Transport properties of pancreatic cancer describe gemcitabine delivery and response
Transport properties of pancreatic cancer describe gemcitabine delivery and response
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DOI：
10.1172/jci73455
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Fleming, Jason B.
中科院分区：
文献类型：
--
作者：
Koay, Eugene J.;Truty, Mark J.;Fleming, Jason B.
背景胰腺导管腺癌（PDAC）的耐药性部分归因于化疗药物对癌细胞的无效递送。我们假设，在血管，细胞外和细胞尺度的物理性质影响吉西他滨为基础的治疗的交付和响应。我们开发了一种方法来测量在常规对比增强CT扫描的个人PDAC肿瘤的质量传输特性。此外，我们评估了12例PDAC切除术期间吉西他滨输注，测量吉西他滨掺入肿瘤DNA并将其摄取与人平衡核苷转运蛋白（hENT1）水平、基质反应和CT衍生的质量转运特性相关联。我们还研究了接受术前吉西他滨为基础的放化疗治疗可切除PDAC的患者的CT衍生转运特性与临床结局之间的相关性。176例CT扫描的传输模型显示了正常胰腺和肿瘤之间传输特性的显著差异，具有广泛的增强特征。尽管血管内药代动力学相似，但切除的肿瘤在吉西他滨DNA掺入方面表现出显著差异，这反映了患者间对比增强的差异。在考虑hENT1水平后，吉西他滨掺入肿瘤DNA与CT衍生的转运参数和PDAC基质评分呈负相关。此外，基质评分与CT参数直接相关。在110例术前接受基于吉西他滨的放化疗的患者中，CT衍生参数与病理反应和生存率相关。吉西他滨与肿瘤DNA的结合是高度可变的，并与常规CT扫描得出的多尺度转运特性相关。此外，治疗前CT衍生特性与临床相关终点相关。
Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.