Zhao L, Ching L-M, Kestell P, Baguley B C
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Br J Cancer. 2002 Aug 12;87(4):465-70. doi: 10.1038/sj.bjc.6600479.
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.
5,6 - 二甲基呫吨酮 - 4 - 乙酸，一种新型抗血管生成抗癌药物，已完成I期临床试验。它在小鼠体内的作用包括诱导肿瘤坏死因子、释放血清素、抑制肿瘤血流以及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基因靶向敲除的小鼠作为结肠38癌的受体，以确定肿瘤坏死因子信号传导在5,6 - 二甲基呫吨酮 - 4 - 乙酸作用中的作用。5,6 - 二甲基呫吨酮 - 4 - 乙酸的药代动力学以及诱导的血浆和组织肿瘤坏死因子水平在肿瘤坏死因子受体 - 1(-/-)小鼠和野生型小鼠中相似。然而，5,6 - 二甲基呫吨酮 - 4 - 乙酸在肿瘤坏死因子受体 - 1(-/-)小鼠中的最大耐受剂量（>100 mg kg(-1)）比野生型小鼠（27.5 mg kg(-1)）高得多。5,6 - 二甲基呫吨酮 - 4 - 乙酸（25 mg kg(-1)）在肿瘤坏死因子受体 - 1(-/-)小鼠中的抗肿瘤活性大大减弱。然而，肿瘤坏死因子受体 - 1(-/-)小鼠中毒性的降低使得能够证明在较高剂量（50 mg kg(-1)）下，5,6 - 二甲基呫吨酮 - 4 - 乙酸具有治愈作用，且效果与野生型小鼠中较低剂量（25 mg kg(-1)）相当。5,6 - 二甲基呫吨酮 - 4 - 乙酸诱导的血浆5 - 羟吲哚乙酸升高用于反映血管反应中的血清素产生，在荷结肠38肿瘤的肿瘤坏死因子受体 - 1(-/-)小鼠中比未荷瘤小鼠更大，但在每种情况下，该反应均小于野生型小鼠中的相应反应。结果表明肿瘤坏死因子在介导5,6 - 二甲基呫吨酮 - 4 - 乙酸的宿主毒性和抗肿瘤活性中起重要作用，但也表明在其抗肿瘤作用中肿瘤坏死因子可被其他血管活性因子替代，这一观察结果与当前临床研究相关。
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