Carbon monoxide, generated by heme oxygenase-1, mediates the enhanced permeability and retention effect in solid tumors

Cancer Sci. 2012 Mar;103(3):535-41. doi: 10.1111/j.1349-7006.2011.02178.x. Epub 2012 Jan 16.


The enhanced permeability and retention (EPR) effect is a unique pathophysiological phenomenon of solid tumors that sees biocompatible macromolecules (>40 kDa) accumulate selectively in the tumor. Various factors have been implicated in this effect. Herein, we report that heme oxygenase-1 (HO-1; also known as heat shock protein 32) significantly increases vascular permeability and thus macromolecular drug accumulation in tumors. Intradermal injection of recombinant HO-1 in mice, followed by i.v. administration of a macromolecular Evans blue-albumin complex, resulted in dose-dependent extravasation of Evans blue-albumin at the HO-1 injection site. Almost no extravasation was detected when inactivated HO-1 or a carbon monoxide (CO) scavenger was injected instead. Because HO-1 generates CO, these data imply that CO plays a key role in vascular leakage. This is supported by results obtained after intratumoral administration of a CO-releasing agent (tricarbonyldichlororuthenium(II) dimer) in the same experimental setting, specifically dose-dependent increases in vascular permeability plus augmented tumor blood flow. In addition, induction of HO-1 in tumors by the water-soluble macromolecular HO-1 inducer pegylated hemin significantly increased tumor blood flow and Evans blue-albumin accumulation in tumors. These findings suggest that HO-1 and/or CO are important mediators of the EPR effect. Thus, anticancer chemotherapy using macromolecular drugs may be improved by combination with an HO-1 inducer, such as pegylated hemin, via an enhanced EPR effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capillary Permeability / physiology*
  • Carbon Monoxide / metabolism*
  • Heme Oxygenase-1 / metabolism*
  • Male
  • Mice
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / metabolism*
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Microenvironment / physiology*


  • Carbon Monoxide
  • Heme Oxygenase-1