Physiological function of thymidine phosphorylase and the involvement of the enzyme in tumor growth

胸苷磷酸化酶的生理功能及其在肿瘤生长中的参与

• 批准号: 10470043
• 负责人: AKIYAMA Shinichi
• 金额: $ 8万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470043/
• 关键词: Thymidine phosphorylase; 2-deoxy-D-ribose; 2-deoxy-L-ribose; TPI; hypoxia; apotosis; metastasis; angiogenesis; PDーECGF; チミジン; 2-depxy-D-ribose; アポトーシス; TPI

Thymidine phosphorylase (TP) is an enzyme involved in the reversible conversion of thymidine to thymine and is identical to an angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), TP is expressed at higher levels in a wide variety of solid tumors than in the adjacent nonneoplastic tissues. KB/TP cells transfected with a PD-ECGF/TP cDNA were resistant to hypoxia-induced apoptosis. Among the degradation products of thymidine produced by PD-ECGF/TP, 2-deoxy-D-ribose partially prevented hypoxia-induced apoptosis, 2-Deoxy-L-ribose abrogated the effects of 2-deoxy-D-ribose. These findings suggested that TP can confer resistance to apoptosis induced by hypoxia and the degeadation products of thymidine are involved in this resistance.In hypoxic condition, the level of HIF-1 α is elevated and the expression levels of Bcl-2 and Bcl-XL are lowered. 2-Deoxy-D-ribose inhibited the response of the cells to hypoxia. Patients with TP-positive colon and esophageal tumors have a … More poorer prognosis than those with TP-negative tumors. We have recently synthesized a new TP inhibitor (TPI), 5-chloro-6-[1-(2-iminopyrrolidinyl)methyl] uracil hydrochloride. We investigated the effect of TPI on angiogenesis in KB cells transfected with PD-ECGF cDNA, KB/TP, and a mock transfecta, KB/CV, using the mouse dorsal air sac assay model. We found that KB/TP cells had a higher angiogeneic ability than KB/CV cells and that TPI completely suppressed angiogenesis by KB/TP. Furthermore, at a dose of 50 mg/kg/day, TPI considerably decreased the growth rate of KB/TP cells xenografted into nude mice. Microvessel density in KB/TP tumors was higher than that in KB/CV tumors, and TPI did not significantly change the density in either of the tumors. The apoptotic index in KB/TP tumors was significantly lower than that in KB/CV tumors, and TPI significantly increased the apoptotic index in KB/TP tumors but not in KB/CV tumors. TPI inhibited the high chemotactic motility and basement membrane invasion of KB/TP cells. In nude mice, oral administration of TPI suppressed macroscopic liver metastases of highly metastasizing KB/TP cells. These findings demonstrate that TP plays a key role in invasiveness and metastasis of TP-expressing solid tumors, and TPI might be a novel anti-metastatic agent for blood-borne metastasis. Less

胸腺嘧啶磷酸化酶（TP）是一种参与胸腺嘧啶可逆转化为胸腺嘧啶的酶，与血管生成因子、血小板来源的内皮细胞生长因子（PD-ECGF）相同，TP在多种实体瘤中的表达水平高于邻近的非肿瘤组织。转染PD-ECGF/TP cDNA的KB/TP细胞对缺氧诱导的细胞凋亡具有抗性。在PD-ECGF/TP产生的胸腺嘧啶降解产物中，2-脱氧-d -核糖部分阻止了缺氧诱导的细胞凋亡，2-脱氧- l -核糖完全消除了2-脱氧-d -核糖的作用。这些发现表明，TP能够抵抗缺氧诱导的细胞凋亡，胸腺嘧啶的降解产物参与了这种抵抗。缺氧条件下，HIF-1 α水平升高，Bcl-2和Bcl-XL表达水平降低。2-脱氧核糖抑制细胞对缺氧的反应。与tp阴性肿瘤相比，tp阳性的结肠和食管肿瘤患者预后更差。我们最近合成了一种新的TP抑制剂（TPI）， 5-氯-6-[1-（2-亚氨基吡啶基）甲基]尿嘧啶盐酸盐。我们利用小鼠背气囊实验模型，研究了TPI对转染PD-ECGF cDNA、KB/TP和模拟转染KB/CV的KB细胞血管生成的影响。我们发现KB/TP细胞比KB/CV细胞有更高的血管生成能力，TPI完全抑制KB/TP的血管生成。此外，50mg /kg/day剂量的TPI显著降低了裸鼠移植KB/TP细胞的生长速度。KB/TP肿瘤的微血管密度高于KB/CV肿瘤，TPI对两种肿瘤的微血管密度均无显著影响。KB/TP肿瘤的凋亡指数显著低于KB/CV肿瘤，TPI对KB/TP肿瘤的凋亡指数有显著升高作用，而对KB/CV肿瘤的凋亡指数无显著升高作用。TPI抑制KB/TP细胞的高趋化运动性和基底膜侵袭。在裸鼠实验中，口服TPI可抑制高转移性KB/TP细胞的宏观肝转移。这些结果表明，TP在表达TP的实体瘤的侵袭和转移中起着关键作用，TPI可能是一种新的血源性转移抗转移剂。少

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