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鉴定 UVA 光激活人细胞中 4-硫代胸腺嘧啶脱氧核苷诱导的潜在细胞毒性损伤。

Identification of potentially cytotoxic lesions induced by UVA photoactivation of DNA 4-thiothymidine in human cells.

机构信息

King's College London, School of Medicine, Division of Genetics and Molecular Medicine, St John's Institute of Dermatology, London, SE1 9RT, UK.

出版信息

Nucleic Acids Res. 2011 Dec;39(22):9620-32. doi: 10.1093/nar/gkr674. Epub 2011 Sep 2.

DOI:10.1093/nar/gkr674
PMID:21890905
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3239200/
Abstract

Photochemotherapy-in which a photosensitizing drug is combined with ultraviolet or visible radiation-has proven therapeutic effectiveness. Existing approaches have drawbacks, however, and there is a clinical need to develop alternatives offering improved target cell selectivity. DNA substitution by 4-thiothymidine (S(4)TdR) sensitizes cells to killing by ultraviolet A (UVA) radiation. Here, we demonstrate that UVA photoactivation of DNA S(4)TdR does not generate reactive oxygen or cause direct DNA breakage and is only minimally mutagenic. In an organotypic human skin model, UVA penetration is sufficiently robust to kill S(4)TdR-photosensitized epidermal cells. We have investigated the DNA lesions responsible for toxicity. Although thymidine is the predominant UVA photoproduct of S(4)TdR in dilute solution, more complex lesions are formed when S(4)TdR-containing oligonucleotides are irradiated. One of these, a thietane/S(5)-(6-4)T:T, is structurally related to the (6-4) pyrimidine:pyrimidone [(6-4) Py:Py] photoproducts induced by UVB/C radiation. These lesions are detectable in DNA from S(4)TdR/UVA-treated cells and are excised from DNA more efficiently by keratinocytes than by leukaemia cells. UVA irradiation also induces DNA interstrand crosslinking of S(4)TdR-containing duplex oligonucleotides. Cells defective in repairing (6-4) Py:Py DNA adducts or processing DNA crosslinks are extremely sensitive to S(4)TdR/UVA indicating that these lesions contribute significantly to S(4)TdR/UVA cytotoxicity.

摘要

光化学疗法 - 其中一种光敏药物与紫外线或可见光结合 - 已被证明具有治疗效果。然而，现有的方法存在缺点，因此临床上需要开发出提供更高靶细胞选择性的替代方法。4-硫代胸腺嘧啶（S(4)TdR）取代 DNA 可使细胞对紫外线 A（UVA）辐射敏感。在这里，我们证明 DNA S(4)TdR 的 UVA 光激活不会产生活性氧或导致直接 DNA 断裂，并且仅具有最小的致突变性。在器官型人皮肤模型中，UVA 穿透足以杀死 S(4)TdR 光敏表皮细胞。我们研究了导致毒性的 DNA 损伤。尽管在稀溶液中 S(4)TdR 是 UVA 光产物中的主要产物，但当含有 S(4)TdR 的寡核苷酸被辐照时，会形成更复杂的损伤。其中之一是噻噁烷/S(5)-(6-4)T:T，其结构与由 UVB/C 辐射诱导的（6-4）嘧啶：嘧啶酮[(6-4) Py:Py]光产物有关。这些损伤可在 S(4)TdR/UVA 处理细胞的 DNA 中检测到，并且角质形成细胞比白血病细胞更有效地从 DNA 中切除。UVA 照射还诱导含有 S(4)TdR 的双链寡核苷酸的 DNA 链间交联。修复（6-4）Py:Py DNA 加合物或处理 DNA 交联有缺陷的细胞对 S(4)TdR/UVA 非常敏感，表明这些损伤对 S(4)TdR/UVA 细胞毒性有重大贡献。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/6acda662bb9c/gkr674f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/bf28dee0cda0/gkr674f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/a22198cff5a4/gkr674f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/148fd03ca8f0/gkr674f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/a9264086174d/gkr674f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/ce66179287c2/gkr674f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/4dce8c38c59a/gkr674f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/6acda662bb9c/gkr674f10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/bf28dee0cda0/gkr674f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/a00ba1c4d189/gkr674f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/21d98dcd1b3b/gkr674f3a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/b8c255a33c21/gkr674f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/a22198cff5a4/gkr674f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/148fd03ca8f0/gkr674f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/a9264086174d/gkr674f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/ce66179287c2/gkr674f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/4dce8c38c59a/gkr674f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ec1a/3239200/6acda662bb9c/gkr674f10.jpg

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