PURPOSE: To develop novel orthotopic xenograft models of medulloblastoma in severe combined immunodeficient mice and to evaluate the in vivo antitumor efficacy of valproic acid. EXPERIMENTAL DESIGN: Orthotopic xenografts were developed by injecting 10(3) to 10(5) tumor cells from four medulloblastoma cell lines (D283-MED, DAOY, MHH-MED-1, and MEB-MED-8A) into the right cerebellum of severe combined immunodeficient mice. Animals were then examined for reproducibility of tumorigenicity, cell number-survival time relationship, and histopathologic features. Tumor growth was monitored in vivo by serially sectioning the xenograft brains at 2, 4, 6, and 8 weeks postinjection. Valproic acid treatment, administered at 600 microg/h for 2 weeks via s.c. osmotic minipumps, was initiated 2 weeks after injection of 10(5) medulloblastoma cells, and treated and untreated animals were monitored for differences in survival. Changes in histone acetylation, proliferation, apoptosis, differentiation, and angiogenesis in xenografts were also evaluated. RESULTS: Tumorigenicity was maintained at 100% in D283-MED, DAOY, and MHH-MED-1 cell lines. These cerebellar xenografts displayed histologic features and immunohistochemical profiles (microtubule-associated protein 2, glial fibrillary acidic protein, and vimentin) similar to human medulloblastomas. Animal survival time was inversely correlated with injected tumor cell number. Treatment with valproic acid prolonged survival time in two (D283-MED and MHH-MED-1) of the three models and was associated with induction of histone hyperacetylation, inhibition of proliferation and angiogenesis, and enhancement of apoptosis and differentiation. CONCLUSION: We have developed intracerebellar orthotopic models that closely recapitulated the biological features of human medulloblastomas and characterized their in vivo growth characteristics. Valproic acid treatment of these xenografts showed potent in vivo anti-medulloblastoma activity. These xenograft models should facilitate the understanding of medulloblastoma pathogenesis and future preclinical evaluation of new therapies against medulloblastoma.
PURPOSE: To develop novel orthotopic xenograft models of medulloblastoma in severe combined immunodeficientmice and to evaluate the in vivo antitumor efficacy of valproic acid. EXPERIMENTAL DESIGN: Orthotopic xenografts were developed by injecting 10(3) to 10(5) tumor cells from four medulloblastoma cell lines (D283-MED, DAOY, MHH-MED-1, and MEB-MED-8A) into the right cerebellum of severe combined immunodeficientmice. Animals were then examined for reproducibility of tumorigenicity, cell number-survival time relationship, and histopathologic features. Tumor growth was monitored in vivo by serially sectioning the xenograft brains at 2, 4, 6, and 8 weeks postinjection. Valproic acid treatment, administered at 600 microg/h for 2 weeks via s.c. osmotic minipumps, was initiated 2 weeks after injection of 10(5) medulloblastoma cells, and treated and untreated animals were monitored for differences in survival. Changes in histone acetylation, proliferation, apoptosis, differentiation, and angiogenesis in xenografts were also evaluated. RESULTS: Tumorigenicity was maintained at 100% in D283-MED, DAOY, and MHH-MED-1 cell lines. These cerebellar xenografts displayed histologic features and immunohistochemical profiles (microtubule-associated protein 2, glial fibrillary acidic protein, and vimentin) similar to humanmedulloblastomas. Animal survival time was inversely correlated with injected tumor cell number. Treatment with valproic acid prolonged survival time in two (D283-MED and MHH-MED-1) of the three models and was associated with induction of histone hyperacetylation, inhibition of proliferation and angiogenesis, and enhancement of apoptosis and differentiation. CONCLUSION: We have developed intracerebellar orthotopic models that closely recapitulated the biological features of humanmedulloblastomas and characterized their in vivo growth characteristics. Valproic acid treatment of these xenografts showed potent in vivo anti-medulloblastoma activity. These xenograft models should facilitate the understanding of medulloblastoma pathogenesis and future preclinical evaluation of new therapies against medulloblastoma.
Authors: Mari Kogiso; Lin Qi; Frank K Braun; Sarah G Injac; Linna Zhang; Yuchen Du; Huiyuan Zhang; Frank Y Lin; Sibo Zhao; Holly Lindsay; Jack M Su; Patricia A Baxter; Adekunle M Adesina; Debra Liao; Mark G Qian; Stacey Berg; Jodi A Muscal; Xiao-Nan Li Journal: Clin Cancer Res Date: 2018-02-20 Impact factor: 12.531
Authors: Jack M Su; Xiao-Nan Li; Patrick Thompson; Ching-Nan Ou; Ashish M Ingle; Heidi Russell; Ching C Lau; Peter C Adamson; Susan M Blaney Journal: Clin Cancer Res Date: 2010-11-29 Impact factor: 12.531
Authors: Don W Coulter; Christine Walko; Jai Patel; Billie M Moats-Staats; Andrew McFadden; Scott V Smith; Wasiuddin A Khan; Arlene S Bridges; Allison M Deal; Javier Oesterheld; Ian J Davis; Julie Blatt Journal: Anticancer Drugs Date: 2013-04 Impact factor: 2.248
Authors: Dolly G Aguilera; Chandra M Das; Neeta D Sinnappah-Kang; Celine Joyce; Pete H Taylor; Sijin Wen; Martin Hasselblatt; Werner Paulus; Greg Fuller; Johannes E Wolff; Vidya Gopalakrishnan Journal: J Neurooncol Date: 2009-01-16 Impact factor: 4.130
Authors: Yanxin Pei; Kun-Wei Liu; Jun Wang; Alexandra Garancher; Ran Tao; Lourdes A Esparza; Donna L Maier; Yoko T Udaka; Najiba Murad; Sorana Morrissy; Huriye Seker-Cin; Sebastian Brabetz; Lin Qi; Mari Kogiso; Simone Schubert; James M Olson; Yoon-Jae Cho; Xiao-Nan Li; John R Crawford; Michael L Levy; Marcel Kool; Stefan M Pfister; Michael D Taylor; Robert J Wechsler-Reya Journal: Cancer Cell Date: 2016-03-14 Impact factor: 31.743