Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy
Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy
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DOI：
10.1158/0008-5472.can-04-0197
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Eriksson, S
中科院分区：
文献类型：
--
作者：
Al-Madhoun, AS;Johnsamuel, J;Eriksson, S
在3-位含有o-carboranylalkyl基团的胸苷类似物被筛选为人胸苷激酶1（TK 1）的潜在底物，TK 1是一种在多种快速增殖细胞（包括肿瘤细胞）中选择性表达的酶。在先前研究的基础上，其中12种被确定为硼中子捕获疗法的潜在递送剂，硼中子捕获疗法是一种用于治疗高级别脑肿瘤的治疗方法。在邻-碳硼烷笼和胸苷支架之间具有亚戊基间隔基的化合物4和在邻-碳硼烷笼处具有额外的二羟丙基取代基的化合物10是TK 1的最佳底物，相对于胸苷，k（cat）/K-m值分别为27%和36%。这些化合物表现出部分竞争性抑制TK 1的胸苷磷酸化。这两种化合物都不是重组人胸苷磷酸化酶的底物，它们各自的5 '-脱氧核苷酸酶1的5'-单磷酸底物也不是，因此表明具有潜在的体内稳定性。化合物10的辛醇/水分配系数为2.09，表明其具有优异的穿过血脑屏障和穿透脑组织的理化性质。在哺乳动物细胞培养物中，12种类似物的体外细胞毒性作用为中度至低度，IC 50值在10至160 mumol/L之间。化合物4和10被鼠成纤维细胞L929细胞系选择性地吸收和保留，与其TK 1缺陷变体相反。这些发现表明，化合物10是一个有前途的候选人选择性交付硼-10恶性细胞，并计划在体内进行额外的研究，以评估它的硼中子捕获治疗脑肿瘤。
Thymidine analogs containing o-carboranylalkyl groups at the 3-position were screened as potential substrates for human thymidine kinase 1 (TK1), an enzyme that is selectively expressed in a variety of rapidly proliferating cells, including tumor cells. On the basis of previous studies, 12 of these were identified as potential delivery agents for boron neutron capture therapy, a therapeutic method used for the treatment of high-grade brain tumors. Compound 4 with a pentylene spacer between the o-carborane cage and the thymidine scaffold and compound 10, which has an additional dihydroxypropyl substituent at the o-carborane cage, were the best substrates for TK1 with k(cat)/K-m values of 27% and 36% relative to that of thymidine, respectively. These compounds showed partial competitive inhibition for thymidine phosphorylation by TK1. Neither compound was a substrate of recombinant human thymidine phosphorylase nor were their respective 5'-monophosphates substrates of 5'-deoxynucleotidase 1, thereby indicating potential in vivo stability. The octanol/water partition coefficient for compound 10 was 2.09, suggesting that it has excellent physiochemical properties for crossing the blood brain barrier and penetrating brain tissue. The in vitro cytotoxic effect of the 12 analogs was moderate to low in mammalian cell cultures with IC50 values between 10 and 160 mumol/L. Compounds 4 and 10 were taken up selectively and retained by the murine fibroblast L929 cell line, in contrast to its TK1-deficient variant. These findings suggest that compound 10 is a promising candidate for selective delivery of boron-10 to malignant cells, and additional in vivo studies are planned to evaluate it for boron neutron capture therapy of brain tumors.