title: Carbon monoxide, generated by heme oxygenase-1, mediates the enhanced permeability and retention effect in solid tumors.
abstract: 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.
authors.affiliation: Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.forename: Haibo
authors.initials: H
authors.lastname: Qin
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsukigawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Shin
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeda
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D002248:Carbon Monoxide / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D002248:Carbon Monoxide; D051547:Heme Oxygenase-1