Balzarini J, De Clercq E, Verbruggen A, Crumpacker C, Ayusawa D, Seno T
Anticancer Res. 1986 Sep-Oct;6(5):1077-84.
Various established antiherpetic drugs, including 1-beta-D-arabinofuranosylthymine (araT), acyclovir (ACV), 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG), 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), and structurally related analogues thereof, i.e. (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), (E)-5-(2-bromovinyl)-2'-deoxycytidine (BVDC), (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), and the carbocyclic analogues of BVDU (C-BVDU), IVDU (C-IVDU) and BVDC (C-BVDC), were evaluated for their inhibitory effects on the growth of murine mammary carcinoma (FM3A/0), murine leukemia (L1210/0) and murine fibroblast (LM/0) cells and the thymidine kinase-deficient (TK-) sublines derived from the FM3A/0, L1210/0 and LM/0 cells. BVDU, IVDU and BVDC showed a markedly increased cytostatic activity against the TK- cell lines. To determine the biochemical mechanism of the increased cytostatic action of these compounds toward TK- cell lines, BVDU and IVDU were further evaluated for their inhibitory effects on pyrimidine nucleotide metabolism, in particular thymidylate synthetase activity, their incorporation into DNA and into trichloroacetic acid (TCA)-insoluble material, and their effects on DNA, RNA and protein synthesis in both TK+ and TK- cells. No marked differences were noted in the interaction of BVDU and IVDU with these potential targets between TK+ and TK- cell lines. Furthermore, neither FM3A/0 nor FM3A/TK- cells expressed a significant phosphorylating activity for (125I) IVDU. However, BVDU and IVDU specifically inhibited the incorporation of (1-14C) mannose and (1-14C) glucose into glycoproteins of FM3A/TK- and L1210/TK- cells. To what extent the inhibition of the incorporation of these monosaccharides into glycoproteins may contribute to the increased cytostatic effects of BVDU and IVDU on TK- cells remains to be determined.
对多种已有的抗疱疹药物进行了评估，这些药物包括1-β-D-阿拉伯呋喃糖基胸腺嘧啶（araT）、阿昔洛韦（ACV）、9-(1,3-二羟基-2-丙氧甲基)鸟嘌呤（DHPG）、5-(2-氯乙基)-2'-脱氧尿苷（CEDU）、(E)-5-(2-溴乙烯基)-2'-脱氧尿苷（BVDU）及其结构相关类似物，即(E)-5-(2-碘乙烯基)-2'-脱氧尿苷（IVDU）、(E)-5-(2-溴乙烯基)-2'-脱氧胞苷（BVDC）、(E)-5-(2-溴乙烯基)-1-β-D-阿拉伯呋喃糖基尿嘧啶（BVaraU），以及BVDU（C-BVDU）、IVDU（C-IVDU）和BVDC（C-BVDC）的碳环类似物，评估它们对小鼠乳腺癌（FM3A/0）、小鼠白血病（L1210/0）和小鼠成纤维细胞（LM/0）细胞以及源自FM3A/0、L1210/0和LM/0细胞的胸苷激酶缺陷（TK-）亚系细胞生长的抑制作用。BVDU、IVDU和BVDC对TK-细胞系显示出明显增强的细胞生长抑制活性。为了确定这些化合物对TK-细胞系细胞生长抑制作用增强的生化机制，进一步评估了BVDU和IVDU对嘧啶核苷酸代谢的抑制作用，特别是胸苷酸合成酶活性、它们掺入DNA和三氯乙酸（TCA）不溶性物质中的情况，以及它们对TK+和TK-细胞中DNA、RNA和蛋白质合成的影响。在TK+和TK-细胞系之间，未发现BVDU和IVDU与这些潜在靶点的相互作用有明显差异。此外，FM3A/0细胞和FM3A/TK-细胞对(125I)IVDU均未表现出显著的磷酸化活性。然而，BVDU和IVDU特异性抑制(1-14C)甘露糖和(1-14C)葡萄糖掺入FM3A/TK-和L1210/TK-细胞的糖蛋白中。这些单糖掺入糖蛋白的抑制作用在多大程度上导致BVDU和IVDU对TK-细胞的细胞生长抑制作用增强仍有待确定。
