title: Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression.
abstract: BACKGROUND
  Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction.
  
  
  OBJECTIVE
  Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction.
  
  
  METHODS
  Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7).
  
  
  METHODS
  Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study.
  
  
  METHODS
  Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology.
  
  
  METHODS
  TSH and free T(4) levels, deiodinase activity, and thyroid histology were assessed.
  
  
  RESULTS
  Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T(3)/rT(3) ratio. In rats, serum T(4) and T(3) decreased, hepatic type 3 deiodinase activity increased, and thyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal.
  
  
  CONCLUSIONS
  Sunitinib induces hypothyroidism due to alterations in T(4)/T(3) metabolism as well as thyroid capillary regression.
authors.affiliation: Division of Pharmacology, Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands. m.h.w.kappers@erasmusmc.nl
authors.forename: Mariëtte H W
authors.initials: MH
authors.lastname: Kappers
authors.forename: Joep H M
authors.initials: JH
authors.lastname: van Esch
authors.forename: Frank M M
authors.initials: FM
authors.lastname: Smedts
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Karel
authors.initials: K
authors.lastname: Eechoute
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.forename: Frank
authors.initials: F
authors.lastname: Leijten
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.forename: Anton H
authors.initials: AH
authors.lastname: van den Meiracker
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000150:complications / Q000188:drug therapy; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000150:complications / Q000188:drug therapy; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced* / Q000201:enzymology; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D007453:Iodide Peroxidase / Q000096:biosynthesis*; D007680:Kidney Neoplasms / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000009:adverse effects* / Q000627:therapeutic use; D051381:Rats; D011921:Rats, Inbred WKY; D012039:Regional Blood Flow; D012044:Regression Analysis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000150:complications / Q000188:drug therapy; D000077210:Sunitinib; D013961:Thyroid Gland / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D014284:Triiodothyronine; D013972:Thyrotropin; D007453:Iodide Peroxidase; D011505:Protein-Tyrosine Kinases; D013974:Thyroxine; D000077210:Sunitinib