COMBINED EFFECT OF CLINICALLY RELEVANT DOSES OF EMITEFUR A NEW 5-FLUOROURACIL DERIVATIVE, AND RADIATION IN MURINE TUMORS

We investigated the combined effect of radiation and clinically releva nt doses of emitefur (BOF-A2), a newly developed anti-cancer agent con sisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibit or of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg(-1) and 25 mg kg(-1) emitefur in m ice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 40 0-600 mg day(-1) in humans. These doses (12.5 and 25 mg kg(-1)) of emi tefur were evaluated either alone or in combination with single (15 Gy ), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII rumours and in combinati on with four fraction (5 Gy each) irradiation using an in vivo-in vitr o assay for EMT6 tumours. The anti-tumour and radiation-enhancing effe cts of 12.5 mg kg(-1) emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg (-1) emitefur given either alone or in combination with radiation prod uced marked effects. The mean tumour growth delay time (the time to do uble in volume for treated tumours minus that for untreated tumours) w as 8.1 days for five administrations of 25 mg kg(-1) emitefur, 10.4 da ys for five fractions of 4 Gy and 22.1 days for five treatments with t he combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractio ns of 5 Gy with 25 mg kg(-1) emitefur in EMT6 tumours was lower than t hat of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the ef fect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg(-1) emitefur was much higher than that of ten fracti ons of 4.2 Gy. In conclusion, emitefur given either alone or in combin ation with radiation appears to have a significant anti-tumour effect even at clinically relevant dose levels, although a threshold dose exi sts between 12.5 and 25 mg kg(-1). Further clinical studies of this co mpound are warranted.