alexa Increasing Bioavailability of Cytotoxic Agents through
ISSN: 2167-0501

Biochemistry & Pharmacology: Open Access
Open Access

OMICS International organises 3000+ Global Conferenceseries Events every year across USA, Europe & Asia with support from 1000 more scientific Societies and Publishes 700+ Open Access Journals which contains over 50000 eminent personalities, reputed scientists as editorial board members.

Open Access Journals gaining more Readers and Citations

700 Journals and 15,000,000 Readers Each Journal is getting 25,000+ Readers

This Readership is 10 times more when compared to other Subscription Journals (Source: Google Analytics)

Research Article

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

Awasthi N1,2*, Schwarz MA1,4, Wang C3, Williams SN3 and Schwarz RE1,2
1Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA
2Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3Department of Biochemistry, the University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4Department of Pediatrics, Indiana University School of Medicine, South Bend, IN 46617, USA
Corresponding Author : Niranjan Awasthi
Department of Surgery
Indiana University School of Medicine
1234 Notre Dame Ave, South Bend, IN 46617, USA
Tel: 574-631-5780
Fax: 574-631-7821
E-mail: [email protected]
Received: June 24, 2015 Accepted: July 21, 2015 Published: July 25, 2015
Citation: Awasthi N, Schwarz MA, Wang C, Williams SN, Schwarz RE (2015) Increasing Bioavailability of Cytotoxic Agents through Prolonged Therapy and Addition of Polymechanistic Antiangiogenic Agents Enhances Antitumor Response in Pancreatic Cancer. Biochem Pharmacol (Los Angel) 4:177. doi:10.4172/2167-0501.1000177
Copyright: © 2015 Awasthi N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 

Abstract

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.

Keywords

Share This Page

Additional Info

Loading
Loading Please wait..
 
Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords