Araki Y, Isomoto H, Shirouzu K
Department of Surgery, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan.
Kurume Med J. 2001;48(2):93-8. doi: 10.2739/kurumemedj.48.93.
In the recent studies associated with the modulation of 5-fluorouracil (5-FU) and the development of new antifolates, attentions have been focused on the expression of the target enzymes, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD), that affect tumor sensitivity and resistance to drugs. In order to evaluate predictability of therapeutic efficacy by intratumoral enzyme activity, we investigated the role of TS content and DPD activity in tumor sensitivity of 5-FU. Surgical specimens were obtained from 51 patients with colorectal cancer and used to measure TS content and DPD activity. TS content and DPD activity in tissues were measured by [3H]-FdUMP binding assay and radioenzymatic assay, respectively. The sensitivity to 5-FU in tumor specimens was determined by collagen-gel droplet embedded-drug sensitivity test (CD-DST). The TS content and DPD activity did not correlate with Dukes' staging. There was no correlation between TS content and DPD activity in any tumors. Simple linear regression analysis showed that neither DPD activity (r = -0.267, p > 0.05) nor TS content (r = -0.277, p > 0.05) in tumors had a significant correlation with 5-FU effectiveness independently. Four out of 24 patients, highly responsive to 5-FU, showed low levels in both DPD and TS. The patients with high value in either DPD activity or TS content proved not to respond to 5-FU. In conclusion, these results demonstrate that both tumor DPD activity and TS content are the factors predicting 5-FU responsiveness in colorectal cancer.
在最近与5-氟尿嘧啶（5-FU）调节及新型抗叶酸剂研发相关的研究中，注意力集中在影响肿瘤对药物敏感性和耐药性的靶酶胸苷酸合成酶（TS）和二氢嘧啶脱氢酶（DPD）的表达上。为了通过肿瘤内酶活性评估治疗效果的可预测性，我们研究了TS含量和DPD活性在5-FU肿瘤敏感性中的作用。从51例结直肠癌患者获取手术标本，用于测量TS含量和DPD活性。组织中的TS含量和DPD活性分别通过[3H]-FdUMP结合试验和放射酶法测定。肿瘤标本对5-FU的敏感性通过胶原凝胶滴包埋药物敏感性试验（CD-DST）确定。TS含量和DPD活性与Dukes分期无关。在任何肿瘤中，TS含量和DPD活性之间均无相关性。简单线性回归分析表明，肿瘤中的DPD活性（r = -0.267，p > 0.05）和TS含量（r = -0.277，p > 0.05）均与5-FU疗效无显著独立相关性。24例对5-FU高度敏感的患者中有4例DPD和TS水平均较低。DPD活性或TS含量高的患者对5-FU无反应。总之，这些结果表明，肿瘤DPD活性和TS含量均是预测结直肠癌对5-FU反应性的因素。
