Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer

被引：2491

作者：

Olive, Kenneth P. ^{[1
]}

Jacobetz, Michael A. ^{[1
]}

Davidson, Christian J. ^{[2
]}

Gopinathan, Aarthi ^{[1
,2
]}

McIntyre, Dominick ^{[1
]}

Honess, Davina ^{[1
]}

Madhu, Basetti ^{[1
]}

Goldgraben, Mae A. ^{[1
]}

Caldwell, Meredith E. ^{[1
]}

Allard, David ^{[1
]}

Frese, Kristopher K. ^{[1
]}

DeNicola, Gina ^{[1
,2
]}

Feig, Christine ^{[1
]}

Combs, Chelsea ^{[2
]}

Winter, Stephen P. ^{[1
]}

Ireland-Zecchini, Heather ^{[1
]}

Reichelt, Stefanie ^{[1
]}

Howat, William J. ^{[1
]}

Chang, Alex ^{[3
,4
,5
]}

Dhara, Mousumi ^{[3
,4
,5
]}

Wang, Lifu ^{[2
,6
]}

Rueckert, Felix ^{[7
]}

Gruetzmann, Robert ^{[7
]}

Pilarsky, Christian ^{[7
]}

Izeradjene, Kamel ^{[8
,9
]}

Hingorani, Sunil R. ^{[8
,9
]}

Huang, Pearl ^{[10
]}

Davies, Susan E. ^{[11
]}

Plunkett, William ^{[12
]}

Egorin, Merrill ^{[13
]}

Hruban, Ralph H. ^{[3
,4
,5
]}

Whitebread, Nigel ^{[14
]}

McGovern, Karen ^{[14
]}

Adams, Julian ^{[14
]}

Iacobuzio-Donahue, Christine ^{[3
,4
,5
]}

Griffiths, John ^{[1
]}

Tuveson, David A. ^{[1
]}

机构：

[1] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 ORE, England

[2] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[3] Sidney Canc Ctr, Sol Goldman Pancreat Canc Res Ctr, Dept Oncol, Baltimore, MD 21287 USA

[4] Sidney Canc Ctr, Sol Goldman Pancreat Canc Res Ctr, Dept Pathol, Baltimore, MD 21287 USA

[5] Johns Hopkins Univ, Baltimore, MD 21287 USA

[6] Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Gastroenterol, Sch Med, Shanghai 200025, Peoples R China

[7] Univ Hosp Dresden, Dept Surg, D-01307 Dresden, Germany

[8] Fred Hutchinson Canc Res Ctr, Clin Res & Publ Hlth Sci Div, Seattle, WA 98109 USA

[9] Univ Washington, Seattle, WA 98109 USA

[10] Merck & Co Inc, Oncol Franchise, N Wales, PA 19454 USA

[11] Cambridge Univ Hosp Natl Hlth Serv Fdn Trust, Addenbrookes Hosp, Dept Histopathol, Cambridge CB2 2QQ, England

[12] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[13] Univ Pittsburgh, Med Ctr, Div Hematol & Oncol, Pittsburgh, PA 15213 USA

[14] Infin Pharmaceut, Cambridge, MA 01239 USA

来源：

SCIENCE | 2009年 / 324卷 / 5933期

关键词：

DUCTAL ADENOCARCINOMA; SONIC HEDGEHOG; GEMCITABINE; GROWTH; METASTASIS; DIAGNOSIS; SURVIVAL; THERAPY; TUMORS; TRIAL;

D O I：

10.1126/science.1171362

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of 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.

引用

页码：1457 / 1461

页数：5

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