Targeting the tumour vasculature: exploitation of low oxygenation and sensitivity to NOS inhibition by treatment with a hypoxic cytotoxin

Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour...

Full description

Saved in:

Bibliographic Details
Published in:	PloS one Vol. 8; no. 10; p. e76832
Main Authors:	Baker, Jennifer H E, Kyle, Alastair H, Bartels, Kirsten L, Methot, Stephen P, Flanagan, Erin J, Balbirnie, Andrew, Cran, Jordan D, Minchinton, Andrew I
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 28-10-2013 Public Library of Science (PLoS)
Subjects:	Animals Anticancer properties Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biology Blood vessels Cancer Cancer therapies Cell death Cell Line, Tumor Chemical compounds Cytotoxicity Cytotoxins Cytotoxins - administration & dosage Deoxyribonucleic acid DNA Drug dosages Drugs Enzymes Exploitation Female Gene mapping Growth rate HCT116 Cells HT29 Cells Humans Hypoxia Immunohistochemistry Inhibition Inhibitors Medical research Mice Mice, Inbred C3H Mice, Inbred NOD Mice, SCID Multiplexing Muscles Neoplasms - blood supply Neoplasms - drug therapy Neoplasms - pathology Neovascularization, Pathologic - metabolism Neovascularization, Pathologic - pathology Neovascularization, Pathologic - prevention & control Nitric oxide Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - metabolism Nitric-oxide synthase Nitroarginine - administration & dosage NMR Nuclear magnetic resonance Oncology Oxygen Oxygen breathing Oxygen content Oxygen tension Oxygenation Perfusion Permeability Prodrugs Respiration Rodents Sensitivity Smooth muscle Stroma Tirapazamine Toxicity Treatment Outcome Triazines - administration & dosage Tumor Burden - drug effects Tumor microenvironment Tumors Xenograft Model Antitumor Assays - methods Vancouver British Columbia Canada Canada
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Many cancer research efforts focus on exploiting genetic-level features that may be targeted for therapy. Tissue-level features of the tumour microenvironment also represent useful therapeutic targets. Here we investigate the presence of low oxygen tension and sensitivity to NOS inhibition of tumour vasculature as potential tumour-specific features that may be targeted by hypoxic cytotoxins, a class of therapeutics currently under investigation. We have previously demonstrated that tirapazamine (TPZ) mediates central vascular dysfunction in tumours. TPZ is a hypoxic cytotoxin that is also a competitive inhibitor of NOS. Here we further investigated the vascular-targeting activity of TPZ by combining it with NOS inhibitor L-NNA, or with low oxygen content gas breathing. Tumours were analyzed via multiplex immunohistochemical staining that revealed irreversible loss of perfusion and enhanced tumour cell death when TPZ was combined with either low oxygen or a NOS inhibitor. Tumour growth rate was reduced by TPZ + NOS inhibition, and tumours previously resistant to TPZ-mediated vascular dysfunction were sensitized by low oxygen breathing. Additional mapping analysis suggests that tumours with reduced vascular-associated stroma may have greater sensitivity to these effects. These results indicate that poorly oxygenated tumour vessels, also being abnormally organized and with inadequate smooth muscle, may be successfully targeted for significant anti-cancer effects by inhibition of NOS and hypoxia-activated prodrug toxicity. This strategy illustrates a novel use of hypoxia-activated cytotoxic prodrugs as vascular targeting agents, and also represents a novel mechanism for targeting tumour vessels.
Bibliography:	Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: JB AM. Performed the experiments: JB KB SM EF AB JC. Analyzed the data: JB AK AM. Contributed reagents/materials/analysis tools: AK. Wrote the paper: JB. Reviewed manuscript: JB AK KB SM EF AB JC AM.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0076832