Effects of Immunosuppressive Therapy on the Induction of Skin Tumors by Ultraviolet Irradiation in Hairless Mice

Kelly, Graham; Meikle, W.; Sheil, A. G. R.

doi:10.1097/00007890-198709000-00021

Cited by 94 publications

(36 citation statements)

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“…It has been suggested that certain immunosuppressive medications, including cyclosporine and azathioprine, may have both mutagenic and immunosuppressive effects. Cyclosporine, through induction of transforming growth factor β, has been shown to induce the progression of murine skin cancers, and azathioprine may function as both a photosensitizer and a mutagen [16][17][18] . In our study cyclosporine and azathioprine were the most common immunosuppressants given to patients who developed skin cancers.…”

Section: Discussionmentioning

confidence: 99%

Skin Cancer Incidence in Renal Transplant Recipients - A Single Center Study

Kalinová¹,

Májek²,

Stehlík³

et al. 2010

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims.To provide the first single-center study of a Czech renal transplant program that compares skin cancer risk estimates to the general population.Methods. We studied a total of 603 patients undergoing renal transplantation at the University Hospital Olomouc Transplant Center between January 1984 and December 2009. The mean time of follow-up was 5.5 years. Three patients were excluded for skin cancer diagnosis before transplant. The cohort was linked with the National Cancer Registry of the Czech Republic. For non-melanoma skin cancer (NMSC), the observed number of cancers were compared to the expected numbers of NMSC based on national cancer incidence rates stratified by age. The standartized incidence ratio (SIR) was calculated as observed-to-expected ratios.Results. We found a total of 127 cases of skin cancers in 55 patients. 52/55 (94.5%) were patients with non-melanoma skin cancers, 2/55 (3.6%) patients had malignant melanoma, and we uncovered one case of merkel cell carcinoma of the skin (1.8%). There were no cases of Kaposi's sarcoma, cutaneous lymphoma or malignant fibrous histiocytoma. For NMSC, the overall SIR was 7.39 (95% confidence interval 5.52-9.70). Thus, skin cancer was the most common malignant condition, representing 64.1% of all malignant tumours detected in study population.Conclusion. We confirmed that skin cancer is a major complication in renal transplant recipients. Therefore it is important to increase the intensity of surveillence for these lesions in transplant patients.

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Section: Discussionmentioning

confidence: 99%

Skin Cancer Incidence in Renal Transplant Recipients - A Single Center Study

Kalinová¹,

Májek²,

Stehlík³

et al. 2010

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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“…Indeed, some commonly used immunosuppressants directly promote cancer growth or affect antitumorigenic responses, such as apoptosis (6)(7)(8). The actions of immunosuppressive drugs used in transplantation practice differ substantially.…”

Section: Introductionmentioning

confidence: 99%

“…Important for the present discussion is that some of these immunosuppressants also affect skin cells, contributing to carcinoma risk. For instance, azathioprine and cyclosporine adversely affect DNA repair and cyclosporine also impairs apoptosis (6,7,13), which are important mechanisms that help protect against UV skin carcinogenesis; azathioprine further enhances DNA damage by photosensitization (8). Indeed, azathioprine and cyclosporine speed up UV carcinogenesis in hairless mice (7,14).…”

Section: Introductionmentioning

confidence: 99%

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

Voskamp

Bodmann

Koehl

et al. 2013

Cancer Prevention Research

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Immunosuppressive drugs are thought to cause the dramatically increased risk of carcinomas in sunexposed skin of organ transplant recipients. These drugs differ in local effects on skin. We investigated whether this local impact is predictive of skin cancer risk and may thus provide guidance on minimizing the risk. Immunosuppressants (azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, and rapamycin) were assessed on altering the UV induction of apoptosis in human skin models and of p53 mutant cell clones (putative tumor precursors) and ensuing skin carcinomas (with mutant p53) in the skin of hairless mice. Rapamycin was found to increase apoptosis (three-fold), whereas cyclosporine decreased apoptosis (three-fold). Correspondingly, a 1.5-to five-fold reduction (P ¼ 0.07) or a two-to three-fold increase (P < 0.001) was found in cell clusters overexpressing mutant p53 in chronically UV-exposed skin of mice that had been fed rapamycin or cyclosporine, respectively. Deep sequencing showed, however, that the allelic frequency ($5%) of the hotspot mutations in p53 (codons 270 and 275) remained unaffected. The majority of cells with mutated p53 seemed not to overexpress the mutated protein. Unexpectedly, none of the immunosuppressants admixed in high dosages to the diet accelerated tumor development, and cyclosporine even delayed tumor onset by approximately 15% (P < 0.01). Thus, in contrast to earlier findings, the frequency of p53-mutant cells was not predictive of the incidence of skin carcinoma. Moreover, the lack of any accelerative effect on tumor development suggests that immunosuppressive medication is not the sole cause of the dramatic increase in skin cancer risk in organ transplant recipients. Cancer Prev Res; 6(2);

