Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy
Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy
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DOI：
10.1002/ijc.10316
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发表时间：
2002-05-01
影响因子：
6.4
通讯作者：
Rojiani, AM
中科院分区：
文献类型：
--
作者：
Siemann, DW;Mercer, E;Rojiani, AM
在实验性啮齿动物（KHT肉瘤）、人乳腺（SKBR 3）和卵巢（OW-1）肿瘤模型中评价了血管靶向剂5，6二甲基-氧杂蒽酮-4-乙酸（DMXAA）和考布他汀A-4磷酸二钠（CA 4DP）与抗癌药物顺铂和环磷酰胺（CP）的组合的效用。确定了导致快速血管关闭和随后广泛的中央肿瘤坏死的血管靶向剂的剂量。组织学评价显示，治疗后几个小时内肿瘤细胞的形态学损伤，随后由于长时间缺血导致广泛出血性坏死和剂量依赖性肿瘤细胞死亡。尽管这些效应是由一系列CA 4DP剂量（10-150 mg/kg）诱导的，但对DMXAA的剂量反应非常陡峭;剂量小于或等于15 mg/kg无效，剂量：20 mg/kg有毒。DMXAA还增强顺铂的肿瘤细胞杀伤，但需要>15 mg/kg的剂量。相比之下，CA 4DP增加顺铂诱导的肿瘤细胞杀伤在所有剂量的研究。顺铂疗效的增强依赖于药物之间的顺序和间隔。当顺铂后1-3小时给予血管靶向剂时，达到最大效果。当在一定剂量的顺铂或CP后1小时给予CA 4DP（100 mg/kg）或DMXAA（17.5 mg/kg）时，肿瘤细胞杀伤比单独化疗所见的大10-500倍。此外，包含抗血管药物不会增加与这些抗癌药物相关的骨髓干细胞毒性，因此产生治疗增益。(C)2002 Wiley-Liss，Inc.
The utility of combining the vascular targeting agents 5,6dimethyl-xanthenone-4 acetic acid (DMXAA) and combretastatin A-4 disodium phosphate (CA4DP) with the anticancer drugs cisplatin and cyclophosphamide (CP) was evaluated in experimental rodent (KHT sarcoma), human breast (SKBR3) and ovarian (OW-1) tumor models. Doses of the vascular targeting agents that led to rapid vascular shutdown and subsequent extensive central tumor necrosis were identified. Histologic evaluation showed morphologic damage of tumor cells within a few hours after treatment, followed by extensive hemorrhagic necrosis and dose-dependent neoplastic cell death as a result of prolonged ischemia. Whereas these effects were induced by a range of CA4DP doses (10-150 mg/kg), the dose response to DMXAA was extremely steep; doses less than or equal to15 mg/kg were ineffective and doses : 20 mg/kg were toxic. DMXAA also enhanced the tumor cell killing of cisplatin, but doses >15 mg/kg were required. In contrast, CA4DP increased cisplatin-induced tumor cell killing at all doses studied. This enhancement of cisplatin efficacy was dependent on the sequence and interval between the agents. The greatest effects were achieved when the vascular targeting agents were administered 1-3 hr after cisplatin. When CA4DP (100 mg/kg) or DMXAA (17.5 mg/kg) were administered I hr after a range of doses of cisplatin or CP, the tumor cell kill was 10-500-fold greater than that seen with chemotherapy alone. In addition, the inclusion of the antivascular agents did not increase bone marrow stem cell toxicity associated with these anticancer drugs, thus giving rise to a therapeutic gain. (C) 2002 Wiley-Liss, Inc.