Antiproliferative effect of thalidomide alone and combined with carmustine against C6 rat glioma

Abstract

Thalidomide could have therapeutic applications in neoplasms and in other diseases, particularly those of autoimmune origin. The objective of this study was to investigate the effect of various doses of thalidomide on the growth of C6 glioma in rats, and to determine its effects on parameters of cell proliferation and angiogenesis. Additionally, we investigated a potential enhancement of the antitumoral action of thalidomide when combined with a low dose of the antineoplastic carmustine. C6 glioma cells were implanted subcutaneously in Wistar rats. A highly malignant glioma developed in 80% of animals. When the tumour reached 2.0 cm diameter thalidomide was administered at doses of 100, 200 or 400 mg/kg/day. When given at a dose of 400 mg/kg/day thalidomide significantly reduced the tumour volume, the mitotic index and cell proliferation but not the vascular density. The combination of thalidomide plus carmustine increased the inhibitory effect on tumoral growth. Our results indicate that thalidomide is effective against malignant glioma; apparently by an antiproliferative effect, rather than by inhibition of angiogenesis; when combined with carmustine it could increase the response of glioma to antineoplastic treatment.

Figure 1

Formalin-fixed paraffin sections of rat C6 glioma, immunostained for PCNA and Von Willebrand factor VIII by the peroxidase antiperoxidase method (positive cells are stained brown, see arrows). (a) PCNA in C6 cells from a control rat (40×) (b) PCNA in C6 cells from a rat treated with thalidomide: a marked decrease in PCNA is observed (40×). (c) Factor VIII in C6 cells from a control rat (20×) (d) Factor VIII in C6 cells from a rat treated with thalidomide. No significant differences on the number of blood vessels are seen (20×).

Figure 2

Percent of variability on vascular density (VD), mitotic index (MI) and proliferation cellular index (PCI) ±ΣE, in animals with C6 glioma treated with thalidomide as compared with values obtained in controls (100%).

Figure 3

Mean tumour size of C6 glioma in rats treated either with thalidomide or with carmustine or with thalidomide/carmustine.