Enhancement of nab-paclitaxel antitumor activity through addition of multitargeting antiangiogenic agents in experimental pancreatic cancer

Niranjan Awasthi, Changhua Zhang, Anna M. Schwarz, Stefan Hinz, Margaret A. Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel, NPT) has recently shown efficacy in pancreatic ductal adenocarcinoma (PDAC). Targeting tumor angiogenesis is a sensible combination therapeutic strategy for cancer, including PDAC. We tested the hypothesis that NPT response in PDAC can be enhanced by the mechanistically different antiangiogenic agents bevacizumab (Bev) or sunitinib (Su), despite its inherently increased tumor penetration and drug delivery. Compared with controls (19 days), median animal survival was increased after NPT therapy (32 days, a 68% increase, P = 0.0008); other regimens with enhanced survival were NPT+Bev (38 days, a 100% increase, P = 0.0004), NPT+Su (37 days, a 95% increase, P = 0.0004), and NPT+Bev+Su (49 days, a 158% increase, P = 0.0001) but not bevacizumab, sunitinib, or Bev+Su therapy. Relative to controls (100 ± 22.8), percentage net local tumor growth was 28.2 ± 23.4 with NPT, 55.6 ± 18 (Bev), 38.8 ± 30.2 (Su), 11 ± 7.2 (Bev+Su), 32.8 ± 29.2 (NPT+Bev), 6.6 ± 10.4 (NPT+Su), and 13.8 ± 12.5 (NPT+Bev+Su). Therapeutic effects on intratumoral proliferation, apoptosis, microvessel density, and stromal density corresponded with tumor growth inhibition data. In AsPC-1PDACcells, NPTIC 50 was reduced >6-fold by the addition of sunitinib (IC 25) but not by bevacizumab. In human umbilical vein endothelial cells (HUVEC), NPT IC50 (82 nmol/L) was decreased to 41 nmol/L by bevacizumab and to 63 nmol/L by sunitinib. In fibroblast WI-38 cells, NPT IC50 (7.2 mmol/L) was decreased to 7.8 nmol/L by sunitinib, but not by bevacizumab. These findings suggest that the effects of one of the most active cytotoxic agents against PDAC, NPT, can be enhanced with antiangiogenic agents, which clinically could relate to greater responses and improved antitumor results.

Original languageEnglish (US)
Pages (from-to)1032-1043
Number of pages12
JournalMolecular Cancer Therapeutics
Volume13
Issue number5
DOIs
StatePublished - May 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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