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

Frese, K. K., Neesse, A., Cook, N., Bapiro, T. E., Lolkema, M. P., Jodrell, D. I., Tuveson, D. A. (2012) nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov, 2 (3). pp. 260-9. ISSN 2159-8290 (Electronic)2159-8274 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/22585996
DOI: 10.1158/2159-8290.cd-11-0242

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.

Item Type: Paper
Uncontrolled Keywords: Albumins/administration & dosage/ pharmacology Animals Antineoplastic Combined Chemotherapy Protocols/ pharmacology Carcinoma, Pancreatic Ductal/ drug therapy/enzymology/pathology Cytidine Deaminase/ metabolism Deoxycytidine/administration & dosage/ analogs & derivatives/pharmacology Disease Models, Animal Drug Synergism Mice Paclitaxel/administration & dosage/ pharmacology Pancreatic Neoplasms/ drug therapy/enzymology/pathology
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > drugs and therapies
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matt Covey
Date Deposited: 23 Jul 2015 14:57
Last Modified: 23 Jul 2015 14:57
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31644

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