Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice
Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice
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DOI：
10.1097/00007890-200405150-00002
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发表时间：
2004-05-15
期刊：
影响因子：
6.2
通讯作者：
Geissler, EK
中科院分区：
文献类型：
--
作者：
Koehl, GE;Andrassy, J;Geissler, EK
癌症是一个日益被认识到的与免疫抑制相关的问题。然而，最近的报告表明，免疫抑制剂雷帕霉素具有抗癌特性，可以解决这个问题。到目前为止，雷帕霉素对免疫和癌症的影响一直是单独研究的。在这里，我们测试了雷帕霉素与环孢素A(CsA)对同时携带同种异体心脏移植的小鼠已建立的肿瘤的影响。在一个肿瘤移植模型中，BALB/c小鼠在C3H耳-心移植前7天接受了皮下同基因CT26结肠腺癌细胞移植。雷帕霉素或CsA治疗是从移植开始的。在第二个模型系统中，在C57BL/6小鼠中建立了B16黑色素瘤，并接受了初步的带血管C3H同种异体心脏移植。在主动脉环实验中检测雷帕霉素和CsA的体外血管生成作用。结果显示，CT26肿瘤生长2周后才出现肿瘤并发症。然而，雷帕霉素保护同种异体移植物，抑制肿瘤生长，并允许动物存活。相比之下，接受CsA治疗的小鼠虽然移植了功能正常的同种异体骨，但仍死于晚期肿瘤。雷帕霉素的抗肿瘤作用在严重联合免疫缺陷的BALB/c小鼠中也起作用。这些药物在C57BL/6小鼠的B16黑色素瘤和原代血运C3H同种异体移植中也有类似的效果。此外，在该模型中，雷帕霉素抑制了CsA对肿瘤生长的促进作用。此外，体外实验表明，CsA通过转化生长因子-β相关机制促进血管生成，这一作用可被雷帕霉素取消。这项研究表明，在复杂的移植-肿瘤情况下，雷帕霉素同时保护同种异体移植物免受排斥反应并攻击肿瘤。值得注意的是，CsA保护同种异体移植物免受排斥反应，但促进了移植受者的癌症进展。
Cancer is an increasingly recognized problem associated with immunosuppression. Recent reports, however, suggest that the immunosuppressive agent rapamycin has anti-cancer properties that could address this problem. Thus far, rapamycin's effects on immunity and cancer have been studied separately. Here we tested the effects of rapamycin, versus cyclosporine A (CsA), on established tumors in mice simultaneously bearing a heart allograft. In one tumor-transplant model, BALB/c mice received subcutaneous syngenic CT26 colon adenocarcinoma cells 7 days before C3H ear-heart transplantation. Rapamycin or CsA treatment was initiated with transplantation. In a second model system, a B16 melanoma was established in C57BL/6 mice that received a primary vascularized C3H heart allograft. In vitro angiogenic effects of rapamycin and CsA were tested in an aortic ring assay. Results show that CT26 tumors grew for 2 weeks before tumor complications occurred. However, rapamycin protected allografts, inhibited tumor growth, and permitted animal survival. In contrast, CsA-treated mice succumbed to advancing tumors, albeit with a functioning allograft. Rapamycin's anti-tumor effect also functioned in severe combined immunodeficient BALB/c mice. Similar effects of the drugs occurred with B16 melanomas and primary vascularized C3H allografts in C57BL/6 mice. Furthermore, in this model, rapamycin inhibited the tumor growth-enhancing effects of CsA. Moreover, in vitro experiments showed that CsA promotes angiogenesis by a transforming growth factor-beta-related mechanism, and that this effect is abrogated by rapamycin. This study demonstrates that rapamycin simultaneously protects allografts from rejection and attacks tumors in a complex transplant-tumor situation. Notably, CsA protects allografts from rejection, but cancer progression is promoted in transplant recipients.