High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil.
High basal level gene expression of thymidine phosphorylase (platelet-derived endothelial cell growth factor) in colorectal tumors is associated with nonresponse to 5-fluorouracil.
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发表时间：
1998-10
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通讯作者：
R. Metzger;K. Danenberg;G. Leichman;D. Salonga;E. Schwartz;S. Wadler;H. Lenz;S. Groshen;L. Leichman;P. Danenberg;H. L.;Albert Einstein Cancer;Scheel Mildred;Stif
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作者：
R. Metzger;K. Danenberg;G. Leichman;D. Salonga;E. Schwartz;S. Wadler;H. Lenz;S. Groshen;L. Leichman;P. Danenberg;H. L.;Albert Einstein Cancer;Scheel Mildred;Stif
应用定量逆转录-聚合酶链式反应技术检测38例经5-氟尿嘧啶(5-FURA)和亚叶酸钙(LV)治疗的大肠肿瘤组织中核苷裂解酶/血管生成因子胸苷磷酸化酶(TP)基因表达水平。在对5-Fura无反应的肿瘤中，TP基因表达(相对mRNA水平)的范围比对5-Fura有反应的肿瘤大得多。与体外研究表明，细胞内TP水平的增加通过将5-Fura转化为更具细胞毒性的核苷5-氟-2‘脱氧尿苷来增强5-Fura的活性不同，基础TP表达最高的肿瘤对5-Fura/LV治疗无效。无反应的肿瘤组织中TP基因的平均水平是有反应的肿瘤患者的2.6倍。我们以前已经证明，5-Fura的靶酶胸苷合成酶(TS)的高表达也是5-Fura无反应的预测因子(L.Leichman等，J.Clin)。Oncol.，15：3223-3229,1997)。TP和TS的表达是这些肿瘤的独立变量，因此，肿瘤中TS和TP的低表达预示着对5-Fura/LV的非常高的应答率(11/14)和显著的更长的生存时间，而在24例TP或TS的高表达的患者中没有一个(0/24)是有效的。
The gene expression levels of the nucleoside cleavage enzyme/angiogenic factor thymidine phosphorylase (TP), also known as platelet-derived endothelial cell growth factor, were measured by quantitative reverse transcription-PCR in 38 pretreatment biopsies of colorectal tumors from patients who were subsequently treated with 5-fluorouracil (5-FUra) and leucovorin (LV). The range of TP gene expression (relative mRNA levels) in those tumors nonresponsive to 5-FUra was much broader than that of the responding tumors. In contrast to in vitro studies that had shown that an increased intracellular level of TP potentiates the activity of 5-FUra by converting it to the more cytotoxic nucleoside form 5-fluoro-2'deoxyuridine, tumors with the highest basal TP expressions were nonresponders to 5-FUra/LV therapy. The mean TP mRNA level in the nonresponding tumors was 2.6-fold higher than that of the responding patients. We had shown previously that high expression of thymidylate synthase (TS), the target enzyme of 5-FUra, was also a predictor of nonresponse to 5-FUra (L. Leichman et al, J. Clin. Oncol., 15: 3223-3229, 1997). TP and TS expressions were found to be independent variables in these tumors, so that low expression levels of both TS and TP in tumors predicted a very high response rate (11 of 14) to 5-FUra/LV as well as a significantly longer survival, whereas none (0 of 24) of the patients with high expression of either TP or TS were responders.