Molecular targets for existing and novel immunosuppressive drugs.
Molecular targets for existing and novel immunosuppressive drugs.
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DOI：
10.1017/s1462399400001769
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发表时间：
2000-06-21
影响因子：
6.2
通讯作者：
Stepkowski, S M
中科院分区：
文献类型：
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作者：
Stepkowski, S M
抗肿瘤细胞抑制性抗增殖剂，如甲氨蝶呤，6-巯基嘌呤和环磷酰胺，最初被用作免疫抑制药物。虽然这些药物仅诱导适度的抗排斥活性，但它们引起严重的非特异性骨髓抑制，损害宿主抵抗力并增加感染的发生率。与这些非选择性药物不同，环孢菌素A、他克莫司和西罗莫司对T淋巴细胞（T细胞）和B淋巴细胞（B细胞）活化周期的不同阶段更具选择性;然而，环孢菌素和他克莫司具有肾毒性，而西罗莫司可引起高胆固醇血症。因此，尽管取得了这一进展，但必须继续努力开发和测试新的、可能具有很强选择性的药剂。试剂15-脱氧精胍菌素适度抑制有丝分裂原刺激的T细胞增殖和细胞毒性T淋巴细胞（CTL）的产生，但不影响白细胞介素2（IL-2）的产生。另一种药物FTY 720通过改变淋巴细胞向淋巴样区室的归巢，具有防止排斥反应的独特作用。抗增殖药物家族的最新成员，即麦考酚酸酯、来氟米特和布奎那，可能比它们的前辈更具选择性。然而，最有前途的药物是使用反义技术生产的。这种方法涉及反义寡聚脱氧核苷酸的设计;这些新型药物旨在通过阻断选定的信使RNA（mRNA）来阻断同种异体移植排斥反应。本文综述了传统药物、新开发药物和反义技术的作用机制、应用局限性和分子或细胞靶点，反义技术是分子医学的一个新应用。
Anti-neoplastic cytostatic antiproliferative agents, such as methotrexate, 6-mercaptopurine and cyclophosphamide, were originally used as immunosuppressive drugs. Although these agents induced only modest anti-rejection activity, they caused serious non-specific bone marrow suppression, impairing host resistance and increasing the incidence of infections. Unlike these non-selective agents, cyclosporine A, tacrolimus and sirolimus act more selectively on different stages of the T-lymphocyte (T-cell) and B-lymphocyte (B-cell) activation cycles; however, cyclosporine and tacrolimus are nephrotoxic, whereas sirolimus causes hypertriglyceridaemia. Thus, despite this progress, continued efforts must be made to develop and test new, potentially very selective agents. The agent 15-deoxyspergualin moderately inhibits both mitogen-stimulated T-cell proliferation and the generation of cytotoxic T lymphocytes (CTLs) but does not affect the production of interleukin 2 (IL-2). Another drug, FTY720, has a unique action to prevent rejection, by altering the homing of lymphocytes to the lymphoid compartments. The newest members of the family of antiproliferative agents, namely mycophenolate mofetil, leflunomide and brequinar, are potentially more selective than their predecessors. However, the most promising agents are produced using antisense technology. This approach involves the design of antisense oligodeoxynucleotides; these novel drugs are designed to block allograft rejection by blocking selected messenger RNA (mRNA). This review outlines the mechanisms of action, the limitations of application and the molecular or cellular targets of traditional agents, newly developed drugs and also antisense technology, which is an example of a new application of molecular medicine.