Involvement of homologous recombination in the synergism between cisplatin and poly (ADP-ribose) polymerase inhibition.

Poly (ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. Inhibition of PARP is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combined treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14, and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients who suffer from aggressive disease that presently lacks effective treatment options.

Involvement of ribonucleotide reductase-M1 in 5-fluorouracil­induced DNA damage in esophageal cancer cell lines.

5-Fluorouracil (5-FU) is one of the most well established chemotherapeutic agents in the treatment of esophageal cancer. Ribonucleotide reductase M1 (RRM-1) is the rate­limiting enzyme in de novo DNA synthesis, and has been considered to play an important role in the 5-FU metabolic pathway. However, the means by which RRM-1 participates in the anticancer effects of 5-FU and cisplatin (CDDP) have not been well studied. Here, we show that RRM-1 significantly contributes to the induction of DNA damage by 5-FU in esophageal cancer cell lines. An assay of γ-H2AX focus formation, a marker of DNA damage, after 5-FU treatment revealed good correlation with the levels of RRM-1 protein expression. Moreover, the increased sensitivity and RAD51 focus formation induced by the combination treatment of 5-FU and CDDP were significantly repressed by RRM-1 depletion. These results suggest that RRM-1 is involved not only in the induction of DNA damage by 5-FU but also in the synergistic cytotoxic effect in the combination therapy of 5-FU and CDDP.

Advanced esophageal cancer with an esophago-bronchial fistula successfully treated by chemoradiotherapy following esophageal bypass surgery: report of a case.

Esophageal bypass surgery using a gastric tube prior to definitive chemoradiotherapy in preparation for the formation of esophago-tracheal or bronchial fistula is a possible strategy for esophageal cancer invading the airway. This report presents the case of a patient with esophageal cancer involving the left main bronchus who underwent esophageal bypass followed by definitive chemoradiotherapy and who has achieved long-term survival without deterioration of his quality of life, in spite of the development of a malignant esophago-bronchial fistula.

Advanced esophageal cancer with situs inversus totalis successfully treated with chemoradiotherapy followed by esophagectomy: case report.

We report a case of advanced esophageal cancer successfully treated with neoadjuvant chemoradiotherapy followed by esophagectomy in a 53-year-old man with situs inversus totalis. Upper gastrointestinal endoscopy in a clinical examination revealed a tumor in the lower third of the esophagus, and moderately differentiated squamous cell carcinoma was diagnosed from the biopsy findings. He was referred to us and the disease was diagnosed as esophageal cancer (clinical T3N1M0, cStage III) after further evaluation. According to the therapeutic strategy of our department, neoadjuvant chemoradiotherapy was commenced. The regimen was composed of radiotherapy (2 Gy/day, 5 days/week, 4weeks, total 40Gy) with cisplatin (70 mg/m2/day, day 1) and 5-FU (700 mg/m2/day, day 1-4). We performed a subtotal esophagectomy with radical lymph node dissection through a left thoracotomy because of the existence of situs inversus totalis. The thoracic operation could be performed with relatively safety because the organs were arranged in a mirror image of their normal positions. On the other hand, it was relatively difficult to construct a gastric tube. In particular, ligation of the gastrosplenic ligaments was difficult and this led to increased blood loss compared with usual operation. Histopathological examination revealed no residual carcinoma at the site of the primary focus. The patient has been followed up periodically on an outpatient basis and has remained free of recurrence for longer than 2 years 5 months after surgery.