Antiangiogenic and antitumor activity of 6-(2-aminoethyl)amino-5-chlorouracil, a novel small-molecule inhibitor of thymidine phosphorylase, in combination with the vascular endothelial growth factor-trap.
Antiangiogenic and antitumor activity of 6-(2-aminoethyl)amino-5-chlorouracil, a novel small-molecule inhibitor of thymidine phosphorylase, in combination with the vascular endothelial growth factor-trap.
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DOI：
10.1158/1078-0432.ccr-08-3203
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发表时间：
2009-08-15
期刊：
影响因子：
--
通讯作者：
Schwartz EL
中科院分区：
文献类型：
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作者：
Lu H;Klein RS;Schwartz EL
肿瘤产生多种促血管生成因子，使得靶向单一血管生成途径的药物不太可能足以治疗临床上发生的肿瘤谱。PD-ECGF（血小板衍生的内皮细胞生长因子）在体外和体内具有血管生成活性，并且在大多数人类癌症中过表达，其中其表达与微血管密度增加、更具侵袭性的肿瘤和较差的患者预后相关。PD-ECGF与胸苷磷酸化酶（TP）相同，与其他血管生成因子不同，TP的促血管生成作用取决于其酶活性。TP催化活性的有效和特异性小分子抑制剂6-（2-氨乙基）氨基-5-氯尿嘧啶（AEAC）在体内人癌症异种移植物中测试抗血管生成和抗肿瘤活性。AEAC的口服给药导致A549非小细胞肺癌和PANC-1胰腺癌异种移植物的生长减少40-50%，但它对第二种胰腺肿瘤BxPC-3没有活性。AEAC降低了肿瘤中的微血管密度，为抗血管生成作用提供了证据。当用VEGF-Trap（一种可溶性VEGF诱饵受体）处理小鼠时，观察到相等或更好的活性，并且AEAC和VEGF-Trap的组合产生的相加的抗肿瘤活性显著大于单独的VEGF-Trap。在A549肿瘤中，该组合产生肿瘤消退。这些研究显示了靶向TP的药物的抗肿瘤活性，并表明TP的抑制剂可用于增强靶向VEGF途径的药物的临床疗效。
Tumors produce multiple pro-angiogenic factors, making it unlikely that agents targeting a single angiogenic pathway will be sufficient to treat the spectrum of tumors which occur clinically. PD-ECGF (platelet-derived endothelial cell growth factor) has angiogenic activity in vitro and in vivo and is overexpressed in most human cancers, where its expression has been correlated with increased microvessel density, more aggressive tumors, and poorer patient prognosis. PD-ECGF is identical to the enzyme thymidine phosphorylase (TP), and unlike other angiogenic factors, TP's pro-angiogenic actions are dependent upon its enzyme activity. A potent and specific small molecule inhibitor of the catalytic activity of TP, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), was tested for antiangiogenic and anti-tumor activity in human cancer xenografts in vivo. Oral administration of AEAC caused 40-50% reductions in the growth of A549 non-small cell lung cancer and PANC-1 pancreatic cancer xenografts, but it was not active against a second pancreatic tumor, BxPC-3. AEAC reduced the microvessel density in the tumors, providing evidence for an anti-angiogenic action. Equal or better activity was seen when the mice were treated with the VEGF-Trap, a soluble VEGF decoy receptor, and the combination of AEAC and the VEGF-Trap produced additive anti-tumor activity that was significantly greater than the VEGF-Trap alone. In the A549 tumors, the combination produced tumor regressions. These studies show antitumor activity for a drug targeting TP, and suggest that inhibitors of TP could be used to augment the clinical efficacy of drugs targeting the VEGF pathway.