Valproic Acid Prolongs SurvivalTime of Severe Combined Immunodeficient Mice Bearing Intracerebellar Orthotopic Medulloblastoma Xenografts QinShu, 1 BarbaraAntalffy, 2 JackMengFengSu, 3 AdekunleAdesina, 2 Ching-NanOu, 2 TorstenPietsch, 4 SusanM.Blaney, 3 ChingC.Lau, 3 andXiao-NanLi 1 Abstract Purpose: Todevelopnovelorthotopicxenograftmodelsofmedulloblastomainseverecombined immunodeficientmiceandtoevaluatethe in vivo antitumorefficacyofvalproicacid. Experimental Design: Orthotopicxenograftsweredevelopedbyinjecting10 3 to10 5 tumor cells from four medulloblastoma celllines (D283-MED, DAOY, MHH-MED-1, and MEB- MED-8A)intotherightcerebellumofseverecombinedimmunodeficientmice.Animalswerethen examined for reproducibility of tumorigenicity, cell number-survival time relationship, and histopathologicfeatures.Tumorgrowthwasmonitored invivo byseriallysectioningthexenograft brainsat2,4,6,and8weekspostinjection.Valproicacidtreatment,administeredat600 Ag/hfor 2weeksvias.c.osmoticminipumps,wasinitiated2weeksafterinjectionof10 5 medulloblastoma cells,andtreatedanduntreatedanimalsweremonitoredfordifferencesinsurvival.Changesin histoneacetylation,proliferation,apoptosis,differentiation,andangiogenesisinxenograftswere alsoevaluated. Results: Tumorigenicity was maintained at100% in D283-MED, DAOY, and MHH-MED-1cell lines.Thesecerebellarxenograftsdisplayedhistologicfeaturesandimmunohistochemicalprofiles (microtubule-associated protein 2, glial fibrillary acidic protein, and vimentin) similar to human medulloblastomas.Animalsurvivaltimewasinverselycorrelatedwithinjectedtumorcellnumber. Treatmentwithvalproicacidprolongedsurvivaltimeintwo(D283-MEDandMHH-MED-1)ofthe three models and was associated with induction of histone hyperacetylation, inhibition of proliferationandangiogenesis,andenhancementofapoptosisanddifferentiation. Conclusion: Wehavedevelopedintracerebellarorthotopicmodelsthatcloselyrecapitulatedthe biologicalfeaturesofhumanmedulloblastomasandcharacterizedtheir in vivo growthcharacter- istics.Valproic acid treatment of these xenografts showed potent in vivo anti-medulloblastoma activity.These xenograft models should facilitate the understanding of medulloblastoma pathogenesisandfuturepreclinicalevaluationofnewtherapiesagainstmedulloblastoma. Medulloblastoma, the most common malignant brain tumor of childhood, is still associated with significant morbidity and mortality, particularly in infants and young children (1, 2). The development of clinically relevant preclinical models of medulloblastoma is essential not only for enhancing our understanding of their biology but also for evaluating the therapeutic potential of novel treatment approaches. Standard models for assessing efficacy of anticancer drugs, such as in vitro human cancer cell lines and s.c. xenograft tumor models (3, 4), do not accurately replicate the cellular complexity, microenvironment, and extracellular compart- ment of the corresponding tumors, particularly tumors of the central nervous system. Moreover, preclinical results obtained from such s.c xenograft models may overpredict the efficacy of candidate drugs for tumors of the central nervous system because intratumoral drug exposure in patients may be much lower as a result of restricted drug delivery by the blood-brain barrier. Thus, there is growing skepticism about the value of traditional preclinical models for in vivo preclinical drug testing (5) and increasing efforts are devoted to developing animal models that will faithfully simulate the biology and genetic alterations in human cancers. In addition to genetically engineered animal models that hold the promise of recapitulating important features of human oncogenesis (3, 6–14), substantial progress has been achieved in establishing orthotopic xenografts of multiple Cancer Therapy: Preclinical Authors’Affiliations: 1 LaboratoryofMolecularNeuro-Oncology, 2 Departmentof Pathology,and 3 TexasChildren’sCancerCenter,TexasChildren’sHospital,Baylor College of Medicine, Houston,Texas and 4 Departmentof Neuropathology, UniversityofBonnMedicalCenter,Bonn,Germany Received12/30/05;revised5/3/06;accepted5/11/06. Grant support: Childhood BrainTumor Foundationand National BrainTumor Foundation (X.N. Li), John S. Dunn Research Foundation, RobertJ. Kleberg, Jr., and Helen C. Kleberg Foundation, Gillson Longenbaugh Foundation and Cancer FightersofHouston,Inc.(C.C.Lau). Thecostsofpublicationofthisarticleweredefrayedinpartbythepaymentofpage charges.Thisarticlemustthereforebeherebymarked advertisement inaccordance with18U.S.C.Section1734solelytoindicatethisfact. Requests for reprints: Xiao-NanLi,LaboratoryofMolecularNeuro-Oncology, TexasChildren’sCancerCenter,TexasChildren’sHospital,6621FanninStreet,MC 3-3320,Houston,TX77030.Phone: 832-824-4580;Fax: 832-825-4038; E-mail:Xiaonan@bcm.tmc.edu. F 2006AmericanAssociationforCancerResearch. doi:10.1158/1078-0432.CCR-05-2849 www.aacrjournals.org ClinCancerRes2006;12(15)August1,2006 4687 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/12/15/4687/1922081/4687.pdf by guest on 21 June 2022