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

胸苷磷酸化酶（TP）是一种参与胸苷可逆转化为胸腺嘧啶的酶，与血管生成因子血小板衍生内皮细胞生长因子（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细胞对缺氧诱导的凋亡具有抵抗性。在PD-ECGF/TP产生的胸苷降解产物中，2-脱氧-D-核糖可部分抑制缺氧诱导的细胞凋亡，2-脱氧-L-核糖可完全阻断2-脱氧-D-核糖的作用。提示TP可抵抗缺氧诱导的细胞凋亡，其机制可能与TP的胸苷降解产物有关，缺氧时TP可使HIF-1 α表达升高，Bcl-2和Bcl-XL表达降低。2-脱氧-D-核糖抑制细胞对缺氧的反应。TP阳性的结肠和食管肿瘤患者， ...更多信息 预后比TP阴性肿瘤差。我们最近合成了一种新的TP抑制剂（TPI），5-氯-6-[1-（2-亚氨基吡咯烷基）甲基]尿嘧啶盐酸盐。我们使用小鼠背侧气囊试验模型研究了TPI对转染PD-ECGF cDNA的KB细胞（KB/TP）和模拟转染物（KB/CV）中血管生成的影响。我们发现KB/TP细胞比KB/CV细胞具有更高的血管生成能力，并且TPI完全抑制KB/TP的血管生成。此外，在50 mg/kg/天剂量下，TPI显著降低了裸鼠异种移植KB/TP细胞的生长速率。KB/TP肿瘤的微血管密度高于KB/CV肿瘤，TPI未显著改变两种肿瘤的密度。KB/TP肿瘤的凋亡指数显著低于KB/CV肿瘤，TPI显著增加KB/TP肿瘤的凋亡指数，但不增加KB/CV肿瘤的凋亡指数。TPI抑制KB/TP细胞的高趋化运动和基底膜侵袭。在裸鼠中，TPI经口给药抑制了高度转移性KB/TP细胞的肉眼可见肝转移。这些结果表明，TP在TP表达的实体瘤的侵袭和转移中起关键作用，TPI可能是一种新的抗血液转移药物。少

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