Effects of radiotherapy and estramustine on the microvasculature in malignant glioma

Tumour angiogenesis is essential for progression of solid tumours and const itutes an interesting target for therapy. However, impaired tumour blood su pply may also be an important obstacle for treatment by radiotherapy and ch emotherapy. Estramustine has been shown to increase tumour blood flow and p otentiate the effect of radiotherapy in experimental glioma. This study inv estigated the effects of fractionated radiotherapy and estramustine on angi ogenesis in malignant glioma. The intracerebral BT4C rat glioma model was u sed and the animals were given whole brain radiotherapy 4 Gy x 5 days alone or in combination with estramustine 20 mg kg(-1) i.p. daily. Tumour microv ascular density (MVD) was assessed by manual and computerized morphometrica l analysis. Expression of vascular endothelial growth factor (VEGF) was stu died by in situ hybridization. Radiotherapy decreased MVD to 157 vessels pe r mm(2) compared to 217 vessels per mm(2) in controls, Estramustine counter acted this anti-angiogenic effect and potentiated the anti-tumoural effect of radiotherapy, In addition, vessel size increased after estramustine trea tment. Five days after completion of radiotherapy the expression of VEGF wa s increased in the centre of the tumours. In conclusion, fractionated radio therapy decreases microvascular density in experimental malignant glioma. T his effect was abolished by estramustine. The anti-vascular effect of irrad iation is important to recognize when combining radiotherapy with cytotoxic drugs.