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EMAP II-Based Antiangiogenic-Antiendothelial In Vivo Combination Therapy of Pancreatic Cancer

  • Translational Research and Biomarkers
  • Published:
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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) frequently resists conventional cytotoxic therapy. The antitumor effects of endothelial monocyte-activating polypeptide II (EMAP) have been attributed to its antiendothelial and antiangiogenic activities. We tested the hypothesis that a combination of EMAP with bevacizumab (Bev) and gemcitabine (Gem) targets different pathways of PDAC progression and represents more effective treatment.

Methods

Proliferation of PDAC and endothelial cell lines was evaluated in vitro. In vivo tumor growth and survival PDAC xenograft experiments were performed with EMAP, Bev, and Gem, either alone or in combination. Intratumoral microvessel density and proliferative activity were analyzed by immunostaining with PECAM-1 and proliferating cell nuclear antigen antibodies, and apoptotic activity was measured by the TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) procedure.

Results

Compared with controls, net reduction in tumor growth in EMAP, Bev, Gem, EMAP + Bev, EMAP + Gem, Bev + Gem, and EMAP + Bev + Gem groups was 58, 40, 40, 67, 68, 69, and 96%, respectively. Addition of EMAP to the Bev + Gem group statistically significantly improved survival at a median of >8 days while inducing long-term survival in some animals after maintenance therapy. Combination treatment of EMAP with Bev and Gem reduced proliferation of endothelial but not of PDAC cells. Addition of EMAP to Bev and Gem statistically significantly decreased proliferative activity while maintaining a comparable rate of microvessel density and apoptosis.

Conclusions

Addition of antiendothelial EMAP to a Bev and Gem regimen improves antitumor effects in a xenograft model of PDAC. This multitargeting strategy to prevent PDAC progression shows therapeutic promise and may overcome limitations by combinations of Gem with anti-vascular endothelial growth factor agents alone.

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Authors and Affiliations

  1. Department of Surgery, Division of Surgical Oncology, UT Southwestern Medical Center, Dallas, TX, USA

    Roderich E. Schwarz MD & Niranjan Awasthi PhD

  2. Department of Pediatrics, Division of Pediatric Critical Care Medicine, UT Southwestern Medical Center, Dallas, TX, USA

    Margaret A. Schwarz MD

  3. Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Divisions of Surgical Oncology and Surgical Sciences, The Cancer Institute of New Jersey, New Brunswick, New Jersey

    Roderich E. Schwarz MD, Niranjan Awasthi PhD, Srivani Konduri PhD, Danielle Cafasso MS & Margaret A. Schwarz MD

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  1. Roderich E. Schwarz MD
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  2. Niranjan Awasthi PhD
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Correspondence to Roderich E. Schwarz MD.

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Schwarz, R.E., Awasthi, N., Konduri, S. et al. EMAP II-Based Antiangiogenic-Antiendothelial In Vivo Combination Therapy of Pancreatic Cancer. Ann Surg Oncol 17, 1442–1452 (2010). https://doi.org/10.1245/s10434-009-0879-5

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