Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.
Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.
复制标题
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。
DOI：
10.1038/bjc.1998.512
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发表时间：
1998-08
影响因子：
8.8
通讯作者：
Wilson, W R
中科院分区：
文献类型：
--
作者：
Lash, C J;Li, A E;Rutland, M;Baguley, B C;Zwi, L J;Wilson, W R
肿瘤血流抑制剂5，6-二甲基氧杂蒽酮-4-乙酸（DMXAA）会导致小鼠肿瘤出现严重的出血性坏死，但只有在接近毒性极限的剂量下才能观察到活性。本研究探讨了两种提高DMXAA治疗率的方法。第一种方法将DMXAA与第二种肿瘤血流抑制剂5-羟色胺（5-HT）相结合。对C3 H小鼠同时给予5-HT（700 μ mol kg（-1））可显著增强DMXAA对MDAH-MCa-4肿瘤的作用，血流抑制（4 h）的剂量修正因子（DMF）>3，坏死（12 h）为2.3，生长延迟为2.0，而不影响DMXAA的最大耐受剂量（90 μ mol kg（-1））。这些数据与肿瘤的缺血性损伤是抗肿瘤活性的主要机制一致。第二种方法将DMXAA（+/- 5-HT）与低氧选择性生物还原药物相结合。DMXAA强烈增强了所有三种测试的生物还原药物（替拉扎明、CI-1010、SN 23816）的抗肿瘤活性，表明DMXAA处理后存在可逆性缺氧肿瘤细胞群。5-HT的共施用进一步增强抗肿瘤活性，但也增加了替拉扎明和CI-1010的宿主毒性，使得几乎没有实现治疗益处。相比之下，DMXAA/5-HT仅略微增加了二硝基苯甲酰胺芥子气SN 23816的宿主毒性，而SN 23816最大耐受剂量下的肿瘤生长延迟从3.5天增加至26.5天。这项研究表明，5-HT和/或生物还原药物可以提高DMXAA在小鼠中的治疗活性，并且与SN 23816一起使用，这两种方法可以提供显著增强的抗肿瘤活性。
The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity.