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

胸苷磷酸化酶（TP）是一种参与胸苷转化为胸腺氨酸的酶，与血管生成因子，血小板衍生的内皮细胞生长因子（PD-ECGF）相同，TP在多种固体肿瘤中比在固定性的非启发性非启发性组织中在较高的固体瘤中表达。 Kb/TP细胞对缺氧诱导的凋亡具有抗性。在PD-ECGF/TP产生的胸苷的降解产物中，2-脱氧-D-核糖部分阻止了缺氧诱导的细胞凋亡，2-脱氧-L-核糖促使2-脱氧-D-核糖的作用。这些发现表明，TP可以赋予缺氧诱导的凋亡的抗性，胸苷的退化产物参与了这种耐药性。在缺氧的情况下，HIF-1α的水平升高，Bcl-2和Bcl-XL的表达水平降低。 2-脱氧-D-核糖抑制了细胞对缺氧的反应。 TP阳性结肠和食管肿瘤的患者的预后较差，比患有TP阴性肿瘤的患者更差。我们最近合成了一种新的TP抑制剂（TPI），5-氯-6- [1-（2-（2-米诺吡啶基）甲基]盐酸尿酸尿素。我们使用小鼠背空气囊测定模型研究了用PD-ECGF cDNA，Kb/tp转染的TPI对KB细胞中血管生成的影响。我们发现KB/TP细胞的血管生成能力比Kb/CV细胞具有更高的血管生成能力，并且TPI完全抑制了Kb/tp的血管生成。此外，在50 mg/kg/天的剂量下，TPI仔细地降低了Kb/TP细胞的生长速率。 Kb/TP肿瘤中的微舍固液密度高于Kb/CV肿瘤的微血管密度，TPI并未显着改变任何肿瘤的密度。 Kb/TP肿瘤中的凋亡指数明显低于Kb/CV肿瘤的凋亡指数，而TPI显着增加了KB/TP肿瘤中的凋亡指数，但在KB/CV肿瘤中却没有明显增加。 TPI抑制了KB/TP细胞的高趋化运动和基底膜侵袭。在裸鼠中，口服TPI抑制了高度转移的KB/TP细胞的宏观肝转移。这些发现表明，TP在表达TP的实体瘤的侵袭性和转移中起着关键作用，而TPI可能是血液传播转移的新型抗转移剂。较少的

项目成果

Matsushita,S.,: "The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in tumors."Cancer Res.,. 59. 1911-1961 (1999)

Matsushita，S.，：“胸苷磷酸化酶抑制剂对肿瘤血管生成和细胞凋亡的影响。”Cancer Res.，。

Chen,Z-S.,: "Effect of multidrug resistance reversing agents on the teansporting activity of human canalicular multispecific organic anino transporter (cMOAT)."Mol.Pharmacol.,. 56. 1219-1228 (1999)

Chen，Z-S.，：“多药耐药逆转剂对人小管多特异性有机阴离子转运蛋白（cMOAT）转运活性的影响。”Mol.Pharmacol.,。

Takebayashi,Y.,: "Thymidine phosphorylase in human esophageal squamous cell carcinoma." Cancer. 85. 282-296 (1999)

Takebayashi，Y.，：“人食管鳞状细胞癌中的胸苷磷酸化酶。”

Kawabe, T., et al.: "Enhanced transport of anticancer agents and leukotriene C4 by the human canalicular multispecific organic anion transporter"FEBS Lett.. 465. 327-331 (1999)

Kawabe, T., et al.：“人小管多特异性有机阴离子转运蛋白增强抗癌剂和白三烯 C4 的转运”FEBS Lett.. 465. 327-331 (1999)

Fukuiwa,T.,: "Expression of thymidine phosphorylase and vascular endothelial cell growth factor in human head and neck squamous cell carcinoma and their different characteristids."Cancer. 85. 960-969 (1999)

Fukuiwa，T.，：“胸苷磷酸化酶和血管内皮细胞生长因子在人头颈鳞状细胞癌中的表达及其不同特征。”癌症。