nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer

Cancer Discovery - Tập 2 Số 3 - Trang 260-269 - 2012
Natalie Cook1,2, Albrecht Neeße1, Tashinga E. Bapiro1, Martijn P. Lolkema1, Duncan I. Jodrell1, David A. Tuveson1
1Authors' Affiliations: 1Cambridge Research Institute, Li Ka Shing Centre, and 2Department of Oncology, University of Cambridge, Cambridge, United Kingdom; 3Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstr, Marburg, Germany; and 4Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
2Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands

Tóm tắt

Abstract Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials. Significance: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Cancer Discovery; 2(3); 260–9. ©2012 AACR. Read the Commentary on this article by Clark, p. 208 This article is highlighted in the In This Issue feature, p. 193

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Cancer Discovery

Tập 2 Số 3

260-269

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