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.