Biochemistry & Pharmacology: Open Access
Open Access

Abstract

Increasing Bioavailability of Cytotoxic Agents through Prolonged Therapy and Addition of Polymechanistic Antiangiogenic Agents Enhances Antitumor Response in Pancreatic Cancer

Awasthi N, Schwarz MA, Wang C, Williams SN and Schwarz RE

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. Meaningful therapeutic options for unresectable PDAC remain limited and therefore more efficient therapeutic strategies are urgently required. We explored the approach of manipulating dose intensity of cytotoxic agents through prolonged therapy and by combination with antiangiogenic agents in experimental PDAC. Median animal survival over controls (19 days) was increased after prolonged therapy (up to 6 weeks) with gemcitabine to 29 days (a 53% increase, p = 0.008). Addition of two antiangiogenic agents, bevacizumab and EMAP, further extended median survival to 46 days (a 142% increase, p = 0.0001). Corresponding survival extension after therapy with similar agents limited to 2 weeks was 37% for gemcitabine and 127% after gemcitabine plus antiangiogenic agents. Pharmacokinetic analysis revealed that the addition of antiangiogenic agents caused a 4.4-fold increase in gemcitabine plasma concentration and 8-fold increase in tumor concentration compared with gemcitabine monotherapy group. Prolonged therapy of docetaxel also increased animal survival (38 days, a 100% increase, p = 0.0004) that was further extended by the addition of the antiangiogenic combination (49 days, a 158% increase, p = 0.0001). In vitro evaluation of exposure time effects on cell proliferation revealed that in PDAC cells (AsPC-1) longer exposure (120 h) of gemcitabine or docetaxel caused greater relative inhibition in cell proliferation compared with 72 h exposure. At 1�M concentration, inhibition in cell proliferation after 72 h and 120 h was 27% and 55% (gemcitabine); 64% and 84% (docetaxel). Only in endothelial cells and fibroblasts but not in PDAC cells did the combination with antiangiogenic agents create additive effects over each cytotoxic agent alone. These findings demonstrate that increasing bioavailability of cytotoxic agents, both via increased exposure through prolonged therapy or greater intratumoral dose intensity by combination with antiangiogenic agents could enhance in vivo antitumor efficacy and thus warrants further investigation.