Radiosensitization by misonidazole (Ro-07-0582) of fractionated X-rays in a murine tumour.

Radiosensitization by misonidazole of fractionated X-rays was determined by measuring the reduction in X-ray dose required for the local control of 50% of implanted tumours. If any 2 out of 5 fractions in 4 days' overall time (5F/4D) were treated with 0·3 mg/g of misonidazole, a sensitizer enhancement ratio (SER) of 1·3 was observed. This suggests that reoxygenation did not bring the oxic cell population up to a significant proportion of the surviving cells at any time after the first fraction. If all 5 fractions were treated with 0·3 mg/g misonidazole, the SER increased to 1.51. If 2 further injections were given after each fraction, so prolonging the contact time to 5-6 h, a SER of 1·59 was obtained. This increase was just significant and suggests negligible hypoxic cell cytotoxicity by misonidazole in this tumour. However, even this prolonged contact time was still short compared with that obtained in man because of the drug's longer half-life in the latter case. Twenty X-ray fractions in 9 days (20F/9D), each of 4·6 Gy with 0·2 mg/g misonidazole, gave an SER of 1·3. This is rather high for a multiple fraction schedule, and suggests that little reoxygenation had occurred. The optimum therapy of this tumour was determined by comparing the tumour control achieved by each fractionation schedule at the dose of X-rays related to a constant level of skin damage. Providing the overall time was not too long, 20 fractions of X-rays were better than 5 fractions. With misonidazole both schedules were improved to a uniformly high level.