Peters G J, Braakhuis B J, de Bruijn E A, Laurensse E J, van Walsum M, Pinedo H M
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Br J Cancer. 1989 Mar;59(3):327-34. doi: 10.1038/bjc.1989.65.
Four human head and neck xenograft (HNX) tumour lines grown in nude mice and two murine colon carcinomas (Colon 26 and 38) were tested for their sensitivity to 5-fluorouracil (5-FU) and its prodrug 5'deoxy-5-fluorouridine (Doxifluridine, 5'd-FUR). 5-FU sensitivity at the maximum tolerated dose (MTD) showed the following pattern; HNX-DU less than HNX-KE = HNX-E = HNX-G less than Colon 26 much less than Colon 38. The sensitivity pattern to 5'd-FUR was: HNX-DU less than HNX-G less than HNX-E less than HNX-KE less than Colon 38 less than Colon 26. For HNX-KE, HNX-E and Colon 26 an increase in therapeutic efficacy was observed with 5'd-FUR as compared to 5-FU; Colon 38 was as sensitive to 5'd-FUR as to 5-FU. Plasma pharmacokinetics of 5'd-FUR and 5-FU were comparable in normal and nude mice. Metabolism of 5-FU and 5'd-FUR was studied in the tumours. Conversion of 5'd-FUR to 5-FU was highest in Colon 26 and 15-20 times lower in HNX-DU, HNX-KE and Colon 38. The Km for 5'd-FUR in all tumours was 1-2 mM. Further anabolism of 5-FU to fluorouridine (FUR) was 5-10 times higher than that of 5-FU to FUR in HNX tumours and 3 times in the colon tumours. 5-FU conversion to FUMP via FUR had the following pattern: Colon 26 much greater than HNX-DU greater than HNX-G greater than HNX-E greater than HNX-KE much greater than Colon 38; of 5-FU to FdUMP via FUdR: Colon 26 greater than HNX-DU = HNX-KE greater than HNX-E greater than HNX-G = Colon 38; and that of 5-FU to FUMP catalysed by orotate phosphoribosyl transferase (OPRT); Colon 26 greater than or equal to Colon 38 greater than HNX-KE greater than HNX-E = HNX-DU = HNX-G. Only those tumours with a relatively high activity of OPRT were sensitive to 5'd-FUR. Colon 26, which has a very high rate of pyrimidine nucleoside phosphorylase, showed a relatively high increase in the therapeutic efficacy. It is concluded that a low rate of pyrimidine nucleoside phosphorylase is enough to convert 5'd-FUR to 5-FU; further anabolism of 5-FU catalysed by OPRT may be limiting and explain the differential sensitivity.
对在裸鼠体内生长的4种人头颈异种移植（HNX）肿瘤细胞系以及两种鼠类结肠癌（结肠26和结肠38）进行了对5-氟尿嘧啶（5-FU）及其前药5'-脱氧-5-氟尿苷（多西氟尿苷，5'-FUR）的敏感性测试。最大耐受剂量（MTD）下的5-FU敏感性呈现以下模式：HNX-DU低于HNX-KE = HNX-E = HNX-G低于结肠26远低于结肠38。对5'-FUR的敏感性模式为：HNX-DU低于HNX-G低于HNX-E低于HNX-KE低于结肠38低于结肠26。对于HNX-KE、HNX-E和结肠26，与5-FU相比，5'-FUR的治疗效果有所提高；结肠38对5'-FUR和5-FU的敏感性相同。5'-FUR和5-FU在正常小鼠和裸鼠体内的血浆药代动力学具有可比性。在肿瘤中研究了5-FU和5'-FUR的代谢。5'-FUR向5-FU的转化在结肠26中最高，在HNX-DU、HNX-KE和结肠38中低15 - 20倍。所有肿瘤中5'-FUR的米氏常数（Km）为1 - 2 mM。在HNX肿瘤中，5-FU进一步合成氟尿苷（FUR）的代谢比5-FU合成FUR的代谢高5 - 10倍，在结肠肿瘤中高3倍。5-FU通过FUR转化为FUMP具有以下模式：结肠26远大于HNX-DU大于HNX-G大于HNX-E大于HNX-KE远大于结肠38；5-FU通过FUdR转化为FdUMP：结肠26大于HNX-DU = HNX-KE大于HNX-E大于HNX-G = 结肠38；以及5-FU由乳清酸磷酸核糖基转移酶（OPRT）催化转化为FUMP：结肠26大于或等于结肠38大于HNX-KE大于HNX-E = HNX-DU = HNX-G。只有那些OPRT活性相对较高的肿瘤对5'-FUR敏感。具有非常高嘧啶核苷磷酸化酶活性的结肠26，其治疗效果有相对较高的提高。得出的结论是，低嘧啶核苷磷酸化酶速率足以将5'-FUR转化为5-FU；由OPRT催化的5-FU进一步合成代谢可能是限制性的，并解释了敏感性差异。
