Concurrent treatment with capecitabine and radiosurgery in the mouse glioblastoma model

Abstract

BACKGROUND: Capecitabine (Xeloda) is a chemotherapeutic agent used in the treatment of colorectal cancers, metastatic breast cancer, gastric cancer and pancreatic cancer. However, the studies of Xeloda for CNS tumor are rare. In CNS tumor, there are only some case reports about metastatic breast cancer treated with Xeloda and that about malignant glioma is absent. Xeloda is enzymatically converted to 5-fluorouracil to be an active chemotherapeutic agent in several steps, and the last step is conversion by thymidine phosphorylase (TP). It has been reported that X-Ray irradiation induces TP and enhances the efficacy of Xeloda in human cancer rodent model. According to these studies, we analyzed the effectiveness of combined therapy with pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl] carbamate (Xeloda

capecitabine) and Gamma Knife radiosurgery (GKRS

Gamma Knife® Model C, Elekta AB, Stockholm, Sweden) in rodent brain tumor model established by U87MG glioma cells.

MATERIAL AND METHODS: In vitro, the dihydropyrimidine dehydrogenase (DPD) and TP gene which are associated with Xeloda metabolism were measured by RT-PCR. Xeloda Cytotoxicity assay and radiation therapy effectiveness were measured via CCK assay. In vivo, 3 × 105 of U87MG glioblastoma cells were stereotactically implanted into balb/c nude mouse brain. Establishment of tumor was confirmed 2 weeks later by magnetic resonance (MR) imaging. The mice were treated with Xeloda (1.5 mmol/KG/Daily, p.o.) for the Xeloda group. Fractionated gamma knife (8 Gy/Daily, Total 3 days), or Xeloda followed by FGKRS at a 1.5-hour interval for the GKRS and Xeloda + GKRS group. The survival time of each mouse was measured

every mouse brain was extracted for the tissue sections at the time of death. The survival time among four groups: control, Xeloda treatment, GKRS and Xeloda + GKRS was statistically compared by using Kaplan-Meier survival estimates and survival days (mean±SEM) among each group compared by unpaired T-test.

RESULTS: In vitro, cytotoxicity assay results showed that concurrent treatment with Xeloda and radiation therapy can reliably decrease the cell viability than the Xeloda treatment group. In vivo, mean survival time showed a significant difference between Xeloda + GKRS and the control group (p < 0.0001). And there is a significant difference between Xeloda + GKRS group and the Xeloda group (p < 0.0401). There is also a marginal significance between GKRS and Xeloda + GKRS group (p < 0.0687).

CONCLUSIONS: We suggest that concurrent treatment with Xeloda and FGKRS is more effective in prolonging survival time compared to Xeloda alone, in the U87MG mouse glioblastoma model.

KEYWORDS: Capecitabine, TP, Gamma Knife, concurrent treatment, glioblastoma

Student Number: 2010-30840