Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
复制标题
DOI：
10.1126/science.1171362
复制
发表时间：
2009-06-12
期刊：
影响因子：
--
通讯作者：
Tuveson DA
中科院分区：
文献类型：
--
作者：
Olive KP;Jacobetz MA;Davidson CJ;Gopinathan A;McIntyre D;Honess D;Madhu B;Goldgraben MA;Caldwell ME;Allard D;Frese KK;Denicola G;Feig C;Combs C;Winter SP;Ireland-Zecchini H;Reichelt S;Howat WJ;Chang A;Dhara M;Wang L;Rückert F;Grützmann R;Pilarsky C;Izeradjene K;Hingorani SR;Huang P;Davies SE;Plunkett W;Egorin M;Hruban RH;Whitebread N;McGovern K;Adams J;Iacobuzio-Donahue C;Griffiths J;Tuveson DA
胰腺导管腺癌（PDA）是最致命的人类癌症之一，部分原因是它对许多化疗药物不敏感。通过研究一种对临床使用的药物吉西他滨具有耐药性的胰腺导管腺癌小鼠模型，我们发现该模型中的肿瘤血液灌注不良且血管化程度低，这些特性与人类胰腺导管腺癌相同。我们测试了通过联合使用IPI - 926是否可以提高吉西他滨在小鼠体内的递送和疗效，IPI - 926是一种通过抑制Hedgehog细胞信号通路来减少肿瘤相关基质组织的药物。联合治疗使肿瘤内血管密度和吉西他滨在肿瘤内的浓度短暂增加，从而使疾病得到短暂稳定。因此，药物递送效率低下可能是胰腺癌化疗耐药的一个重要原因。
Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers, in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by co-administration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibiting the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
登录
查看更多内容
影响因子：
45.3
作者：
Van Cutsem, Eric;Vervenne, Walter L.;Moore, Malcolm J.
通讯作者：
Moore, Malcolm J.
影响因子：
11.2
作者：
Shimamura, Takeshi;Royal, Richard E.;Puri, Raj K.
通讯作者：
Puri, Raj K.
影响因子：
64.8
作者：
Thayer, SP;di Magliano, MP;Hebrok, M
通讯作者：
Hebrok, M
影响因子：
2.9
作者：
Sakamoto, Hiroki;Kitano, Masayuki;Kudo, Masatoshi
通讯作者：
Kudo, Masatoshi
DOI：
10.1073/pnas.0813203106
发表时间：
2009-03-17
影响因子：
11.1
作者：
Tian, Hua;Callahan, Christopher A.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.