title: nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer.
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.
  
  
  CONCLUSIONS
  This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer.
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Frese
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.|Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstr, 35043 Marburg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Neesse
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.|Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Cook
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.|Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Tashinga E
authors.initials: TE
authors.lastname: Bapiro
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.|Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.|Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.affiliation: Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, UK.|Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D000418:Albumins / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D003564:Cytidine Deaminase / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000093542:Gemcitabine
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D017239:Paclitaxel; D000093542:Gemcitabine