The combined antiproliferative and metabolism-altering properties of rapamycin may therefore be important in preventing tumor regrowth post-transplantation and may explain the lower incidence of HCC and skin malignancies observed in transplant recipients taking this drug. Calorie restriction is known to extend lifespan21 and its effect is apparently mediated Wnt activity through mTOR,22 with superoxide-based signals playing a role.23 The effect

of calorie restriction on longevity is highly conserved, because rapamycin also increases murine lifespan, even when administered late in life.24 However, as we have noted above, rapamycin treatment is also associated with insulin resistance (IR), hyperlipidemia, and IS, thus making it important to identify competing downstream mechanisms of the rapamycin/mTOR interaction that may affect aging,

as some groups HDAC inhibitor are all ready doing with some success.25, 26 As well as suppressing graft rejection, rapamycin and its analogs have multiple effects with exciting implications for their therapeutic use. By inducing Tregs, rapamycin may prevent the reemergence of autoimmune disease post-transplantation. It may also prevent weight gain, reduce the incidence of malignancy, and increase longevity. However, the negative effect of rapamycin treatment on metabolism, including induction of glucose intolerance and IR, also need to be considered. Regulatory processes are critical for deciding on the balance of efficacy and side effects required for approval of any drug. Occasionally, data prove to be inaccurate or incomplete, and drugs may need to be removed from the market. However, mistaken assumptions and poor study design may also lead to an incorrect interpretation of a drug’s potential benefit and result in its failure to be approved or correctly utilized. Regulatory agencies should be just as eager to identify these oversights and have mechanisms in place to resurrect drugs once new supportive evidence for their beneficial use is selleck compound found. The potential for rapamycin to prevent hepatoma recurrence

affects over 1,000 patients in the United States every year (almost one fifth of liver transplant recipients), and promotes graft tolerance in thousands of patients, if the Levitsky hypothesis bears out. To demand stringent new double-blind registration trials is unrealistic, because the drug’s patent life is about to expire. A new paradigm must be developed by the U.S. Food and Drug Administration, together with the physician and scientific communities, to realize the extended therapeutic benefit of this and other drugs for the benefit of all patients. “
“Hepatocellular carcinoma (HCC) is a highly invasive tumor with frequent intrahepatic or pulmonary metastasis, which is the main reason for high recurrence and poor survival of HCC after liver resection.