Early and late effects of the immunosuppressants rapamycin and mycophenolate mofetil on UV carcinogenesis

Abstract

Increased skin cancer risk in organ transplant recipients has been experimentally emulated with enhanced UV carcinogenesis from administering conventional immunosuppressants. However, newer generation immunosuppressive drugs, rapamycin (Rapa) and mycophenolate mofetil (MMF), have been shown to impair angiogenesis and outgrowth of tumor implants. To ascertain the overall effect on UV carcinogenesis, Rapa and MMF were admixed into the food pellets of hairless SKH1 mice receiving daily sub-sunburn UV dosages. With immunosuppressive blood levels neither of the drugs affected onset of tumors (<2 mm), but in contrast to MMF, Rapa significantly increased latency of large tumors (!4 mm, medians of 190 vs 125 days) and reduced their multiplicity (1.6 vs 4.5 tumors per mouse at 200 days). Interestingly, tumors (>2 mm) from the Rapa-fed group showed a reduction in UV-signature p53 mutations (39% vs 90%) in favor of mutations from putative base oxidation. This shift in mutation spectrum was not essentially linked to the reduction in large tumors because it was absent in large tumors similarly reduced in number when feeding Rapa in combination with MMF, possibly owing to an antioxidant effect of MMF. Significantly fewer tumor cells were Vegf-positive in the Rapa-fed groups, but a correspondingly reduced expression of Hif1a target genes (Vegf, Ldha, Glut1, Pdk1) that would indicate altered glucose metabolism with increased oxidative stress was not found. Remarkably, we observed no effect of the immunosuppressants on UV-induced tumor onset, and with impaired tumor outgrowth Rapa could therefore strongly reduce skin carcinoma morbidity and mortality rates in organ transplant recipients.One of the most remarkable feats of modern Western medicine in the last century has undoubtedly been organ transplantation. However, as the initially leading mortality from immunologic and nonimmunologic graft failure diminished and life expectancy of organ transplant recipients increased, other complications have arisen. A major complication, which worsens as the graft survival is extended, is posttransplantation malignancy, among which skin carcinomas are most prominent. 1,2 The carcinomas tend to be more aggressive in organ transplant recipients, causing substantial mortality, 3 and the abundance of precursor lesions (actinic keratoses) can have serious blemishing effects.Skin carcinomas among Caucasians are clearly related to solar UV exposure, 4 and so are the skin carcinomas in organ transplant recipients, 2,5 as reflected by predominant occurrence in sun-exposed skin. A striking observation is that the ratio of squamous cell carcinoma (SCC) over basal cell carcinoma (BCC) in the general population ranges around 1:3, whereas the ratio is reversed in organ transplant recipients. In the Netherlands it was estimated that about 40% of the kidney transplant recipients will have contracted at least 1 skin carcinoma by 20 years after transplantation 6 ; in Australia this percentage is already exceeded after 9 years. 7 From classic animal experimen...

Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas

“…Rapamycin had no effect on the development of small tumors, but decreased the outgrowth of tumors. Growth inhibition was reported earlier by our group (28), and the growth inhibition by rapamycin was more prominent in that experiment. Other UV carcinogenesis studies with different treatment schemes have shown either lower tumor yields (38) or higher tumor yields (39) in rapamycin-treated mice, indicating that the precise treatment regimen may be decisive for the outcome of the tumorigenesis experiment.…”

“…28). For cyclosporine, mycophenolate mofetil and rapamycin dosages in the food were used that resulted in long-term average blood levels in the mice that were similar to the high-end average blood levels in renal transplant patients (cyclosporine at 150 mg/kg in food: 800 ng/ mL in blood, mycophenolate mofetil at 660 mg/kg: 2.9 mg/ mL mycophenolic acid, rapamycin at 20 mg/kg: 50 ng/mL; mice of 25-35 g body weight ate 5-7 g per day).…”

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

“…Bioavailability of rapamycin also depends on the administration protocol, such as intraperitoneal injection, gavage, or food. 36 Because our experiments indicate that the sirolimus dose is critical to achieve an optimal effect on PKD in mice, it is difficult to compare our data with a previously published study on the Pkd1-deletion model, for which the blood levels have not been reported and intraperitoneal injection was used. 30 Our results indicate that low-dose sirolimus does not significantly reduce mTOR activity in renal epithelia over time and that levels of the p-S6Rp…”

Sirolimus and Non-melanoma Skin Cancer Prevention after Kidney Transplantation: A Meta-analysis

“…In addition, mTOR inhibitors also inhibit the growth of endothelial cells and the progression of tumor neovascularization at serum concentrations that correspond to the target levels for transplant recipients, both through a decrease of synthesis and a signaling inhibition of vascular endothelial growth factor (Guba et al, 2004). Furthermore, Sirolimus had a better effect on the progression of ultraviolet radiation (UV)-induced tumors than on the initiation of such tumors (de Gruijl et al, 2010). Thus, there are obvious evidences for the specific antineoplastic activity of Sirolimus in the prevention of skin cancer.…”