Raltitrexed increases radiation sensitivity of esophageal squamous carcinoma cells

Abstract

Background Radiation 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. Methods This 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. Results The 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. Conclusion Raltitrexed increases the radiosensitivity of ESCC. This antimetabolite drug is promising for future clinical trials with concurrent radiation in esophageal cancer.

Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments

“…As the uracil distribution pattern in drug-treated cells shows correlation with the early replication timing, we wish to directly investigate if there is any cell cycle arrest occurring under our experimental conditions. Figure 5 shows characteristic scatter plots indicating an expected cell cycle arrest in the drug-treated cells, namely delayed S-phase entry and progression ( Blackledge, 1998 ; Ding et al, 2019 ; Huehls et al, 2016 ; Yan et al, 2016 ; Zhao et al, 2016 ). In agreement with the literature ( Luo et al, 2008 ), our data clearly show no observable cell cycle effect of UGI expression in our non-treated samples ( Figure 5A ).…”

“…Phenotypic differences in cell cycle progression upon the two drug treatments were also reported. The 5FdUR treatment was shown to cause an S-phase arrest in the second cycle ( Huehls et al, 2016 ; Yan et al, 2016 ), while the actual time point of cell cycle arrest upon RTX treatment is still controversial ( Blackledge, 1998 ; Ding et al, 2019 ; Zhao et al, 2016 ). Similarly, we also detected slightly altered cell cycle distribution patterns in case of the two drug treatments, which were differently influenced by the MMR status ( Figure 5 ).…”

Genome-wide alterations of uracil distribution patterns in human DNA upon chemotherapeutic treatments

“…Phenotypic differences in cell-cycle progression upon the two drug treatments were also reported. The 5FdUR treatment was shown to cause an S-phase arrest in the second cycle (Huehls et al, 2016; Yan et al, 2016), while the actual time point of cell-cycle arrest upon RTX treatment is still controversial (Blackledge, 1998; Ding et al, 2019; Zhao, Zhang, Sun, Zhan, & Zhao, 2016).…”

Clinical efficacy of irinotecan plus raltitrexed chemotherapy in refractory esophageal squamous cell cancer: a retrospective study

“…Although there are a few reports on raltitrexed combination chemotherapy in patients with advanced gastro-esophageal adenocarcinoma [20,21], the clinical experience of raltitrexed in patients with ESCC is still unavailable. Recently, Ding et al reported that raltitrexed could decrease cell viability and proliferation, cause apoptosis and enhance the radiosensitivity of ESCC cells [22]. In patients with advanced colorectal cancer, raltitrexed has produced comparable efficacy as first line treatment when compared to 5-FU-based regimen [9] and still showed activity when combined with irinotecan as second line chemotherapy [16].…”