Metronomic gemcitabine suppresses tumour growth, improves perfusion, and reduces hypoxia in human pancreatic ductal adenocarcinoma

Br J Cancer. 2010 Jun 29;103(1):52-60. doi: 10.1038/sj.bjc.6605727. Epub 2010 Jun 8.

Abstract

Background: The current standard of care for pancreatic cancer is weekly gemcitabine administered for 3 of 4 weeks with a 1-week break between treatment cycles. Maximum tolerated dose (MTD)-driven regimens as such are often associated with toxicities. Recent studies demonstrated that frequent dosing of chemotherapeutic drugs at relatively lower doses in metronomic regimens also confers anti-tumour activity but with fewer side effects.

Methods: Herein, we evaluated the anti-tumour efficacy of metronomic vs MTD gemcitabine, and investigated their effects on the tumour microenvironment in two human pancreatic cancer xenografts established from two different patients.

Results: Metronomic and MTD gemcitabine significantly reduced tumour volume in both xenografts. However, K(trans) values were higher in metronomic gemcitabine-treated tumours than in their MTD-treated counterparts, suggesting better tissue perfusion in the former. These data were further supported by tumour-mapping studies showing prominent decreases in hypoxia after metronomic gemcitabine treatment. Metronomic gemcitabine also significantly increased apoptosis in cancer-associated fibroblasts and induced greater reductions in the tumour levels of multiple pro-angiogenic factors, including EGF, IL-1alpha, IL-8, ICAM-1, and VCAM-1.

Conclusion: Metronomic dosing of gemcitabine is active in pancreatic cancer and is accompanied by pronounced changes in the tumour microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / blood supply
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / pathology
  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / blood supply
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Hypoxia*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Endothelial Cells / drug effects
  • Humans
  • Male
  • Mice
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • gemcitabine