Antitumour activity of sunitinib in combination with gemcitabine in experimental pancreatic cancer

HPB (Oxford). 2011 Sep;13(9):597-604. doi: 10.1111/j.1477-2574.2011.00333.x. Epub 2011 Jun 7.

Abstract

Background: Gemcitabine (Gem) has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Sunitinib (Su) is a novel, multi-target receptor tyrosine kinase inhibitor that has antitumour activities. This study tested the benefits of combined gemcitabine and sunitinib in PDAC.

Methods: Cell viability and protein expression were evaluated by WST-1 assay and Western blotting. Tumour growth and survival experiments were performed in murine xenografts.

Results: In PDAC cells, Gem, Su and Su + Gem, respectively, caused 28%, 22% and 48% inhibition in proliferation at 100 nM. In endothelial cells, Gem, Su and Su + Gem, respectively, caused 49%, 32% and 72% inhibition in proliferation. In fibroblasts, Gem, Su and Su + Gem, respectively, caused 65%, 14% and 79% inhibition in proliferation. Su increased apoptosis, as evidenced by the cleavage of caspase-3 and PARP-1 proteins. Net tumour growth compared with controls in the Gem, Su and Su + Gem groups was 57%, 6% and 1%, respectively. Intratumoral proliferative activity was reduced by 33%, 82% and 75% in the Gem, Su and Su + Gem groups, respectively, compared with controls. Median survival in the control, Su, Gem and Su + Gem groups was 16, 21, 24 and 30 days, respectively (P=0.007).

Conclusions: These findings support a combination approach using multi-target antiangiogenic agents such as sunitinib with standard gemcitabine therapy in the treatment of PDAC.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Angiogenesis Inhibitors / administration & dosage
  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Indoles / administration & dosage
  • Mice
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage
  • Pyrroles / administration & dosage
  • Sunitinib
  • Time Factors
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inhibitors
  • Antimetabolites, Antineoplastic
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrroles
  • Deoxycytidine
  • gemcitabine
  • Sunitinib