{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:56:13Z","timestamp":1790258173787,"version":"4.1.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2006,1,11]],"date-time":"2006-01-11T00:00:00Z","timestamp":1136937600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Cancer"],"published-print":{"date-parts":[[2006,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Case presentation<\/jats:title>\n            <jats:p>Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2407-6-7","type":"journal-article","created":{"date-parts":[[2006,1,23]],"date-time":"2006-01-23T12:36:56Z","timestamp":1138019816000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":112,"title":["The carcinogenic potential of tacrolimus ointment beyond immune suppression: a hypothesis creating case report"],"prefix":"10.1186","volume":"6","author":[{"given":"J\u00fcrgen C","family":"Becker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland","family":"Houben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia S","family":"Vetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva B","family":"Br\u00f6cker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2006,1,11]]},"reference":[{"key":"359_CR1","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1067\/mjd.2002.120942","volume":"46","author":"P Nghiem","year":"2002","unstructured":"Nghiem P, Pearson G, Langley RG: Tacrolimus and pimecrolimus: from clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis. J Am Acad Dermatol. 2002, 46: 228-241. 10.1067\/mjd.2002.120942.","journal-title":"J Am Acad Dermatol"},{"key":"359_CR2","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/S0140-6736(94)92855-X","volume":"344","author":"H Nakagawa","year":"1994","unstructured":"Nakagawa H, Etoh T, Ishibashi Y, Higaki Y, Kawashima M, Torii H, Harada S: Tacrolimus ointment for atopic dermatitis. Lancet. 1994, 344: 883-10.1016\/S0140-6736(94)92855-X.","journal-title":"Lancet"},{"key":"359_CR3","unstructured":"US FDA advisory committee recommends approval of tacrolimus ointment. Skin Therapy Lett. 2000, 6: 5-"},{"key":"359_CR4","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S0733-8635(02)00067-0","volume":"21","author":"D Eisen","year":"2003","unstructured":"Eisen D: The clinical manifestations and treatment of oral lichen planus. Dermatol Clin. 2003, 21: 79-89.","journal-title":"Dermatol Clin"},{"key":"359_CR5","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1001\/archderm.138.10.1335","volume":"138","author":"V Olivier","year":"2002","unstructured":"Olivier V, Lacour JP, Mousnier A, Garraffo R, Monteil RA, Ortonne JP: Treatment of chronic erosive oral lichen planus with low concentrations of topical tacrolimus: an open prospective study. Arch Dermatol. 2002, 138: 1335-1338. 10.1001\/archderm.138.10.1335.","journal-title":"Arch Dermatol"},{"key":"359_CR6","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1001\/archderm.140.12.1508","volume":"140","author":"JA Byrd","year":"2004","unstructured":"Byrd JA, Davis MD, Bruce AJ, Drage LA, Rogers RS: Response of oral lichen planus to topical tacrolimus in 37 patients. Arch Dermatol. 2004, 140: 1508-1512. 10.1001\/archderm.140.12.1508.","journal-title":"Arch Dermatol"},{"key":"359_CR7","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1067\/mjd.2002.126275","volume":"47","author":"L Morrison","year":"2002","unstructured":"Morrison L, Kratochvil FJ, Gorman A: An open trial of topical tacrolimus for erosive oral lichen planus. J Am Acad Dermatol. 2002, 47: 617-620. 10.1067\/mjd.2002.126275.","journal-title":"J Am Acad Dermatol"},{"key":"359_CR8","first-page":"466","volume":"13","author":"TA Hodgson","year":"2003","unstructured":"Hodgson TA, Sahni N, Kaliakatsou F, Buchanan JA, Porter SR: Long-term efficacy and safety of topical tacrolimus in the management of ulcerative\/erosive oral lichen planus. Eur J Dermatol. 2003, 13: 466-470.","journal-title":"Eur J Dermatol"},{"key":"359_CR9","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1111\/j.0007-0963.2004.05875.x","volume":"150","author":"L Esquivel-Pedraza","year":"2004","unstructured":"Esquivel-Pedraza L, Fernandez-Cuevas L, Ortiz-Pedroza G, Reyes-Gutierrez E, Orozco-Topete R: Treatment of oral lichen planus with topical pimecrolimus 1% cream. Br J Dermatol. 2004, 150: 771-773. 10.1111\/j.0007-0963.2004.05875.x.","journal-title":"Br J Dermatol"},{"key":"359_CR10","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/S1368-8375(03)00051-4","volume":"39","author":"A Larsson","year":"2003","unstructured":"Larsson A, Warfvinge G: Malignant transformation of oral lichen planus. Oral Oncol. 2003, 39: 630-631. 10.1016\/S1368-8375(03)00051-4.","journal-title":"Oral Oncol"},{"key":"359_CR11","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1177\/154411130201300503","volume":"13","author":"U Mattsson","year":"2002","unstructured":"Mattsson U, Jontell M, Holmstrup P: Oral lichen planus and malignant transformation: is a recall of patients justified?. Crit Rev Oral Biol Med. 2002, 13: 390-396.","journal-title":"Crit Rev Oral Biol Med"},{"key":"359_CR12","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1111\/j.1524-4725.2004.30148.x","volume":"30","author":"S Euvrard","year":"2004","unstructured":"Euvrard S, Ulrich C, Lefrancois N: Immunosuppressants and skin cancer in transplant patients: focus on rapamycin. Dermatol Surg. 2004, 30: 628-633. 