Limited tissue penetration of taxanes: A mechanism for resistance in solid tumors
Limited tissue penetration of taxanes: A mechanism for resistance in solid tumors
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DOI：
10.1158/1078-0432.ccr-06-1941
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Minchinton, Andrew I.
中科院分区：
文献类型：
--
作者：
Kyle, Alastair H.;Huxham, Lynsey A.;Minchinton, Andrew I.
目的：药物在实体瘤中的有限渗透是许多抗癌药物耐药的潜在机制。紫杉烷类药物，目前正在经历一个新的一轮的发展，但很少知道他们的能力，渗透和分布相对于血管内的实体tumor.Experimental Design：我们评估了紫杉醇和多西他赛的HCT-116肿瘤异种移植物和多层细胞培养（MCC），肿瘤血管外腔室的三维细胞培养模型的组织渗透。在异种移植物中，紫杉烷相对于血管进行映射，以获得作为与脉管系统的距离的函数的药物谱。对于MCC，培养物暴露于搅拌药物水库和紫杉烷作为深度到tissue.Results的函数测量：两个紫杉烷表现出有限的渗透，很少的药物达到进一步超过100克进入组织。其中，紫杉醇的渗透性是多西他赛的2倍。在治疗后绘制肿瘤细胞增殖允许评估有限药物渗透的后果。在肿瘤异种移植物中，远离血管系统的细胞的药物暴露减少是影响治疗反应的几个因素之一，在最接近血管的细胞中，S期细胞减少了高达75%，但在组织中仅观察到50%的减少150 μ m远。在基于MCC的数据中，避免了细胞增殖随组织深度而减少的影响，（紫杉醇）和10倍（多西他赛）的储库药物浓度的增加需要在细胞中产生相当于直接暴露于药物的细胞中所见的150 μ m进入组织的响应。这些结果表明，有限分布是肿瘤对紫杉烷类耐药的重要机制。
Purpose: Limited drug penetration in solid tumors is a potential mechanism of resistance for many anticancer drugs. Taxanes represent a class of drugs that are currently undergoing a new round of development, but with little known of their ability to penetrate and distribute relative to blood vessels within solid tumors.Experimental Design: We assessed the tissue penetration of paclitaxel and docetaxel in HCT-116 tumor xenografts and in multilayered cell culture (MCC), a three-dimensional cell culture model of the tumor extravascular compartment. In xenografts, taxanes were mapped relative to blood vessels to obtain drug profiles as a function of distance from vasculature. For MCC, cultures were exposed to stirred drug reservoirs and taxanes measured as a function of depth into tissue.Results: Both taxanes exhibited limited penetration, with little drug reaching further than 100 gm into the tissue. Of the two, paclitaxel exhibited up to 2-fold greater penetration than docetaxel. Mapping tumor cell proliferation following treatment allowed the consequences of limited drug penetration to be assessed. In tumor xenografts where reduced drug exposure to cells far from vasculature is one of several factors influencing response to treatment, up to a 75% reduction in S-phase cells was achieved in cells nearest the vessels, but only 50% reduction was observed in the tissue 150 mu m away. In MCC-based data, where the influence of reduced cell proliferation with depth into tissue was circumvented, a 5-fold (paclitaxel) and 10-fold (docetaxel) increase in reservoir drug concentration was required to produce a response in cells 150 Am into the tissue equivalent to that seen in cells directly exposed to the drug.Conclusion: These results indicate that limited distribution is an important mechanism of tumor resistance to taxanes.