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Novel Immunosuppression in Patients with Hepatic Malignancies
Orthotopic liver transplantation (OLT) for malignancy, specifically hepatocellular carcinoma (HCC), has dramatically increased in the last several decades. Unfortunately, cancer recurrence remains a formidable problem. At present, calcineurin-based immunosuppression (IS) regimens are employed by most transplant centers around the world. However, preclinical data suggest that calcineurin inhibitors (CNIs) may promote both primary tumor growth and distant metastasis. Several clinical series link CNI-based IS to reduced recurrence-free survival in the setting of OLT and concomitant HCC. An immunosuppressive agent with both antiproliferative and antineoplastic properties is theoretically attractive.
Sirolimus (SRL), a macrocyclic lactone, is a natural fermentation product of Streptomyces hygroscopicus . Originally isolated from Easter Island in 1969, SRL maintains potent antifungal and immunosuppressive properties. These effects are mediated by a well-characterized intracellular protein termed mammalian target of rapamycin (mTOR). SRL binding to mTOR results in blockade of IL-2 receptor-mediated signal transduction, which in turn results in cell cycle arrest in T lymphocytes. Originally approved by the Food and Drug Administration in 1999 for kidney transplant, phase III trials in North America were conducted in conjunction with full-dose cyclosporine (CSA). SRL may have a direct antineoplastic effect in the setting of HCC. The clinical significance of these effects are unclear.
Preclinical Influence of Immunosuppression on Malignancy
Early reports of HCC recurrence following OLT are as high as 40% in patients with large tumors. With refined and more conservative selection criteria, HCC recurrence ranges from 10% to 20%. A classic study by Hojo et al documents the prooncogenic influence of CNIs. Pretreatment of adenocarcinoma cells with CSA induced dramatic morphological changes, including increased motility and pseudopodial protrusions. The authors conclude that CNIs may promote malignant progression independent of the immunosuppressive influence. Freise et al at the University of California, San Francisco, observed that mice receiving CSA in the setting of HCC had a higher mortality and increased incidence of tumor recurrence. Although the specific mechanisms are yet to be determined, SRL has demonstrated some antiproliferative effects in vivo. Several investigators have documented a direct antineoplastic effect on human hepatoma cells in vitro. In 2002 Guba et al demonstrated that SRL treatment inhibits primary tumor growth and neovascularization by reducing vascular endothelial growth factor (VEGF) expressed in a murine model of metastatic colon cancer. Interestingly, SRL may directly influence blood vessel function and has been shown to induce tumor-specific microvascular thrombosis yet has no effect on normal tissue. This microvascular effect may be responsible for a reduction in cancer recurrence suspected clinically. SRL treatment in several murine models of HCC has resulted in significant reductions in tumor volume, blood vessel density, and plasma VEGF levels.
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