Photoactivation of DNA thiobases as a potential novel therapeutic option
Photoactivation of DNA thiobases as a potential novel therapeutic option
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DOI：
10.1016/s0960-9822(01)00272-x
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发表时间：
2001-07-24
期刊：
影响因子：
9.2
通讯作者：
Karran, P
中科院分区：
文献类型：
--
作者：
Massey, A;Xu, YZ;Karran, P
硫代嘌呤、6-硫代鸟嘌呤和6-巯基嘌呤是抗白血病药物，通过嘌呤补救途径回收后掺入DNA中（综述见[1]）。它们的毒性需要主动的DNA错配修复（MMR），并且硫嘌呤抗性是MMR缺陷细胞的公认表型[2，3]。除了这些直接的细胞毒性作用外，DNA硫代碱基具有独特的光化学性质[4]，其治疗潜力尚未得到广泛评价。我们在这里报告，硫代嘧啶核苷4-硫代胸苷被纳入DNA。它不诱导MMR相关毒性，但它与UVA光协同作用，并显著使培养的人类细胞对非常低的非致死UVA剂量敏感。4-硫胸苷在DNA修复熟练细胞中诱导约100倍的UVA剂量增强。核苷酸切除修复缺陷着色性干皮病细胞致敏高达1000倍，牵连庞大的DNA光产物的致死作用。硫胸苷加上UVA的协同作用需要胸苷激酶，表明对快速增殖的细胞的选择性毒性。UVA协同细胞毒性是DNA硫代碱基的一般性质，6-硫代鸟嘌呤和4-硫代脱氧尿苷也是UVA敏化剂。硫基/UVA治疗可能为银屑病等非恶性疾病或可接受光疗的浅表肿瘤的临床管理提供一种新的治疗方法。
The thiopurines, 6-thioguanine and 6-mercaptopurine, are antileukemic agents that are incorporated into DNA following retrieval by the purine salvage pathway (see [1] for a review). Their toxicity requires active DNA mismatch repair (MMR), and thiopurine resistance is an acknowledged phenotype of MMR-defective cells [2, 3]. In addition to these direct cytotoxic effects, DNA thiobases have distinctive photochemical properties [4], the therapeutic potential of which has not been extensively evaluated. We report here that the thiopyrimidine nucleoside 4-thiothymidine is incorporated into DNA. It does not induce MMR-related toxicity, but it interacts synergistically with UVA light and dramatically sensitizes cultured human cells to very low, nonlethal UVA doses. 4-thiothymidine induced UVA dose enhancements of around 100-fold in DNA repair-proficient cells. Nucleotide excision repair-defective xeroderma pigmentosum cells were sensitized up to 1000-fold, implicating bulky DNA photoproducts in the lethal effect. The synergistic action of thiothymidine plus UVA required thymidine kinase, indicating a selective toxicity toward rapidly proliferating cells. Cooperative UVA cytotoxicity is a general property of DNA thiobases, and 6-thioguanine and 4-thiodeoxyuridine were also UVA sensitizers. Thiobase/UVA treatment may offer a novel therapeutic approach for the clinical management of nonmalignant conditions like psoriasis or for superficial tumors that are accessible to phototherapy.