title: Pretherapeutic drug evaluation by tumor xenografting in anaplastic thyroid cancer.
abstract: BACKGROUND
  Despite various attempts at modifying usual treatment modalities, anaplastic thyroid cancer (ATC) is still associated with unfavorable prognosis. Results of preclinical investigations are often of limited transferability to clinical tumor biology. Individualized multimodal treatment regimens, including novel growth-inhibiting drugs, might be a future option.
  
  
  METHODS
  Tumor tissue, freshly prepared from a patient operated for ATC, was xenotransplanted to nude mice. While the patient obtained a hyperfractionated external beam radiation, mice carrying xenotransplanted tumors were randomized (n = 6) and treated by multikinase inhibitors (sorafenib [S]: vascular endothelial growth factor receptor [VEGF-R], platelet derived growth factor receptor, RET; vandetanib [V]: VEGF-R, endothelial growth factor receptor [EGF-R]; and MLN8054 [M]: Aurora kinases [AK]). Antiproliferative, antiangiogenic, and proapoptotic effects were evaluated.
  
  
  RESULTS
  Treatment of successfully xenotransplanted fresh ATC tumor tissue by multikinase inhibitors and aurora kinase inhibitor reduced the tumor volume up to 61% depending on the drug and time of application (3 wk of treatment: 46% [M], 34% [V], 30% [S]; 5 wk of treatment: 61% [S]). Tumor cell proliferation (BrdU) was reduced between 34% and 58% [S] and [V]. Reduction of tumor vascularity was between 67% [V] and 33% [S] and was accompanied by decreased EGF-R/VEGF-R2 receptor activity [V/V,S]. Tumor cell apoptosis (caspase 3 activity) increased up to 2.4-fold [S].
  
  
  CONCLUSIONS
  Successful in vivo evaluation of novel drugs in xenotransplanted fresh tumor tissue allows in-time (while patient receives standard treatment) prospective analysis for possible additional clinical application. However, technical specifications have to be taken into account to obtain stable in vivo tumor growth. Based on the individual results, a tailored clinical drug application seems possible.
authors.affiliation: Department of Surgery, Philipps-University Marburg, Marburg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Wunderlich
authors.forename: Maryna
authors.initials: M
authors.lastname: Khoruzhyk
authors.forename: Silvia
authors.initials: S
authors.lastname: Roth
authors.forename: Annette
authors.initials: A
authors.lastname: Ramaswamy
authors.forename: Brandon H
authors.initials: BH
authors.lastname: Greene
authors.forename: Dietrich
authors.initials: D
authors.lastname: Doll
authors.forename: Detlef K
authors.initials: DK
authors.lastname: Bartsch
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D011897:Random Allocation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D001552:Benzazepines; C518940:MLN8054; D010671:Phenylurea Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; C452423:vandetanib
keywords: Anaplastic thyroid cancer; Aurora kinase; Multikinase inhibitor; Patient-derived human tumor tissue xenografting; Tailored tumor therapy