title: Glioma-associated endothelial cells are chemoresistant to temozolomide.
abstract: Temozolomide is considered the standard of care and drug of choice for the treatment of initially diagnosed malignant gliomas. Although well tolerated, temozolomide still has limited clinical efficacy. Following drug treatment, patient prognosis still remains poor; tumor recurrence is almost universal. We hypothesized that this lack of effectiveness with temozolomide is because this drug does not target the glioma microenvironment, which is highly vascular in malignant gliomas. To test this hypothesis we analyzed the effects of temozolomide on the tumor vasculature in vitro and in vivo. We found that this drug did not affect the viability or proliferation rate of endothelial cells isolated from human glioma specimens, although temozolomide was highly cytotoxic to the glioma cell lines U87MG and U251. Furthermore, temozolomide did not inhibit the migration of these glioma-associated endothelial cells, a key mechanism responsible for tumor angiogenesis. In in vivo studies, using the intracranial glioma mouse model, temozolomide did not cause a pronounced effect on microvessel density. Our findings show that temozolomide has no apparent effect on the glioma vascular microenvironment. Thus combination therapy with anti-vascular agents may enhance temozolomide effectiveness as glioma therapeutic protocol.
authors.affiliation: Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
authors.forename: Jenilyn J
authors.initials: JJ
authors.lastname: Virrey
authors.affiliation: Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
authors.forename: Encouse B
authors.initials: EB
authors.lastname: Golden
authors.affiliation: Departments of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
authors.forename: Walavan
authors.initials: W
authors.lastname: Sivakumar
authors.affiliation: Departments of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
authors.forename: Weijun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
authors.forename: Ligaya
authors.initials: L
authors.lastname: Pen
authors.affiliation: Departments of Microbiology and Immunology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 405, Los Angeles, CA, 90033, USA.
authors.forename: Axel H
authors.initials: AH
authors.lastname: Schönthal
authors.affiliation: Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA. hofman@usc.edu.
authors.forename: Florence M
authors.initials: FM
authors.lastname: Hofman
authors.affiliation: Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA. tcchen@usc.edu.|, 1200 N. State Street, Suite #5046, Los Angeles, CA, 90033, USA. tcchen@usc.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation / Q000379:methods; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D000077204:Temozolomide; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013778:Tetrazolium Salts; D013844:Thiazoles; D003606:Dacarbazine; C022616:thiazolyl blue; D000077204:Temozolomide