title: Antitumor actions of ruthenium(III)-based nitric oxide scavengers and nitric oxide synthase inhibitors.
abstract: The role of endogenous nitric oxide (NO) in the growth and vascularization of a rat carcinosarcoma (P22) has been investigated. Tumor-bearing animals were treated with (i) nitric oxide synthase (NOS) inhibitors, administered via the drinking water, including N(G)-nitro-l-arginine methyl ester (L-NAME), a nonisoform-selective inhibitor, and 2 others that target the inducible (NOS II) enzyme preferentially, namely 1-amino-2-hydroxyguanidine or N-[3-(aminomethyl)benzyl]acetamidine hydrochloride; or (ii) daily injections (intraperitoneally) of 2 Ru(III) polyaminocarboxylates, AMD6221 and AMD6245, both of which are effective NO scavengers. L-NAME, AMD6221, and AMD6245 reduced tumor growth by approximately 60% to 75% of control rates. Tumor sections stained with abs to CD-31/platelet endothelial cell adhesion molecule-1 or NOS III showed that this was associated with a marked reduction (60%-77%) of tumor microvascular densitiy (MVD). Tumors resumed growing promptly when treatment was discontinued, accompanied by partial or complete restoration of MVDs. In contrast, NOS-II selective inhibitors had no effect on tumor growth or vascularization, indicating that both responses require complete blockade of NO production. The results corroborate the view that endogenous NO facilitates tumor development. We suggest that NO deprivation causes tumor feeder vessels to constrict, reducing tumor blood flow. The delivery of oxygen and essential nutrients to the developing tumor is impaired as a consequence, hampering further growth. Normalizing NO levels by withholding treatment causes tumor feeder vessels to dilate, increasing tumor perfusion and reestablishing conditions that allow tumors to begin growing again.
authors.affiliation: School of Biology, University of St Andrews, St Andrews, Scotland, UK.
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Flitney
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Pritchard
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Kennovin
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Bisland
authors.forename: David G
authors.initials: DG
authors.lastname: Hirst
authors.forename: Simon P
authors.initials: SP
authors.lastname: Fricker
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009942:Organometallic Compounds / Q000494:pharmacology; D004369:Pentetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012428:Ruthenium / Q000494:pharmacology*; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism; D014185:Transplantation, Isogeneic; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C453459:AMD 6221; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D009569:Nitric Oxide; D004369:Pentetic Acid; D012428:Ruthenium; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester