Effect of dose fractionation on the enhancement by radiation or cyclophosphamide of artificial pulmonary metastases.

Thoracic irradiation or cyclophosphamide (CP) treatment of mice before an i.v. injection of tumour cells enhances the number of lung colonies produced by a factor of up to 100+. The effect of fractionation of the X-ray or CP dose on this phenomenon was investigated in several ways.The dose-response curve for the number of lung colonies as a function of the dose of thoracic irradiation was linear, and the degree of enhancement was independent of the number of tumour cells injected. Splitting a dose of 1,000 rad into 2 equal fractions separated by times varying from 1 to 24 h gave the same enhancement as that produced by a single dose of 1000 rad. Similarly, fractionation of 1000 rad into 5 × 200 rad, or 2000 rad into 5 × 400 rad (each interval between fractions being 3 h) had no effect on the radiation enhancement of colony formation.A single dose of 200 mg/kg of CP was compared with 3 doses of 66·7 mg/kg (each dose separated by 12 h) and with a continuous infusion of 200 mg/kg given over 24 h. In this case, fractionation and infusion produced a small reduction in the CP-induced increase, but the factor of colony enhancement compared to control mice remained >100.These data emphasize the potential hazard of prophylactic treatment of pulmonary metastases by X-rays or CP in clinical situations in which control of the primary tumour is not achieved.