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“…Combined effects of UV exposure and immunosuppressive drugs cannot be excluded. Kelly et al 10 have documented the tumor-promoting effect of chemical immunosuppressants on UV light induced skin carcinogenesis in hairless albino mice. Therefore, it seems likely that TBI (3 Gy), Cy (200 mg/kg body weight), chronic scleroderma-like GVHD and our patient's history of extensive UV exposure pre and post transplant due to his outdoor activities have caused the cutaneous SCC.…”

Section: Discussionmentioning

confidence: 99%

Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD)

Gmeinhart

Hinterberger

Greinix

et al. 1999

Bone Marrow Transplant

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Summary:We describe an allogeneic bone marrow (BM) recipient who developed aggressive, metastasizing squamous cell cancer (SCC) of the skin, and discuss possible risk factors in the development of this secondary solid tumor. The patient had been treated with cyclosporine (CsA), methyl-prednisolone and thalidomide for 3 years because of extensive de novo chronic cutaneous GVHD occurring 1 year after BMT. Ten years after BMT a locally invasive and metastasizing SCC occurred on the patient's neck, and diagnosis was confirmed by H&E histopathology and cytokeratin-immunohistochemistry. Analysis of genomic DNA did not reveal p53 mutations nor were HPV sequences detectable. Risk factors included conditioning for BMT with total body irradiation (TBI) and cyclophosphamide (Cy), immunosuppressive treatment for GVHD, and extensive exposure to UV radiation before and after BMT. Despite surgery and adjuvant chemotherapy with 5-fluorouracil (5-FU) the patient died 1 year after the diagnosis of SCC. Keywords: secondary malignancy; squamous cell carcinoma; GVHD; immunosuppression With numbers of BM transplants from related and unrelated donors increasing recently the frequency of secondary neoplasms which impair long-term outcome and survival of the BM recipients has also been increasing. The risk of developing secondary cancer after allogeneic BMT has been reported to be increased 6.69-to 11-fold over that of an age-matched population. 1,2 Whereas lymphoproliferative cancers, myelodysplastic syndrome, acute leukemia and non-Hodgkin's lymphoma predominate in the first years after BMT, solid cancers including neoplasms of the central nervous system, bone, inner organs, skin and mucosal sur- faces occur progressively 10-15 years thereafter. 1-3 The largest cohort study on nearly 20 000 allogeneic BM recipients showed the cumulative incidence for secondary solid tumors to be 6.7%. Case reportSCC was diagnosed in a previously healthy 26-year-old Caucasian male patient in January 1985 who subsequently received 8 units of packed red blood cells and 4 units of platelets. Five months later, after conditioning with 200 mg Cy/kg body weight (b.w.) over 4 days and TBI of 3 Gy, he received 2.7 ϫ 10 8 nucleated cells (NC)/kg b.w. from his HLA class I and II identical brother. Methotrexate (MTX) according to the Seattle protocol was used as GVHD prophylaxis. Neutrophil counts of more than 0.5 ϫ 10 9 /l and 1 ϫ 10 9 /l were reached on days ϩ35 and ϩ53, respectively, after BMT. Unsupported platelets Ͼ20 ϫ 10 9 /l, hematocrit Ͼ30% and reticulocytes Ͼ20 000/ml without the need for further transfusion were reached on days ϩ24 and ϩ12, respectively. Donor cell engraftment was documented by the presence of donor ABO blood group. Because of poor marrow function MTX was stopped on day ϩ39. The patient showed no signs of acute GVHD and was discharged on day ϩ49 post BMT.One year after BMT, he developed de novo onset chronic cutaneous GVHD with lichenoid lesions on the lips and oral mucosa. We initiated systemic immunosuppression with 1.5 mg prednisolo...

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Effects of Immunosuppressive Therapy on the Induction of Skin Tumors by Ultraviolet Irradiation in Hairless Mice

Cited by 94 publications

References 0 publications

Skin Cancer Incidence in Renal Transplant Recipients - A Single Center Study

Skin Cancer Incidence in Renal Transplant Recipients - A Single Center Study

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

Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD)

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