Shibamoto Y, Murata R, Miyauchi S, Hirohashi M, Takagi T, Sasai K, Shibata T, Oya N, Takahashi M
Department of Oncology, Faculty of Medicine, Kyoto University, Japan.
Br J Cancer. 1996 Dec;74(11):1709-13. doi: 10.1038/bjc.1996.619.
We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor 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 mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day-1 in humans. These doses (12.5 and 25 mg kg-1) of emitefur 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 tumours and in combination with four-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects 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 produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-1 emitefur. 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that 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 effect 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 fractions of 4.2 Gy. In conclusion, emitefur given either alone or in combination with radiation appears to have a significant anti-tumour effect even at clinically relevant dose levels, although a threshold dose exists between 12.5 and 25 mg kg-1. Further clinical studies of this compound are warranted.
我们研究了辐射与临床相关剂量的艾替伏（BOF-A2）的联合作用，艾替伏是一种新开发的抗癌药物，由5-氟尿嘧啶（5-FU）的掩蔽形式和5-FU降解的强效抑制剂组成，用于两种小鼠肿瘤模型。在初步药代动力学研究中，小鼠给予12.5 mg kg-1和25 mg kg-1艾替伏后，血浆中5-FU的曲线下面积，分别与人类开始给予400 - 600 mg day-1后的第一天和第七天所测得的相似。使用SCCVII肿瘤的肿瘤生长延迟试验，评估了这些剂量（12.5和25 mg kg-1）的艾替伏单独使用或与单次（15 Gy）、五分次（每次4 Gy）或十分次（每次2.8 Gy）照射联合使用的情况；使用EMT6肿瘤的体内-体外试验，评估了其与四分次（每次5 Gy）照射联合使用的情况。除了十分次实验外，12.5 mg kg-1艾替伏的抗肿瘤和辐射增强作用均不显著。另一方面，多次给予25 mg kg-1艾替伏单独使用或与辐射联合使用均产生了显著效果。给予五次25 mg kg-1艾替伏时，平均肿瘤生长延迟时间（治疗组肿瘤体积翻倍时间减去未治疗组肿瘤体积翻倍时间）为8.1天；给予五次4 Gy照射时为10.4天；两者联合进行五次治疗时为22.1天。因此，这种联合治疗所带来的生长延迟增加至少是相加的。在EMT6肿瘤中，25 mg kg-1艾替伏与四次5 Gy照射联合的效果低于四次7.5 Gy照射的效果，但在SCCVII肿瘤中，该剂量艾替伏与五次4 Gy照射联合的效果与五次6 Gy照射的效果相似，且25 mg kg-1艾替伏与十分次2.8 Gy照射联合的效果远高于十分次4.2 Gy照射的效果。总之，即使在临床相关剂量水平，艾替伏单独使用或与辐射联合使用似乎都具有显著的抗肿瘤作用，尽管在12.5和25 mg kg-1之间存在一个阈值剂量。有必要对该化合物进行进一步的临床研究。
