文章：

当前医学实践中的硫嘌呤：分子机制和对治疗相关癌症的贡献

Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer

原文发布日期：2008-01-01

DOI: 10.1038/nrc2292

类型: Review Article

开放获取: 否

要点：

1. The thiopurines azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) have been available to medical practitioners for over half a century. They are used as anticancer and immunosuppressive agents. The introduction of azathioprine as an immunosuppressant revolutionized solid-organ transplantation from unrelated donors and resulted in much improved graft survival. The thiopurines are recognized treatment options for an increasing number of chronic inflammatory and autoimmune disorders, including arthritis and colitis.
2. Largely on the basis of epidemiological data of cancer in transplant patients, the International Agency for Research on Cancer classifies azathioprine as a human carcinogen. Much of this increased cancer can be attributed to the effects of immunosuppression and the involvement of oncogenic viruses. In some cases, however, demonstration of a viral aetiology has proved elusive. This is particularly true of skin cancer, which is the major treatment-related cancer among transplant patients.
3. Thiopurines are prodrugs and one outcome of their complex metabolism is the incorporation of 6-TG into DNA during replication. 6-TG is chemically more reactive than canonical DNA bases and undergoes methylation in situ in DNA. Methylated DNA 6-TG is ultimately cytotoxic by a mechanism that depends on the cell's DNA mismatch repair system.
4. One route of escape from the cytotoxicity of thiopurines is by inactivation of mismatch repair. Mismatch repair defects are associated with high rates of spontaneous mutation and are common in certain types of cancer. Acute myeloid leukaemia occurs more frequently than expected in transplant patients. These azathioprine-related cancers are often defective in mismatch repair.
5. DNA 6-TG is also photochemically reactive and has a maximum absorbance at 340 nm in the UVA region of the ultraviolet spectrum. UVA comprises more than 90% of solar radiation that reaches the earth and, on exposure to UVA, the 6-TG DNA chromophore generates reactive oxygen species (ROS), which can damage DNA, proteins and other cellular macromolecules.
6. DNA 6-TG itself is particularly susceptible to oxidation by ROS to form guanine-6-sulphonate. This photoproduct is a powerful block to replication but can be bypassed by Y-family polymerases which have a relatively relaxed stringency. The photochemical reactions of DNA 6-TG are mutagenic and this might contribute to an increased risk of transplant-related squamous cell carcinoma of the skin.
7. The association of azathioprine with therapy-related cancers and its increasing use in treatment of chronic inflammatory and autoimmune disorders suggests that careful monitoring of these patients for signs of possible therapy-related cancer is advisable.

要点翻译：

1. 硫嘌呤类药物如硫唑嘌呤、6-巯基嘌呤和6-硫代鸟嘌呤(6-TG)在临床应用已逾半个世纪，常作为抗肿瘤药和免疫抑制剂使用。硫唑嘌呤作为免疫抑制剂的问世，彻底改变了非亲属供体的实体器官移植领域，显著提高了移植存活率。这类药物已被公认为治疗多种慢性炎症和自身免疫性疾病（包括关节炎和结肠炎）的有效选择。
2. 基于移植患者癌症流行病学数据，国际癌症研究机构将硫唑嘌呤归类为人类致癌物。这种致癌风险增加主要归因于免疫抑制效应及致癌病毒的参与。然而在某些病例中，病毒病因学的证据难以确证，这在皮肤癌中尤为明显——该病症是移植患者中最主要的治疗相关癌症。
3. 硫嘌呤类药物属于前体药物，其复杂代谢过程会导致6-TG在DNA复制时掺入基因组。6-TG的化学反应活性高于常规碱基，会在DNA中原位发生甲基化。甲基化DNA 6-TG通过依赖细胞DNA错配修复系统的机制最终产生细胞毒性。
4. 逃避硫嘌呤细胞毒性的途径之一是错配修复功能失活。错配修复缺陷与高自发突变率相关，常见于特定癌症类型。移植患者中急性髓系白血病发生率异常偏高，这些硫唑嘌呤相关癌症常存在错配修复缺陷。
5. DNA 6-TG还具有光化学活性，在紫外线光谱UVA区340纳米处有最大吸收峰。UVA占到达地表太阳辐射的90%以上，当暴露于UVA时，6-TG DNA发色团会产生活性氧(ROS)，进而损伤DNA、蛋白质及其他细胞大分子。
6. DNA 6-TG本身尤其易被ROS氧化形成鸟嘌呤-6-磺酸盐。这种光产物会强力阻碍DNA复制，但可被严格性相对宽松的Y家族聚合酶旁路合成。DNA 6-TG的光化学反应具有致突变性，这可能增加移植相关皮肤鳞状细胞癌的发病风险。
7. 硫唑嘌呤与治疗相关癌症的关联性，及其在慢性炎症和自身免疫性疾病治疗中日益广泛的应用，提示有必要对这些患者进行严密监测以警惕潜在的治疗相关癌症迹象。

英文摘要：

Thiopurines have diverse clinical applications and their long-term use as anti-rejection drugs in transplant patients has been associated with a significantly increased risk of various types of cancer. Although they are slowly being replaced by a new generation of non-thiopurine immunosuppressants, it is anticipated that their use in the management of inflammatory and autoimmune diseases will continue to increase. Therapy-related cancer will remain a potential consequence of prolonged treatment for these generally non-life-threatening conditions. Understanding how thiopurines contribute to the development of cancer will facilitate clinical decisions about the potential risks to patients of long-term treatment for chronic inflammatory disorders.

摘要翻译： 

硫嘌呤类药物具有广泛的临床应用，其作为抗排斥药物在器官移植患者中的长期使用与多种癌症风险的显著增加有关。尽管它们正逐步被新一代非硫嘌呤类免疫抑制剂所取代，但预计其在炎症和自身免疫疾病治疗中的使用仍将增加。对于这些通常非致命的疾病，长期治疗所带来的治疗相关癌症仍将是一个潜在后果。深入理解硫嘌呤如何促进癌症的发生，将有助于临床医生在面对慢性炎症性疾病的长期治疗时，权衡患者可能面临的风险。

原文链接：

Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer