title: 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.affiliation: Authors' Affiliations: Departments of Surgery and Pediatrics; Indiana University Health Goshen Center for Cancer Care, Indiana University School of Medicine, South Bend, Indiana; Division of Surgical Oncology, Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas; and Department of Gastrointestinopancreatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Anna M
authors.initials: AM
authors.lastname: Schwarz
authors.forename: Stefan
authors.initials: S
authors.lastname: Hinz
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
mesh_terms: D000418:Albumins / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D017239:Paclitaxel