Journal
CANCER DISCOVERY
Volume 2, Issue 3, Pages 260-269Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-11-0242
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Funding
- University of Cambridge
- Cancer Research UK
- Li Ka Shing Foundation
- Hutchison Whampoa Limited
- NIHR Cambridge Biomedical Research Centre
- NIH Ruth L. Kirschstein National Research Service Award [F32CA123887-01]
- European Community Grant [EPC-TM-Net 256974]
- Deutsche Krebshilfe Mildred Scheel Postdoctoral Fellowship
- Cancer Research UK Clinician Fellowship
- Dutch Cancer Foundation Fellowship grant [UU2008-4380]
- Cancer Research UK [15678] Funding Source: researchfish
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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. (c) 2012 AACR.
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