Journal
CANCER SCIENCE
Volume 103, Issue 3, Pages 535-541Publisher
WILEY
DOI: 10.1111/j.1349-7006.2011.02178.x
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Funding
- Ministry of Education, Science, Culture, Sports and Technology of Japan [22700927, 17016076, 20015405]
- Ministry of Welfare, Health and Labor of Japan [H23-sanjig-ann-ippan-001]
- Grants-in-Aid for Scientific Research [22700927, 17016076] Funding Source: KAKEN
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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 bluealbumin complex, resulted in dose-dependent extravasation of Evans bluealbumin 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 bluealbumin 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. (Cancer Sci 2012; 103: 535541)
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