Development of de novo cancer in p53 knock-out mice is dependent on the type of long-term immunosuppression used

Background. Development of cancer in transplant recipients may be influenced by different immunosuppressive agents. Recent publications suggest that rapamycin (RAPA), or possibly mycophenolate mofetil (MMF), may reduce established tumor growth; however, experimental data is lacking for de novo cancer prevention. Methods. We tested the effects of long-term immunosuppression on spontaneous tumor formation in p53 knock-out mice. Mice received no treatment, or were given RAPA, MMF, or cyclosporine (CsA) starting on week nine after birth, with the experimental endpoint being week 29. Results. All (9/9) untreated mice developed clinically evident tumors before week 26, as confirmed by histology (6 lymphomas, 2 sarcomas, I lymphoma + sarcoma). All CsA-treated mice (9/9) also developed clinical tumors before the endpoint (7 lymphomas, I sarcoma, I lymphoma + sarcoma). With MMF, 7/10 mice showed clinical evidence of tumor before the experimental endpoint (4 lymphomas, 2 sarcomas, I lymphoma + sarcoma), however, histologic tissue analysis revealed that the remaining three mice had subclinical cancer (3 lymphomas). In contrast, RAPA treatment resulted in only three mice with clinical tumors (all lymphomas), with histology revealing subclinical lymphomas in three additional mice, but no evidence of cancer in four animals. Statistically, cancer development was decreased with RAPA treatment (P = 0.002), but was not affected with either MMF or CsA (P > 0.10). Conclusion. These experiments are the first to show immunosuppression under RAPA can reduce spontaneous de novo cancer associated with p53 mutations. Although neither CsA nor MMF treatment affects p53-associated tumor incidence, MMF may have some tendency to reduce clinical tumor appearance.