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Cancer Discov. 2012 Mar;2(3):260-269. doi: 10.1158/2159-8290.CD-11-0242. Epub 2012 Feb 28.

nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer.

Author information

1
Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
2
Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstr, 35043 Marburg, Germany.
3
Department of Oncology, University of Cambridge, Cambridge, UK.
4
Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
#
Contributed equally

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.

PMID:
22585996
PMCID:
PMC4866937
DOI:
10.1158/2159-8290.CD-11-0242
[Indexed for MEDLINE]
Free PMC Article

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