Glioma-associated endothelial cells are chemoresistant to temozolomide.
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.
Virrey
Jenilyn J
JJ
Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
Golden
Encouse B
EB
Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
Sivakumar
Walavan
W
Departments of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
Wang
Weijun
W
Departments of Neurosurgery, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
Pen
Ligaya
L
Departments of Pathology, Keck School of Medicine, University of Southern California, 2011 Zonal Avenue, Hoffman Medical Research Building 315, Los Angeles, CA, 90033, USA.
Schönthal
Axel H
AH
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.
Hofman
Florence M
FM
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.
Chen
Thomas C
TC
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.
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
D018906:Antineoplastic Agents, Alkylating; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D013778:Tetrazolium Salts; D013844:Thiazoles; D003606:Dacarbazine; C022616:thiazolyl blue; D000077204:Temozolomide