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

胸腺嘧啶核苷磷酸化酶(TP)是一种参与胸腺嘧啶核苷可逆转化为胸腺嘧啶的酶，与一种血管生成因子--血小板衍化内皮细胞生长因子(PD-ECGF)一样，TP在多种实体肿瘤中的表达水平均高于其周围的非肿瘤组织。转导PD-ECGF/TP基因的KB/TP细胞对低氧诱导的细胞凋亡具有抵抗作用。在PD-ECGF/TP产生的胸苷降解产物中，2-脱氧-D-核糖可部分拮抗缺氧诱导的细胞凋亡，2-脱氧-L-核糖可拮抗2-脱氧-D-核糖的作用。提示茶多酚对缺氧诱导的细胞凋亡具有抵抗作用，其机制可能与胸腺嘧啶核苷降解产物有关。缺氧状态下，HIF-1α表达水平升高，Bcl2和Bclxl表达水平降低。2-脱氧-D-核糖抑制细胞对低氧的反应。TP阳性的结肠和食道肿瘤患者的…与TP阴性的肿瘤相比，预后更差。我们最近合成了一种新的TP抑制剂，5-氯-6-[1-(2-亚氨基吡咯烷基)甲基]尿嘧啶盐酸盐。采用小鼠背部气囊实验模型，观察TPI对转导PD-ECGF基因的KB/TP细胞和空白对照KB/CV细胞血管生成的影响。我们发现KB/TP细胞具有比KB/CV细胞更强的血管生成能力，并且TPI完全抑制了KB/TP细胞的血管生成。此外，在50 mg/kg/d剂量下，TPI可显著降低KB/TP细胞裸鼠移植瘤的生长速度。KB/TP肿瘤的微血管密度高于KB/CV肿瘤，而TPI对两种肿瘤的微血管密度均无明显影响。Kb/TP肿瘤细胞凋亡指数显著低于Kb/CV肿瘤，TPI显著增加Kb/TP肿瘤细胞凋亡指数，但对Kb/CV肿瘤细胞凋亡指数无显著影响。TPI抑制KB/TP细胞的高趋化运动和基底膜侵袭。在裸鼠中，口服TPI抑制了高转移性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关键作用，TPI可能是一种新型的抗血道转移药物。较少

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