title: Targeting the tumour vasculature: exploitation of low oxygenation and sensitivity to NOS inhibition by treatment with a hypoxic cytotoxin.
abstract: 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.
authors.affiliation: Integrative Oncology - Radiation Biology Unit, BC Cancer Research Centre, Vancouver, British Columbia, Canada.
authors.forename: Jennifer H E
authors.initials: JH
authors.lastname: Baker
authors.forename: Alastair H
authors.initials: AH
authors.lastname: Kyle
authors.forename: Kirsten L
authors.initials: KL
authors.lastname: Bartels
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Methot
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Flanagan
authors.forename: Andrew
authors.initials: A
authors.lastname: Balbirnie
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Cran
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D000860:Hypoxia; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine / Q000008:administration & dosage; D000077704:Tirapazamine; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D003603:Cytotoxins; D014227:Triazines; D000077704:Tirapazamine; D019335:Nitroarginine; D019001:Nitric Oxide Synthase