Kawakami K, Omura K, Kanehira E, Watanabe Y
Department of Surgery (I), Kanazawa University School of Medicine, Japan.
Anticancer Res. 1999 Jul-Aug;19(4B):3249-52.
Thymidylate synthase (TS) is a target enzyme of 5-fluorouracil (5-FU), and the TS gene has a polymorphic tandem repeated sequence in the 5'-untranslated region. We investigated the polymorphism on the repeat length of the TS gene and its relation to the number of 5-fluoro-dUMP (FdUMP) binding sites in human gastrointestinal cancers.
Seventy adenocarcinoma samples were used. Twenty-one patients received UFT and 49 patients received no treatment before surgery. Tandem repeat length of TS gene was determined by PCR amplification of genomic DNA. The number of FdUMP binding sites were measured by 3H-FdUMP binding assay.
Double- (2R) and triple-repeated (3R) sequences of the TS gene were found in the cancer tissues. Three genotypes of TS were found: 2R/2R (n = 3), 2R/3R (n = 16) and 3R/3R (n = 51). The free TS level for the 3R/3R genotype was significantly higher than for the 2R/3R genotype in UFT (+) group. Similar genotype-dependent difference of TS level was observed in UFT (-) group.
Our results suggest the link between TS genotype and TS protein expression. This link might offer an advantage for selection of patients to receive 5-FU-based chemotherapy.
胸苷酸合成酶（TS）是5-氟尿嘧啶（5-FU）的靶酶，TS基因在5'-非翻译区有一个多态性串联重复序列。我们研究了TS基因重复长度的多态性及其与人类胃肠道癌症中5-氟脱氧尿苷一磷酸（FdUMP）结合位点数量的关系。
使用70份腺癌样本。21例患者术前接受优福定（UFT）治疗，49例患者术前未接受治疗。通过基因组DNA的PCR扩增确定TS基因的串联重复长度。通过³H-FdUMP结合试验测量FdUMP结合位点的数量。
在癌组织中发现了TS基因的双重复（2R）和三重复（3R）序列。发现了三种TS基因型：2R/2R（n = 3）、2R/3R（n = 16）和3R/3R（n = 51）。在接受UFT治疗（+）的组中，3R/3R基因型的游离TS水平显著高于2R/3R基因型。在未接受UFT治疗（-）的组中也观察到了类似的TS水平基因型依赖性差异。
我们的结果表明TS基因型与TS蛋白表达之间存在联系。这种联系可能为选择接受基于5-FU的化疗的患者提供优势。