10.1111\/j.1524-4725.2004.30148.x.","journal-title":"Dermatol Surg"},{"key":"359_CR13","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1111\/j.1365-2133.2004.06315.x","volume":"152","author":"T Langeland","year":"2005","unstructured":"Langeland T, Engh V: Topical use of tacrolimus and squamous cell carcinoma on the penis. Br J Dermatol. 2005, 152: 183-185. 10.1111\/j.1365-2133.2004.06315.x.","journal-title":"Br J Dermatol"},{"key":"359_CR14","unstructured":"US Food and Drug Administration: FDA Public Health Advisory: Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. 3-10-2005, [http:\/\/www.fda.gov\/medwatch\/SAFETY\/2005\/safety05.htm#Elidel]"},{"key":"359_CR15","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1111\/j.1365-2133.2003.05735.x","volume":"149","author":"Y Niwa","year":"2003","unstructured":"Niwa Y, Terashima T, Sumi H: Topical application of the immunosuppressant tacrolimus accelerates carcinogenesis in mouse skin. Br J Dermatol. 2003, 149: 960-967. 10.1111\/j.1365-2133.2003.05735.x.","journal-title":"Br J Dermatol"},{"key":"359_CR16","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1111\/j.1468-3083.2004.01123.x","volume":"19","author":"Y Niwa","year":"2005","unstructured":"Niwa Y, Nasr I: Are we starting to induce skin cancer in order to avoid topical steroids?. J Eur Acad Dermatol Venereol. 2005, 19: 387-389. 10.1111\/j.1468-3083.2004.01123.x.","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"359_CR17","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/ncb894","volume":"5","author":"M Shirane","year":"2003","unstructured":"Shirane M, Nakayama KI: Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol. 2003, 5: 28-37. 10.1038\/ncb894.","journal-title":"Nat Cell Biol"},{"key":"359_CR18","doi-asserted-by":"publisher","first-page":"2427","DOI":"10.1016\/j.bcp.2004.08.028","volume":"68","author":"MJ Gomez-Lechon","year":"2004","unstructured":"Gomez-Lechon MJ, Serralta A, Donato MT, Jimenez N, O'connor E, Castell JV, Mir J: The immunosuppressant drug FK506 prevents Fas-induced apoptosis in human hepatocytes. Biochem Pharmacol. 2004, 68: 2427-2433. 10.1016\/j.bcp.2004.08.028.","journal-title":"Biochem Pharmacol"},{"key":"359_CR19","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1038\/sj.bjp.0702422","volume":"126","author":"S Hortelano","year":"1999","unstructured":"Hortelano S, Lopez-Collazo E, Bosca L: Protective effect of cyclosporin A and FK506 from nitric oxide-dependent apoptosis in activated macrophages. Br J Pharmacol. 1999, 126: 1139-1146. 10.1038\/sj.bjp.0702422.","journal-title":"Br J Pharmacol"},{"key":"359_CR20","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.nbd.2004.07.002","volume":"17","author":"S Almeida","year":"2004","unstructured":"Almeida S, Domingues A, Rodrigues L, Oliveira CR, Rego AC: FK506 prevents mitochondrial-dependent apoptotic cell death induced by 3-nitropropionic acid in rat primary cortical cultures. Neurobiol Dis. 2004, 17: 435-444. 10.1016\/j.nbd.2004.07.002.","journal-title":"Neurobiol Dis"},{"key":"359_CR21","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1159\/000076565","volume":"13","author":"BG Gold","year":"2004","unstructured":"Gold BG, Zhong YP: FK506 requires stimulation of the extracellular signal-regulated kinase 1\/2 and the steroid receptor chaperone protein p23 for neurite elongation. Neurosignals. 2004, 13: 122-129. 10.1159\/000076565.","journal-title":"Neurosignals"},{"key":"359_CR22","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/S1044-7431(03)00036-8","volume":"22","author":"M Zawadzka","year":"2003","unstructured":"Zawadzka M, Kaminska B: Immunosuppressant FK506 affects multiple signaling pathways and modulates gene expression in astrocytes. Mol Cell Neurosci. 2003, 22: 202-209. 10.1016\/S1044-7431(03)00036-8.","journal-title":"Mol Cell Neurosci"},{"key":"359_CR23","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1006\/rtph.2000.1427","volume":"32","author":"LB Silva","year":"2000","unstructured":"Silva LB, Van der Laan JW: Mechanisms of nongenotoxic carcinogenesis and assessment of the human hazard. Regul Toxicol Pharmacol. 2000, 32: 135-143. 10.1006\/rtph.2000.1427.","journal-title":"Regul Toxicol Pharmacol"},{"key":"359_CR24","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.toxlet.2004.04.004","volume":"151","author":"HM Bolt","year":"2004","unstructured":"Bolt HM, Foth H, Hengstler JG, Degen GH: Carcinogenicity categorization of chemicals-new aspects to be considered in a European perspective. Toxicol Lett. 2004, 151: 29-41. 10.1016\/j.toxlet.2004.04.004.","journal-title":"Toxicol Lett"}],"container-title":["BMC Cancer"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-6-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/1471-2407-6-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-6-7","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2407-6-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T22:33:33Z","timestamp":1630449213000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmccancer.biomedcentral.com\/articles\/10.1186\/1471-2407-6-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,1,11]]},"references-count":24,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2006,12]]}},"alternative-id":["359"],"URL":"https:\/\/doi.org\/10.1186\/1471-2407-6-7","relation":{},"ISSN":["1471-2407"],"issn-type":[{"value":"1471-2407","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,1,11]]},"assertion":[{"value":"4 August 2005","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 January 2006","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 January 2006","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"7"}}