Abstract
BackgroundRadiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Many strategies have been developed to increase the radiosensitivity of esophageal cancer, with some success.MethodsThis study was conducted to determine whether raltitrexed can enhance radiosensitivity of esophageal squamous cell carcinoma (ESCC). ESCC cell lines 24 h were incubated with raltitrexed or DMSO with or without subsequent irradiation. Cell Counting Kit assay-8 assay and clonogenic survival assay were used to measure the cell proliferation and radiosensitization, respectively. Flow cytometry was utilized to examine cell apoptosis and cell cycle distribution in different groups. Immunofluorescence analysis was performed to detect deoxyribonucleic acid (DNA) double-strand breaks. In addition, the expression levels of proteins that are involved in radiation induced signal transduction including Bax, Cyclin B1, Cdc2/pCdc2, and Cdc25C/pCdc25C were examined by western blot analysis.ResultsThe results indicated that raltitrexed enhanced radiosensitivity of ESCC cells with increased DNA double-strand breaks, the G2/M arrest, and the apoptosis of ESCC cells induced by radiation. The sensitization enhancement ratio of 1.23–2.10 was detected for ESCC cells with raltitrexed treatment in TE-13 cell line. In vitro, raltitrexed also increased the therapeutic effect of radiation in nude mice.ConclusionRaltitrexed increases the radiosensitivity of ESCC. This antimetabolite drug is promising for future clinical trials with concurrent radiation in esophageal cancer.
Highlights
Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection
Raltitrexed increased radiation sensitivity of Esophageal squamous cell carcinoma (ESCC) cell lines TE-13 and Kyse150 cells were incubated with Raltitrexed at different concentrations for 24, 48 and 72 h
After exposure to raltitrexed at 4 nM for 24 h, the cells were subsequently treated with irradiation at different doses
Summary
Radiation therapy remains an important therapeutic modality, especially for those patients who are not candidates for radical resection. Esophageal squamous cell carcinoma (ESCC) accounts for more than 90% of this cancer in China [2]. There are three major treatment modalities for esophageal cancer including surgery, radiotherapy and chemotherapy, radiotherapy is widely applied to the patients who are not Raltitrexed, named ZD1694 or Tomudex, has been considered as a specific and long-lasting inhibitor against thymidylate synthase (TS). Raltitrexed, as an TS inhibitor, is well known to be effective in the treatment of colorectal cancer. There is little known about the effect of raltitrexed in improving the radiosensitivity of ESCC and according molecular mechanism. We investigated raltitrexed-mediated radiosensitization and the underlying molecular mechanism
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