Geissler E K
University Hospital Regensburg, University of Regensburg, Regensburg, Germany.
Transplant Proc. 2010 Nov;42(9 Suppl):S32-5. doi: 10.1016/j.transproceed.2010.07.004.
The risk of renal transplant recipients developing a malignancy is increasingly recognized as a major issue impacting long-term overall survival. As immunosuppression is thought to contribute to the development of cancer but is therapeutically required to protect against kidney rejection, reducing cancer in this setting is a challenging objective. An important question is whether there is a selective difference between pharmacological immunosuppressants regarding effects on malignancy. Both experimental and clinical studies thus far suggest that calcineurin inhibitors tend to promote tumor development; mycophenolic acid prodrugs such as mycophenolate mofetil have exhibited some capacity to inhibit tumors, but the concentrations needed for this effect are well above levels sustainable in transplant recipients. In contrast to these immunosuppressive substances, despite its potent immunosuppressive effects, rapamycin has demonstrated an impressive ability to inhibit de novo tumor development, as well as reduce tumor growth once cancer is already established. The antitumor effects of rapamycin are being studied extensively and appear to stem from the central role that the mammalian target of rapamycin molecule plays in basic cellular processes such as cell growth and proliferation, which are also essential for neoplasm development. Pilot trials and retrospective analyses of clinical data, especially using sirolimus, are highly suggestive that rapamycin can inhibit tumors in the clinical transplant setting. Prospective clinical trials are currently underway that will bring definitive answers as to whether rapamycin treatment can act simultaneously as an immunosuppressive and anticancer agent, with the aim of reducing the long-term problem of posttransplant malignancy.
肾移植受者发生恶性肿瘤的风险日益被视为影响长期总体生存的一个主要问题。由于免疫抑制被认为会促进癌症的发生，但在治疗上又需要它来防止肾脏排斥反应，因此在这种情况下降低癌症风险是一个具有挑战性的目标。一个重要的问题是，在对恶性肿瘤的影响方面，各种药理免疫抑制剂之间是否存在选择性差异。迄今为止，实验和临床研究均表明，钙调神经磷酸酶抑制剂往往会促进肿瘤发展；麦考酚酸前体药物，如霉酚酸酯，已表现出一定的抑制肿瘤的能力，但产生这种效果所需的浓度远高于移植受者能够维持的水平。与这些免疫抑制物质不同，尽管雷帕霉素具有强大的免疫抑制作用，但它已显示出令人印象深刻的抑制肿瘤发生的能力，并且在癌症已经形成后还能减缓肿瘤生长。雷帕霉素的抗肿瘤作用正在得到广泛研究，其作用似乎源于雷帕霉素作用靶点分子在细胞生长和增殖等基本细胞过程中所起的核心作用，而这些过程对肿瘤的发展也至关重要。对临床数据进行的初步试验和回顾性分析，尤其是使用西罗莫司的分析，强烈表明雷帕霉素在临床移植环境中可以抑制肿瘤。目前正在进行前瞻性临床试验，这些试验将最终回答雷帕霉素治疗是否能同时作为一种免疫抑制剂和抗癌药物，以解决移植后恶性肿瘤这一长期问题。
