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

Abstract

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 co-administration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels due to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase (Cda). Correspondingly, paclitaxel reduced Cda protein levels 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.

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

“…As was recently demonstrated by Frese et al 47 , approaches which favorably alter gemcitabine's biodistribution properties (e.g., enhanced intratumoral concentration) have important implications for the treatment of a variety of tumors. In projecting on GSG's possible clinical use, we are encouraged to continue to evaluate it further at the preclinical level, anticipating that GSG (as a prodrug) could ultimately lead to significant reduction of gemcitabine's effective dose and adverse effects.…”

Combination therapy with gemcitabine and nab-paclitaxel for locally advanced unresectable pancreatic cancer

“…By doing so, the intratumoral concentration of GEM is increased by ~3-fold (12). In addition, nab-PTX decreases the plasma concentration of cytidine deaminase, one of the enzymes that metabolizes GEM, and has also been reported to stabilize the active form of an intratumoral GEM metabolite, gemcitabine triphosphate (13). Therefore, the direct anticancer and synergistic effects of nab-PTX used in combination with GEM enable powerful tumor-reducing effects.…”

CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer

“…Here we investigated whether increased accumulation of active gemcitabine triphosphate (2′,2′-difluorodeoxycytidine-5′-triphosphate; dFdCTP) without additional modifications of the tumor vasculature or stromal composition would be sufficient to improve therapeutic response in tumor-bearing KPC mice. Gemcitabine is either rapidly phosphorylated inside cells to the active compound dFdCTP or quickly enzymatically inactivated both inside and outside cells from its native form (2′,2′-difluorodeoxycytidine; dFdC) to the inactivate metabolite 2′,2′-difluorodeoxyuridine (dFdU) by the enzyme cytidine deaminase (CDA), and CDA is highly expressed in murine PDA neoplastic cells (29). First, we established the pharmacokinetic and pharmacodynamic profile of gemcitabine metabolites in KPC mice using a highly sensitive LC-MS/MS assay (30).…”