COX-2 Inhibition Combined with Radiation Reduces Orthotopic Glioma Outgrowth by Targeting the Tumor Vasculature

Abstract

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.

Impaired Orthotopic Glioma Growth and Vascularization in Transgenic Mouse Models of Alzheimer's Disease

“…Tumor volumes were calculated from surface area measurements of every 10 th tissue section of the tumor following hematoxylin/eosin staining using an image analysis software (ImagePro Plus, Media Cybernetics, MD, USA) as previously described (Wagemakers et al, 2009). …”

Celecoxib steigert die Strahlenempfindlichkeit von sekundären Knochentumoren eines nicht-kleinzelligen humanen Lungenkarzinoms durch Anti-Angiogenese in vivo

“…In this regard, selective COX-2 inhibitors were recently reported to enhance the response of primary tumors to radiation in vitro and in vivo [30,32,33,35,37,40,52]. On the other hand, the COX-2 inhibitor nimesulide did not increase the radiation response of squamous cell carcinoma cells in vitro [5].…”

Use of Selective Cyclooxygenase-2 Inhibitors, Other Analgesics, and Risk of Glioma

“…None of the aforementioned studies [ 34 – 44 ] investigated the association between use of selective COX-2 inhibitors specifically and glioma risk. A large number of laboratory investigations reported on inhibitory effects of selective COX-2 inhibitors on various stages of glioma pathogenesis [ 3 – 6 , 8 – 13 , 15 , 18 – 23 ], prompting clinical trials to investigate selective COX-2 inhibitors as adjuvant therapy for glioma [ 24 – 32 ]. The discrepancy between the laboratory findings and our results may be explained by a number of factors.…”