Differential expression of uridine phosphorylase in tumors contributes to an improved fluoropyrimidine therapeutic activity.
Differential expression of uridine phosphorylase in tumors contributes to an improved fluoropyrimidine therapeutic activity.
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DOI：
10.1158/1535-7163.mct-11-0202
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发表时间：
2011-12
影响因子：
5.7
通讯作者：
Pizzorno G
中科院分区：
文献类型：
--
作者：
Cao D;Ziemba A;McCabe J;Yan R;Wan L;Kim B;Gach M;Flynn S;Pizzorno G
尿苷磷酸化酶（UPase）的消除导致嘧啶代谢异常和宿主对5-氟尿嘧啶（5-FU）毒性的保护。我们阐明了在我们的UPase敲除（UPase −/−）模型中5-FU和卡培他滨对代谢和抗肿瘤疗效的影响。5-FU（85 mg/kg）或卡培他滨（1000 mg/kg）每周5天，持续4周给药，对野生型（WT）小鼠的肠道造成严重毒性和结构损伤，但在UPase −/−动物中没有。卡培他滨治疗导致WT动物的血细胞计数下降70%，在UPase −/−小鼠中仅产生轻微影响。在UPase −/−小鼠中植入的表达UPase的结肠38肿瘤显示，当用5-FU和卡培他滨治疗时，由于在UPase −/−小鼠中可达到的氟嘧啶的最大耐受剂量较高，治疗效果得到改善。肿瘤中卡培他滨代谢的19 F-MRS评价显示，与WT相比，UPase −/−小鼠中前药的活化相似。在WT小鼠中，约60%的卡培他滨在3小时内转化为其活性代谢产物，而在UPase −/−小鼠中植入的肿瘤中转化率为80%。在UPase −/−小鼠中，5′dFUR的长期保留允许肿瘤组织成比例增加。氟化分解代谢物质的类似存在证实了UPase −/−小鼠中二氢嘧啶脱氢酶活性没有改变。总体而言，这些结果表明了UPase在氟嘧啶活化中的重要性，尿苷在保护正常组织中的作用，以及5-FU或卡培他滨化疗中磷酸分解活性的肿瘤特异性调节作用。
Abrogation of uridine phosphorylase (UPase) leads to abnormalities in pyrimidine metabolism and host protection against 5-fluorouracil (5-FU) toxicity. We elucidated the effects on the metabolism and antitumor efficacy of 5-FU and Capecitabine in our UPase knockout (UPase −/−) model. Treatment with 5-FU (85 mg/kg) or Capecitabine (1000 mg/kg) 5 days a week for 4 weeks caused severe toxicity and structural damage to the intestines of wild-type (WT) mice, but not in UPase −/− animals. Capecitabine treatment resulted in a 70% decrease in blood cell counts of WT animals, with only a marginal effect in UPase −/− mice. UPase expressing colon 38 tumors implanted in UPase −/− mice revealed an improved therapeutic efficacy when treated with 5-FU and Capecitabine due to the higher maximum tolerated dose for fluoropyrimidines achievable in UPase −/− mice. 19F-MRS evaluation of Capecitabine metabolism in tumors revealed similar activation of the pro-drug in UPase −/− mice compared to WT. In WT mice, approximately 60% of Capecitabine was transformed over 3 hours into its active metabolites, while 80% was transformed in tumors implanted in UPase −/− mice. In UPase −/− mice, prolonged retention of 5′dFUR allowed a proportional increase in tumor tissue. The similar presence of fluorinated catabolic species confirms that dihydropyrimidine dehydrogenase activity was not altered in UPase −/− mice. Overall, these results indicate the importance of UPase in the activation of fluoropyrimidines, the effect of uridine in protecting normal tissues, and the role for tumor-specific modulation of the phosphorolytic activity in 5-FU or Capecitabine-based chemotherapy.