Radiosensitisation in normal tissues with oxygen, carbogen or nicotinamide: therapeutic gain comparisons for fractionated x-ray schedules.
METHODS
Radiosensitisation with oxygen, carbogen or nicotinamide alone and oxygen or carbogen combined with nicotinamide was compared in early and late responding normal tissues in rodents. X-ray treatments were delivered as single doses or fractionated schedules of 2 fractions in 1 day, 2, 12 and 36 fractions in an overall time of 12 days and 10 fractions in 5 or 12 days. Acute skin reactions, survival of intestinal crypts, breathing rate, reduction in the packed red-cell volume and clearance of 51Cr-EDTA were used as assays of epidermal, gut, lung and renal damage.


RESULTS
Relative to air-breathing mice, carbogen or oxygen produced a small, and not always significant, increase in sensitivity (enhancement ratios < or = 1.15) in gut, lung and kidneys; however, in skin a dose enhancement of 1.2-1.3 was observed. The effect of nicotinamide in air, carbogen or oxygen was studied only in lung and gut. The drug produced variable but generally significant increases in radiosensitisation ( < or = 1.26) in all three gases. Relative to treatments in air, enhancement ratios for nicotinamide alone were usually slightly higher than those observed when either carbogen or oxygen were administered without the drug. With all three modifiers (i.e. oxygen, carbogen, nicotinamide alone or for the drug-gas combinations) there was no significant change in the enhancement ratios observed as the number of radiation dose fractions was varied.


CONCLUSIONS
Comparisons with fractionated X-ray studies done previously in rodent tumours indicate that a therapeutic benefit, relative to lung, gut and renal damage, would be observed with oxygen or carbogen alone but not with nicotinamide alone. The greatest gain would be achieved with the combination of carbogen and nicotinamide, with which a benefit was observed even relative to epidermal damage. These results indicate that some decrease in normal tissue tolerance could be observed when using these modifiers in clinical radiotherapy and, although small, the appropriate dose reductions should be considered; caution should be exercised especially when carbogen and nicotinamide are used in conjunction with the more radical accelerated schedules.
Rojas
A
A
Gray Laboratory Cancer Research Trust, Mount Vernon Hospital, Northwood, Middlesex, UK.
Vojnovic
B
B
Johns
H
H
Joiner
M C
MC
Martindale
C
C
Fowler
J F
JF
Denekamp
J
J
D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage / Q000627:therapeutic use*; D002860:Chromium Radioisotopes; D004307:Dose-Response Relationship, Radiation; D004338:Drug Combinations; D004492:Edetic Acid / Q000378:metabolism; D005260:Female; D006400:Hematocrit; D007413:Intestinal Mucosa / Q000378:metabolism / Q000528:radiation effects; D007668:Kidney / Q000378:metabolism / Q000528:radiation effects; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D008657:Metabolic Clearance Rate; D051379:Mice; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D009536:Niacinamide / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000008:administration & dosage / Q000627:therapeutic use*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D012119:Respiration / Q000528:radiation effects; D012867:Skin / Q000378:metabolism / Q000528:radiation effects; D014964:X-Ray Therapy
D002860:Chromium Radioisotopes; D004338:Drug Combinations; D011838:Radiation-Sensitizing Agents; D002245:Carbon Dioxide; D009536:Niacinamide; C011700:carbogen; D004492:Edetic Acid; D010100:Oxygen