Efficacy of agents counteracting hypoxia in fractionated radiation regimes.
OBJECTIVE
Solid tumours contain hypoxic cells which are resistant to radiotherapy. This study compares the efficacy of several strategies to counteract diffusion-limited hypoxia, or intermittent hypoxia in a fractionated regimen of 1 to 6 x 2 Gy.


METHODS
Nicotinamide (250 mg/kg), perflubron emulsion (Oxygent) (4 ml/kg), tirapazamine (SR4233) (0.10 mmol/kg) and carbogen breathing, administered alone or in combination, were investigated on two tumour cell lines: EMT6 (a rodent mammary carcinoma) and HRT18 (a human rectal adenocarcinoma) using a clonogenic assay. The radiosensitizing effect of the agents was assessed after 1 and 6 x 2 Gy for drugs used alone, and 1, 2, 4, 6 x 2 Gy for drugs used in combination.


RESULTS
At the end of the fractionated radiation regimen, the combination of nicotinamide + carbogen induced the greatest radiosensitization for EMT6 tumours, while greatest radiosensitization of HRT18 was obtained with nicotinamide + carbogen + tirapazamine.


CONCLUSIONS
The efficacy of the strategies for overcoming hypoxia using a fractionated regimen depends on the tumour cell line. These differences could be linked to differences in the initial percentages of acute and chronic hypoxic cells, and to changes in the two types of hypoxia during treatment.
Stern
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Laboratoire de Radiobiologie Cellulaire, Institut Gustave Roussy, Villejuif, France.
Guichard
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D000230:Adenocarcinoma / Q000532:radiotherapy; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects; D004655:Emulsions; D005260:Female; D005466:Fluorocarbons / Q000494:pharmacology; D006801:Humans; D006842:Hydrocarbons, Brominated; D008325:Mammary Neoplasms, Experimental / Q000532:radiotherapy; D051379:Mice; D009536:Niacinamide / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011878:Radiotherapy / Q000379:methods*; D011879:Radiotherapy Dosage; D012004:Rectal Neoplasms / Q000532:radiotherapy; D000077704:Tirapazamine; D014227:Triazines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D004655:Emulsions; D005466:Fluorocarbons; D006842:Hydrocarbons, Brominated; D011838:Radiation-Sensitizing Agents; D014227:Triazines; D002245:Carbon Dioxide; D000077704:Tirapazamine; D009536:Niacinamide; C011700:carbogen; C003072:perflubron; D010100:Oxygen