Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma.
Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma.
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DOI：
10.1038/sj.bjc.6605727
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发表时间：
2010-06-29
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
目前治疗胰腺癌的标准是每周给予吉西他滨治疗3周，共4周，治疗周期之间休息1周。最大耐受量(MTD)驱动的方案本身往往与毒性有关。最近的研究表明，在节律疗法中，经常以相对较低的剂量服用化疗药物也具有抗肿瘤活性，但副作用较少。在此，我们比较了节律和甲氨蝶呤吉西他滨的抗肿瘤效果，并研究了它们对两个不同患者建立的两个人胰腺癌移植瘤微环境的影响。节拍法和MTD吉西他滨显著减少了两种异种移植瘤的体积。然而，节律吉西他滨治疗的肿瘤的KTRANS值高于MTD治疗的肿瘤，这表明前者的组织灌注度更好。这些数据进一步得到肿瘤图谱研究的支持，这些研究显示节律吉西他滨治疗后缺氧显著减少。节律吉西他滨还显著增加了癌症相关成纤维细胞的凋亡，并导致多种促血管生成因子的肿瘤水平大幅下降，包括表皮生长因子、IL-1α、IL-8、ICAM-1和VCAM-1。节律剂量的吉西他滨在胰腺癌中是活跃的，并伴随着肿瘤微环境的显著变化。
The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects. Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients. Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, Ktrans values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1α, IL-8, ICAM-1, and VCAM-1. Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.
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影响因子：
5.7
作者：
Laquente, Berta;Lacasa, Cristina;Vinals, Francesc
通讯作者：
Vinals, Francesc
影响因子：
8.8
作者：
Boven, E;Schipper, H;Erkelens, C A;Hatty, S A;Pinedo, H M
通讯作者：
Pinedo, H M
影响因子：
11.2
作者：
Hamano, Y;Sugimoto, H;Kalluri, R
通讯作者：
Kalluri, R
影响因子：
5.4
作者：
Ghiringhelli, F;Larmonier, N;Martin, F
通讯作者：
Martin, F
影响因子：
45.3
作者：
Burris, HA;Moore, MJ;VanHoff, DD
通讯作者：
VanHoff, DD