Preclinical studies on how to deal with patient intolerance to nicotinamide and carbogen

Accelerated radiation carbogen nicotinamide (ARCON) therapy is generally well tolerated, but some patients experience intolerance to nicotinamide and carbogen (95% O(2)+5% CO(2)). This study investigated the effect of reducing both the nicotinamide dose and carbogen CO(2) content on radiation response.

A C3H mouse mammary carcinoma grown in the right rear foot of female CDF1 was used and treated when at 200 mm(3). Nicotinamide was intraperitoneally injected 20 min prior to irradiation. Carbogen (CO(2) content of either 2 or 5%, balance O(2)) breathing was started 5 min before, and continued during, additional treatments. Radiation was given locally to tissues of restrained non-anaesthetised mice either as a single or fractionated (10 fractions in 12 days) schedule. The endpoints were local tumour control at 90 days, development of moist desquamation 11-23 days after treatment of normal foot skin, or tumour oxygenation measured with the Eppendorf electrode.

The TCD50 values in this tumour following single or fractionated radiation treatment were 52 and 71Gy, respectively. Carbogen (5% CO(2) content) breathing with every radiation treatment in the fractionated schedule significantly (Chi-squared test; P<0.05) enhanced radiation response (ER 1.25). Significant enhancements were also seen with nicotinamide given either as 10x120 mg/kg (ER 1.25), 6x120 mg/kg (ER 1.11) or 10x90 mg/kg (ER 1.18), although the 6x120 schedule was significantly less effective than 10x120. Combining nicotinamide with carbogen resulted in ERs of 1.39-1.44, and these were independent of the nicotinamide treatments. There was also no significant difference in the enhancement of tumour radiation response or improved tumour oxygenation status if the CO(2) content of the gas breathing was varied from 0% (i.e. 100% O(2)) to 2 or 5% (balance O(2)), although a CO(2) content of 2% did give a smaller enhancement of radiation-induced normal skin damage than 5%.

Both the nicotinamide dose, but not the frequency, and carbogen CO(2) content may be reduced in patients experience intolerance without any significant loss of sensitisation.