Targeting tumour hypoxia to improve outcome of stereotactic radiotherapy.
BACKGROUND
Hypoxia is a characteristic feature of solid tumours that significantly reduces the efficacy of conventional radiation therapy. In this study we investigated the role of hypoxia in a stereotactic radiation schedule by using a variety of hypoxic modifiers in a preclinical tumour model.


METHODS
C3H mammary carcinomas were irradiated with 3 × 15 Gy during a one-week period, followed three days later by a clamped top-up dose to produce a dose response curve; the endpoint was tumour control. The hypoxic modifiers were nimorazole (200 mg/kg), nicotinamide (120 mg/kg) and carbogen (95% O2 + 5% CO2) breathing, OXi4503 (10 mg/kg), and hyperthermia (41.5°C; 1 h).


RESULTS
The radiation dose controlling 50% of clamped tumours (TCD50) following 3 × 15 Gy was 30 Gy. Giving nimorazole or nicotinamide+ carbogen prior to the final 15 Gy fraction non-significantly (χ(2)-test; p < 0.05) reduced this TCD50 to 20-23 Gy; when administered with each 3 × 15 Gy fraction these values were significantly reduced to ≤ 2.5 Gy. Injecting OXi4503 or heating after irradiating significantly reduced the TCD50 to 9-12 Gy regardless of whether administered with one or all three 15 Gy fractions. Combining OXi4503 and heat with the final 15 Gy had a significantly larger effect (TCD50 = 2 Gy).


CONCLUSIONS
Clinically relevant modifiers of hypoxia effectively enhanced an equivalent stereotactic radiation treatment confirming the importance of hypoxia in such schedules.
a Department of Experimental Clinical Oncology , Aarhus University Hospital , Aarhus , Denmark.
Thomas R
TR
Wittenborn
a Department of Experimental Clinical Oncology , Aarhus University Hospital , Aarhus , Denmark.
Michael R
MR
Horsman
D000280:Administration, Inhalation; D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage; D015687:Cell Hypoxia; D011756:Diphosphates / Q000494:pharmacology; D005260:Female; D006979:Hyperthermia, Induced; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy*; D008809:Mice, Inbred C3H; D009536:Niacinamide / Q000494:pharmacology; D009554:Nimorazole / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D016634:Radiosurgery; D011879:Radiotherapy Dosage; D013267:Stilbenes / Q000494:pharmacology; D014803:Vitamin B Complex / Q000494:pharmacology
D011756:Diphosphates; C465018:Oxi 4503; D011838:Radiation-Sensitizing Agents; D013267:Stilbenes; D014803:Vitamin B Complex; D002245:Carbon Dioxide; D009536:Niacinamide; D009554:Nimorazole; C011700:carbogen; D010100:Oxygen