Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model.
The chemotherapeutic agent temozolomide (TMZ) and the anti-angiogenic agent thalidomide (THD) have both demonstrated anti-tumor activity in patients with recurrent malignant glioma. Combination treatment with TMZ and THD in patients with glioblastoma multiforme (GBM) appears to be more effective than treatment with either drug alone. To investigate the mechanism of this anti-tumor effect, we examined the combined effects of TMZ and THD in a rat glioma xenograft model. We found that combination treatment markedly inhibited the growth of tumors that were orthotopically implanted into rat brains. Using proliferating cell nuclear antigen (PCNA) staining, we observed a significant decrease in cell proliferation in these tumors. CD31 staining of the microvasculature revealed a significant decrease in angiogenesis. We also found increased apoptosis in treated tumors by terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. We further demonstrated that the expression of angiogenic factors, such as vascular endothelial cell growth factor (VEGF) and basic fibroblastic growth factor (bFGF), were inhibited by THD. THD also decreased the number of ED1-positive, activated macrophages or microglial cells, which produce pro-angiogenic molecules around the glioma. Taken together, these results suggest that combination treatment with TMZ and THD inhibits tumor growth via the induction of apoptosis and the inhibition of angiogenesis in a rat model and may be a promising therapy for malignant gliomas.
Son
Myung Jin
MJ
Department of Neurosurgery, Samsung Medical Center and Samsung Biomedical Research Institute, SungKyunKwan University School of Medicine, Seoul, Korea.
Kim
Jong-Soo
JS
Kim
Mi Hyun
MH
Song
Hyun Seok
HS
Kim
Ji Tae
JT
Kim
Heechul
H
Shin
Taekyun
T
Jeon
Hyun Jung
HJ
Lee
Dong-Sup
DS
Park
Shi-Young
SY
Kim
Yung-Jin
YJ
Kim
Jong-Hyun
JH
Nam
Do-Hyun
DH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D020869:Gene Expression Profiling; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D009389:Neovascularization, Pathologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077204:Temozolomide; D013792:Thalidomide / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D013792:Thalidomide; D003606:Dacarbazine; D000077204:Temozolomide