Schedule-dependent therapeutic gain from the combination of fractionated irradiation plus c-DDP and 5-FU or plus c-DDP and cyclophosphamide in C3H/Km mouse model systems

Abstract

Cytotoxic drugs were administered either in single or fractionated doses before, during, or after a standard course of 5 daily X ray exposures. SCCVII and RIF-1 tumors were grown from cells implanted in the gastrocnemius muscles of syngeneic C3H/Km mice, and treatments were evaluated by regrowth delay (GD). Non-tumor-bearing mice were irradiated locally to the upper abdomen for analysis of intestinal crypt cell survival, an acute normal tissue effect; other non-tumor-bearing mice were irradiated locally to the thorax for analysis of early (pneumonitis) and late (fibrosis) effects on the lungs, as reflected in changes in breathing rates. In a series of experiments to test the combination of i.p. 5-FU, cis-DDP, and X ray, dose effect factors (DEF's) were compared so that therapeutic gain factors (TGF's) could be calculated from the ratio, DEF (tumor)/DEF (normal tissue). The highest TGF, 6.7 (tumor/duodenum), was obtained for the schedule in which 100 mg/kg 5-FU was given 24 hr before the simultaneous administration of 1.6 mg/kg cis-DDP and X ray for 5 consecutive days. The following summary refers only to tumor growth delay data. In confirmation of previous extensive experiments, the combination of cis-DDP + X ray showed supra-additivity, whether the drug was given in a single dose (abbreviated P) or simultaneously with X ray (abbreviated px), that is, P x x x x x or px px px px px. For CY + X ray, the greatest supra-additivity was obtained for either C x x x x x or x x x x x C. 5-FU alone did not act supra-additively with fractionated irradiation, but the addition of 5-FU to cis-DDP + X ray was supra-additive for certain schedules, maximally for F px px px px px. CY combined to give greater than additivity with either cis-DDP or X ray alone, and the combination of CY + cis-DDP + X ray appeared to be supra-additive for five different schedules, maximally for C x x x x x P. Normal tissue effects are being evaluated for these same schedules so that TGF's might soon be obtained.