Early and late effects of the immunosuppressants rapamycin and mycophenolate mofetil on UV carcinogenesis.
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 (>or=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 Hif1alpha 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.
de Gruijl
F R
FR
Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
Koehl
G E
GE
Voskamp
P
P
Strik
A
A
Rebel
H G
HG
Gaumann
A
A
de Fijter
J W
JW
Tensen
C P
CP
Bavinck
J N Bouwes
JN
Geissler
E K
EK
D042501:Angiogenic Proteins / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D004032:Diet; D005260:Female; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D009154:Mutation / Q000235:genetics; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009381:Neoplasms, Radiation-Induced / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000008:administration & dosage*; D012867:Skin / Q000528:radiation effects*; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014916:Whole-Body Irradiation
D042501:Angiogenic Proteins; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D009173:Mycophenolic Acid; D020123:Sirolimus