Abstract
ABSTRACTProton beam therapy (PBT) combined with chemotherapy, such as cis-diamminedichloroplatinum (II) (CDDP) and 5-fluorouracil (5-FU), has been employed as an alternative approach to improve clinical outcomes. PBT has been reported to be effective against esophageal cancer. However, apart from 5-FU and CDDP, almost no other drug has been tested in combined chemotherapy with PBT. Therefore, we investigated the effects of a poly (ADP-ribose) polymerase inhibitor on enhancing proton beam effects using esophageal cancer cell lines that exhibit resistance to radiation and CDDP. Esophageal squamous cell carcinoma cell lines OE-21 and KYSE-450 were exposed to the drugs for 1 h prior to irradiation. The cell survival curve was obtained using a clonogenic assay and the sensitizing effect ratio (SER) was calculated. The clonogenic assay was used to compare the effect of multi-fractioned irradiation between 8 Gy/1 fraction (fr) and 8 Gy/4 fr. γH2AX, Rad51, BRCA1, BRCA2 and 53BP1 foci were detected via immunofluorescence. Olaparib exhibited an SER of 1.5–1.7 on PBT. The same sensitizing effect was exhibited in multi-fractioned irradiation, and the combined use increased the expression of double-strand breaks and homologous recombination-related genes in an additive manner. Such additive effects were not observed on non-homologous end joining-related genes. We demonstrated that olaparib has a high sensitizing effect on PBT in platinum- and radiation-resistant esophageal cancer cells. Our results suggest a potential clinical application of olaparib-proton irradiation (PT) against platinum- and radiation-resistant esophageal cancer.
Highlights
Chemoradiotherapy for esophageal cancer The efficacy of chemoradiotherapy in combination with 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (II) (CDDP) was demonstrated in 1999; since it has served as a standard treatment for esophageal cancer [1, 2]
We demonstrated the effect of proton beam therapy (PBT) combined with olaparib on esophageal cancer cell lines and investigated the Olaparib sensitizes esophageal carcinoma cells underlying mechanism of this method to establish an effective treatment for platinum- and radiation-resistant esophageal cancer, which is of clinical relevance
Sensitivity of esophageal cancer cell lines to anticancer agents and radiation We confirmed that esophageal cancer cell lines OE-21 and KYSE-450 displayed resistance to photon and proton irradiation and 5-FU and CDDP, respectively (Figs. 1 and 2)
Summary
Chemoradiotherapy for esophageal cancer The efficacy of chemoradiotherapy in combination with 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (II) (CDDP) was demonstrated in 1999; since it has served as a standard treatment for esophageal cancer [1, 2]. Several combination therapies involving taxan, a cytotoxic drug that targets microtubules, and gefitinib and cetuximab, two drugs that target the EGFR, have been tested. These drugs have not displayed superiority to FP-RT in clinical trials [3, 4]. Technological advancements in photon RT delivery, such as intensity-modulated RT, have decreased the risk of such toxicities, mounting evidence indicates that further risk reductions can be achieved with proton beam therapy (PBT) [6]. Chemotherapy combined with PBT uses therapies that have previously been used in combination with photon therapy, such as CDDP and 5-FU, and are not based on clear evidence. The elucidation of sensitizers and their mechanisms in the context of proton beams is necessary
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