Modification of tumor blood flow: current status and future directions.
Suboptimal drug distribution and hypoxia, which can contribute to treatment failure, are a direct consequence of the spatial and temporal heterogeneity in perfusion that occurs in solid tumors. Therefore, improvements in tumor blood flow have wide-ranging therapeutic importance. Paradoxically, controlled decreases in tumor blood flow can also be exploited and, if permanent, induce extensive tumor cell death on their own. We review the current knowledge of the factors controlling tumor blood flow with emphasis on the roles of the endogeneous vasodilator nitric oxide and the endogenous vasoconstrictor endothelin-1. The potential importance and application of approaches that irreversibly damage vascular function, so-called vascular targeting, are also discussed. Emphasis is given to the drug-based approaches to vascular targeting that are now entering clinical evaluation. There is no doubt that increased understanding of the processes that determine blood flow in tumors, coupled with the availability of techniques to monitor blood flow noninvasively in the clinic, will enable strategies for selectively modifying tumor blood flow to be transferred from the laboratory to the clinical setting.
Chaplin
D J
DJ
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Hill
S A
SA
Bell
K M
KM
Tozer
G M
GM
D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001808:Blood Vessels / Q000187:drug effects; D016923:Cell Death; D015687:Cell Hypoxia; D019332:Endothelin-1 / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D009569:Nitric Oxide / Q000502:physiology; D012039:Regional Blood Flow / Q000502:physiology; D014018:Tissue Distribution; D017211:Treatment Failure; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000970:Antineoplastic Agents; D019332:Endothelin-1; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide