙酸的宿主毒性和抗肿瘤活性中起重要作用，但也表明肿瘤坏死因子在其抗肿瘤作用中可被其他血管活性因子所替代，这一观察结果与目前的临床研究有关。《英国癌症杂志》(2002)87,465-470。DOI：10.1038/sj.bjc.6600479 www.bjancer.com2002英国癌症研究中心
5,6-dimethylxanthenone-4-acetic acid, a novel antivascular anticancer drug, has completed Phase I clinical trial. Its actions in mice include tumour necrosis factor induction, serotonin release, tumour blood flow inhibition, and the induction of tumour haemorrhagic necrosis and regression. We have used mice with a targeted disruption of the tumour necrosis factor receptor-1 gene as recipients for the colon 38 carcinoma to determine the role of tumour necrosis factor signalling in the action of 5,6-dimethylxanthenone-4-acetic acid. The pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid, as well as the degree of induced plasma and tissue tumour necrosis factor, were similar in tumour necrosis factor receptor-1−/− and wild-type mice. However, the maximum tolerated dose of 5,6-dimethylxanthenone-4-acetic acid was considerably higher in tumour necrosis factor receptor-1−/− mice (>100 mg kg−1) than in wild-type mice (27.5 mg kg−1). The antitumour activity of 5,6-dimethylxanthenone-4-acetic acid (25 mg kg−1) was strongly attenuated in tumour necrosis factor receptor-1−/− mice. However, the reduced toxicity in tumour necrosis factor receptor-1−/− mice allowed the demonstration that at a higher dose (50 mg kg−1), 5,6-dimethylxanthenone-4-acetic acid was curative and comparable in effect to that of a lower dose (25 mg kg−1) in wild-type mice. The 5,6-dimethylxanthenone-4-acetic acid -induced rise in plasma 5-hydroxyindoleacetic acid, used to reflect serotonin production in a vascular response, was larger in colon 38 tumour bearing than in non-tumour bearing tumour necrosis factor receptor-1−/− mice, but in each case the response was smaller than the corresponding response in wild-type mice. The results suggest an important role for tumour necrosis factor in mediating both the host toxicity and antitumour activity of 5,6-dimethylxanthenone-4-acetic acid, but also suggest that tumour necrosis factor can be replaced by other vasoactive factors in its antitumour action, an observation of relevance to current clinical studies. British Journal of Cancer (2002) 87, 465–470. doi:10.1038/sj.bjc.6600479 www.bjcancer.com © 2002 Cancer Research UK
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通过与 5-羟色胺和生物还原药物联合使用，增强抗血管剂 5,6-二甲基呫吨酮-4-乙酸 (DMXAA) 的抗肿瘤作用。
影响因子：
8.8
作者：
Lash, C J;Li, A E;Rutland, M;Baguley, B C;Zwi, L J;Wilson, W R
通讯作者：
Wilson, W R
影响因子：
8.8
作者：
Ching LM;Xu ZF;Gummer BH;Palmer BD;Joseph WR;Baguley BC
通讯作者：
Baguley BC
DOI：
10.1016/0277-5379(89)90072-2
发表时间：
1989-09-01
期刊：
EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY
影响因子：
--
作者：
KERR, DJ;KAYE, SB
通讯作者：
KAYE, SB
影响因子：
3
作者：
Kestell, P;Zhao, LL;Ching, LM
通讯作者：
Ching, LM
影响因子：
19.6
作者：
Messner, UK;Briner, VA;Pfeilschifter, J
通讯作者：
Pfeilschifter, J