Shibamoto Y, Mimasu Y, Tachi Y, Hatta H, Nishimoto S
Department of Radiology, Nagoya City University Medical School, Japan.
J Chemother. 2002 Aug;14(4):390-6. doi: 10.1179/joc.2002.14.4.390.
The purpose of this study was to clarify whether 5-fluoro-2'-deoxyuridine (FdUrd) is superior to 5-fluorouracil (5-FU) as an effector in the radiation-activated prodrugs which we have been developing. The in vitro cytotoxicity of 5-FU and FdUrd was compared in two murine tumor and four human pancreatic cancer cell lines using a colony assay and in vivo efficacy was compared with SCCVII tumor using a growth delay time assay. FdUrd was slightly more hydrophilic than 5-FU. In vitro, FdUrd was more efficient than 5-FU in two lines, whereas 5-FU was more efficient in two lines and the two drugs were almost equal in efficacy in the remaining two. The concentration to reduce tumor cell survival to 50% after 24-h drug exposure was 5-32 microM for both 5-FU and FdUrd in murine lines, while it was 30-210 microM in human pancreatic cancer cell lines. The difference in relative efficacy of the two drugs among these cell lines could not be attributed to the rate of intracellular uptake of the compounds. FdUrd was less toxic than 5-FU in C3H/He mice, and FdUrd was less efficient than 5-FU in SCCVII tumors in vivo. These results suggest that FdUrd is not necessarily more potent than 5-FU, and development of the FdUrd prodrugs may not necessarily turn out to be fruitful.
本研究的目的是阐明在我们一直在研发的放射激活前体药物中，5-氟-2'-脱氧尿苷（FdUrd）作为效应剂是否优于5-氟尿嘧啶（5-FU）。使用集落形成试验比较了5-FU和FdUrd在两种小鼠肿瘤细胞系和四种人胰腺癌细胞系中的体外细胞毒性，并使用生长延迟时间试验比较了它们在SCCVII肿瘤中的体内疗效。FdUrd比5-FU略具亲水性。在体外，FdUrd在两个细胞系中比5-FU更有效，而5-FU在两个细胞系中更有效，在其余两个细胞系中两种药物的疗效几乎相同。在小鼠细胞系中，5-FU和FdUrd在24小时药物暴露后将肿瘤细胞存活率降低至50%的浓度为5-32微摩尔，而在人胰腺癌细胞系中为30-210微摩尔。这两种药物在这些细胞系中的相对疗效差异不能归因于化合物的细胞内摄取率。在C3H/He小鼠中，FdUrd的毒性低于5-FU，在体内SCCVII肿瘤中，FdUrd的疗效低于5-FU。这些结果表明，FdUrd不一定比5-FU更有效，FdUrd前体药物的研发不一定会取得成果。
