Can immunosuppressive strategies be used to reduce cancer risk in renal transplant patients?

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.