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

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-1 PDAC cells, NPT IC(50) was reduced >6-fold by the addition of sunitinib (IC(25)) but not by bevacizumab. In human umbilical vein endothelial cells (HUVEC), NPT IC(50) (82 nmol/L) was decreased to 41 nmol/L by bevacizumab and to 63 nmol/L by sunitinib. In fibroblast WI-38 cells, NPT IC(50) (7.2 μmol/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.

• Authors: Niranjan Awasthi, Changhua Zhang, Anna M Schwarz, Stefan Hinz, Margaret A Schwarz, Roderich E Schwarz
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 5 Pg. 1032-43 (May 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 24608575 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 130-nm albumin-bound paclitaxel
• Albumins
• Angiogenesis Inhibitors
• Antineoplastic Agents
• Paclitaxel

Topics

• Albumins (pharmacology)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Synergism
• Female
• Humans
• Mice
• Paclitaxel (pharmacology)
• Pancreatic Neoplasms (drug therapy, mortality, pathology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays