Cyclooxygenase 2 (COX-2) inhibitors have been shown to enhance
tumor's response to radiation in several animal models. The strong association of COX-2 and angiogenesis suggests that the
tumor vasculature may be involved in this process. The current study investigated whether treatment with the
COX-2 inhibitor E-6087 could influence response to local radiation in orthotopically growing murine
gliomas and aimed to analyze the involvement of the
tumor vasculature. GL261
glioma cells were injected into the cerebrum of C57bl/6 mice. From day 7 after
tumor cell injection, mice were treated with
COX-2 inhibitor at 50 mg/kg i.p. every third day. Radiation consisted of three fractions of 2 Gy given daily from day 9 to day 11. Mice were killed at day 21. The
COX-2 inhibitor significantly enhanced the response to radiation, reducing mean volume to 32% of
tumors treated with radiation only. The combination treatment neither increased apoptosis of
tumor cells or stromal cells nor affected
tumor microvascular density. In vitro,
E-6087 and its active metabolite did not affect clonogenic survival of GL261 cells or human umbilical vein endothelial cell after radiation. In vivo, however, there was a nonsignificant increase in
Angiopoietin (Ang)-1 and Tie-2
mRNA levels and a decrease of Ang-2
mRNA levels after combination treatment. These changes coincided with a significant increase in alpha-smooth muscle actin-positive pericyte coverage of
tumor vessels. In conclusion, the antitumor effect of radiation on murine intracranial
glioma growth is augmented by combining with COX-2 inhibition. Our findings suggest an involvement of the
tumor vasculature in the observed effects.