Induction of hypoxia in experimental murine tumors by the nitric oxide synthase inhibitor, NG-nitro-L-arginine

• Published in: Cancer research (Chicago, Ill.) Ill.), 1994-12, Vol.54 (24), p.6458-6463
• Main Authors: WOOD, P. J, SANSOM, J. M, BUTLER, S. A, STRATFORD, I. J, COLE, S. M, SZABO, C, THIEMERMANN, C, ADAMS, G. E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Arginine - analogs & derivatives; Arginine - pharmacology; Biological and medical sciences; Carcinoma - drug therapy; Carcinoma - metabolism; Carcinoma - radiotherapy; Cell Hypoxia; Cell Survival - drug effects; Chemotherapy; Drug Screening Assays, Antitumor; Drug Synergism; Energy Metabolism - drug effects; Female; Magnetic Resonance Spectroscopy; Male; Medical sciences; Mice; Mice, Inbred C3H; Nitroarginine; Nitroimidazoles - pharmacology; Pharmacology. Drug treatments; Phosphates - metabolism; Prodrugs - pharmacology; Sarcoma, Experimental - drug therapy; Sarcoma, Experimental - metabolism; Sarcoma, Experimental - radiotherapy
• ISSN: 0008-5472; 1538-7445

The nitric oxide synthase inhibitor NG-nitro-L-arginine (NOARG) was examined for its ability to alter energy metabolism in three murine tumors using 31P magnetic resonance spectroscopy. NOARG (10 mg/kg, i.v.) increased the inorganic phosphate:total phosphate ratio (Pi:total) 2-3-fold in the KHT, RIF-1, and SCCVII/Ha intradermal back tumors from 30 min to 6 h after injection, but the 31P magnetic resonance spectrum from normal tissue on the mouse back was unchanged after this treatment. NOARG (10 mg/kg, i.v.) injected 30 min before X-rays increased tumor cell survival 3-5-fold in SCCVII/Ha and 50-200-fold in RIF-1, measured using an in vivo/in vitro clonogenic assay. These effects were equivalent to those obtained from clamped tumors, indicating full radiobiological hypoxia. In KHT, only a 2-fold increase in radioresistance was observed after NOARG, which was less than the response of clamped tumors. In RIF-1 tumors, NOARG induced full radiobiological hypoxia when given from 30 min to 6 h prior to X-rays, consistent with the time course for the increase in Pi:total, measured by 31P magnetic resonance spectroscopy. Pi:total after NOARG doses of 0.1-10 mg/kg, i.v., increased in a dose-dependent manner in this tumor. Increased RIF-1 tumor radioresistance was similarly dependent on NOARG dose. The combination of the bioreductive agent RB6145 (300 mg/kg, i.p.) 15 min prior to NOARG (10 mg/kg, i.v.) produced greater than 5 decades of KHT tumor cell killing at 24 h after treatment. This combination also increased Pi:total 4.5-fold over the control value at 24 h in the KHT tumor. Histological examination of tumors at this time indicated extensive necrosis.