Rapamycin prevents calcineurin inhibitor-associated tumor progression

M. Hojo MD, F. Luan MD, M. Maluccio MD, K. Yamaji MD and M. Suthanthiran MD

Division of Nephrology/Transplantation Medicine New York Presbyterian Hospital/Weill Medical College of Cornell University, New York, NY USA

AIM. Post-transplant malignancy is a life-threatening complication. It has become an increasingly important concern as patient and allograft survival have improved. We investigated whether an immunosuppressive regimen that preserves transplants while preventing tumor growth is feasible. METHOD. We explored the effects of rapamycin on tumor progression in immune competent mice, and in mice treated with cyclosporin A (CsA) or tacrolimus, as well as in immune deficient mice. A highly malignant murine renal carcinoma was used to induce tumor in immune competent Balb/c mice and SCID-beige mice that lack functional T cells, B-cells and NK cells. RESULTS. We found that effects of these two categories of immunosuppressive agents on tumor behavior were diametrically opposite. Whereas CsA (20 mg/kg/QOD, SQ) and tacrolimus (4 mg/kg/QOD, SQ) increased the numbers of pulmonary metastasis (p<0.05, Bonferrroni p value), rapamycin (2 mg/kg/QD, oral) inhibited the development of pulmonary metastasis (p<0.001). Furthermore addition of rapamycin into a calcineurin inhibitor-containing immunosuppressive regimen prevented calcineurin inhibition-induced increases in pulmonary metastasis (p<0.001). This dramatic effect of rapamycin was evident both in immune competent mice (Balb/c) and in immune deficient mice (SCID-beige). Studies exploring mechanisms of such effects of rapamycin revealed: 1) reversal of invasive phenotype of renal carcinoma; 2) enhanced expression of cell adhesion molecules; 3) inhibition of cell cycle progression at G1/S phase; 4) alterations in mRNA encoding cell cycle-related proteins such as cyclin D1 and p27KIP. CONCLUSION. Our studies demonstrated that rapamycin has a diametrically opposite effect to that of calcineurin inhibitors on solid tumor progression and suggest a rational for the use of rapamycin in combination with calcineurin inhibitors to curtail increased malignancy incidence observed in transplant population.

KEY WORDS: post-transplant malignancy, rapamycin, cyclosporin A, tacrolimus.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.