Kiss-László Zsuzsanna, Nagy Beatrix, Thurzó László, Szabó János
Orvosi Genetikai Intézet, Szegedi Tudományegyetem, Altalános Orvostudományi Kar, Szent-Györgyi Albert Orvos- és Gyógyszerésztudományi Centrum, Szeged 6720, Hungary.
Magy Onkol. 2006;50(1):33-7. Epub 2006 Apr 17.
Thymidylate synthase (TS) is a rate-limiting enzyme in the DNA synthetic pathway, and represents a cellular target of antimetabolite drug 5-fluorouracil. It catalyzes the reductive methylation of deoxyuridine-5'-monophosphate to deoxythymidine-5'-monophosphate. Inhibition of TS will result in depletion of both dTMP and, subsequently, dTTP. As a consequence, dUTP is misincorporated into DNA, resulting in DNA breakage and cell death. Developing resistance against 5-fluorouracil (FURA) based drugs might be due to the failure of inhibition of thymidylate synthase enzyme function. In the promoter region of the TS gene there is a tandem repeat sequence (2R or 3R), which was found to be polymorphic and influences the gene expression. Effectiveness and tolerability of Tegafur treatment might be influenced by expression of the TS gene. Our purpose was to determine the effectiveness and tolerability of concomitant radiotherapy and low-dose chemotherapy using Tegafur in respect of promoter polymorphism of thymidilate synthase gene.
TS promoter polymorphism (2R/2R, 2R/3R, 3R/3R) was determined by polymerase chain reaction using genomic DNA, in 47 patients with advanced head and neck cancer.
Thirty patients out of 47 showed complete response, and genotyping of these patients revealed 2R/2R in 22 (73.3%), 2R/3R in 2 (6.7%) and 3R/3R in 6 (20%). Seventeen out of 47 patients reacted with partial response, and 2R/2R or 2R/3R were revealed in 5 (29.4%) and 3 (17.6%) patients, respectively, and 3R/3R genotype was identified in 9 patients (53%).
We did not find any correlation between patient's data and response to therapy, but strong correlation was found between the latter and the patient's genotype. This facts indicate that the analysis of promoter polymorphism of thymidylate synthase gene might be a useful target to examine before FURA-based chemotherapy, and might allow to go into the direction of individualized treatment of head and neck cancer. We suppose that tumor response depends on genomic features of the patients.
胸苷酸合成酶（TS）是DNA合成途径中的限速酶，是抗代谢药物5-氟尿嘧啶的细胞靶点。它催化脱氧尿苷-5'-单磷酸还原甲基化为脱氧胸苷-5'-单磷酸。抑制TS会导致dTMP以及随后的dTTP耗竭。结果，dUTP错误掺入DNA，导致DNA断裂和细胞死亡。对基于5-氟尿嘧啶（FURA）的药物产生耐药性可能是由于胸苷酸合成酶功能抑制失败。在TS基因的启动子区域存在一个串联重复序列（2R或3R），该序列具有多态性并影响基因表达。替加氟治疗的有效性和耐受性可能受TS基因表达的影响。我们的目的是就胸苷酸合成酶基因启动子多态性来确定同步放疗和低剂量替加氟化疗的有效性和耐受性。
采用聚合酶链反应，利用基因组DNA对47例晚期头颈癌患者的TS启动子多态性（2R/2R、2R/3R、3R/3R）进行检测。
47例患者中有30例显示完全缓解，对这些患者的基因分型显示，22例（73.3%）为2R/2R，2例（6.7%）为2R/3R，6例（20%）为3R/3R。47例患者中有17例部分缓解，其中5例（29.4%）患者为2R/2R或2R/3R，3例（17.6%）患者为2R/2R或2R/3R，9例（53%）患者为3R/3R基因型。
我们未发现患者数据与治疗反应之间存在任何相关性，但发现后者与患者基因型之间存在强相关性。这些事实表明，胸苷酸合成酶基因启动子多态性分析可能是基于FURA的化疗前检查的一个有用靶点，可能有助于对头颈癌进行个体化治疗。我们推测肿瘤反应取决于患者的基因组特征。
