Gimeracil sensitizes cells to radiation via inhibition of homologous recombination

Takagi, Masaru; Sakata, Koh‐ichi; Someya, Masanori; Tauchi, Hiroshi; Iijima, Kenta; Matsumoto, Yoshihisa; Torigoe, Toshihiko; Takahashi, Akari; Hareyama, Masato; Fukushima, Masakazu

doi:10.1016/j.radonc.2010.05.020

Cited by 36 publications

(34 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a previous report, the CDHP in S-1 (acting as a dihydropyrimidine dehydrogenase inhibitor) exhibited a radiosensitizing activity [27,28]. Nakata et al [15 ]reported that when tumor DLD-1/FU xenografts derived from human colon carcinoma cells resistant to 5-FU were treated with S-1, the response of these tumors to local tumor radiotherapy was enhanced.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

Sadahiro¹,

Suzuki²,

Tanaka³

et al. 2011

Oncology

View full text Add to dashboard Cite

Purpose: To assess the maximum tolerability of a combination of S-1 and preoperative radiotherapy and to evaluate the feasibility and activity in patients with locally advanced rectal cancer. Methods: Patients (n = 30) with adenocarcinoma of the middle or lower rectum were enrolled in a phase I (n = 9) and/or phase II (n = 21) trial. A total dose of 45 Gy was delivered in 25 fractions over 5 weeks, and S-1 was orally administered twice a day on days 1–14 and 22–35. Surgical resection was scheduled 4–8 weeks after the completion of chemoradiation. Results: In phase I, the recommended dose (RD) of S-1 was 80 mg/m²/day, and the maximum-tolerated dose was never reached. A total of 27 cases, including the 6 RD cases in phase I, were enrolled in phase II. In phase II, a pathological complete response (pCR) was observed in 6/27 patients (22%), pathological downstaging was observed in 21/27 patients (78%), and a tumor volume reduction of 69 ± 22% was obtained. These results were similar to the previously reported pCR rates of 16–18%, pathological downstaging rates of 49–59%, and tumor volume reduction of 68% after chemoradiotherapy with capecitabine. Grade 3 adverse events consisted of one case of leukopenia (4%), 2 cases of anemia (7%) and 3 cases of diarrhea (11%). Overall, the adverse events were very mild. Hand-foot syndrome was not observed. Conclusion: The efficacy of chemoradiotherapy with S-1 seems to be equivalent to the efficacy reported for chemoradiotherapy with capecitabine, but the adverse events were much milder, although further study is warranted.

show abstract

Section: Discussionmentioning

confidence: 99%

Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

Sadahiro¹,

Suzuki²,

Tanaka³

et al. 2011

Oncology

View full text Add to dashboard Cite

show abstract

“…Studies have shown that the half-life of 5-FU after oral S-1administration was markedly prolonged compared with that of 5-FU after intravenous administration (20,21). Second, gimeracil, a component of S-1, has been found to enhance the efficacy of RT through the inhibition of the repair of radiation-induced DNA damage (22,23). A preclinical study using human cancer xenograft models showed that oral S-1 produced better response than intravenous 5-FU in the CRT (23).…”

Section: Original Articlementioning

confidence: 99%

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer

Qiu

Sheng

et al. 2016

J. Thorac. Dis.

View full text Add to dashboard Cite

Background: Concurrent chemoradiotherapy (CRT) with 5-fluorouracil (5-FU) and cisplatin (CDDP) are often associated with significant incidence of toxic effects in elderly patients with esophageal cancer. This phase I trial was designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of S-1, an oral 5-FU derivative, when given with radiotherapy in elderly patients. Methods:Patients who were age of 70 years or older with histologically confirmed esophageal cancer, and had an Eastern Cooperative Oncology Group (ECOG) score of 0-2 were eligible for this study. Radiotherapy was administered in 1.8 Gy fractions 5 times weekly to a total dose of 54 Gy. S-1 was administered on days 1-14 and 29-42 at the following dosages: 60, 70, and 80 mg/m 2 /day. Trial registration: NCT01175447 (ClinicalTrials.gov).Results: Twelve previously untreated patients were enrolled in this study. No grade 3 or 4 toxicity was observed in six patients treated at the 60 and 70 mg/m 2 dose levels. DLT was observed in four of six patients treated at the 80 mg/m 2 dose level. Two patients developed grade 3 esophagitis, one patient developed grade 3 esophagitis and pneumonitis, and one patient developed grade 3 thrombocytopaenia. Endoscopic complete response (CR) was observed in eight patients (66.7%). The median progression free survival (PFS) was 20 months and median overall survival was 29 months. Conclusions:The MTD of S-1 was 80 mg/m 2 , and the recommended dose (RD) for phase II studies was 70 mg/m 2 . This regimen was well tolerated and active in elderly patients with esophageal cancer, meriting further investigation in phase II studies. partially because of medical comorbidities and reduced functional reserve of organs (5-7). A population-based study of the National Cancer Registry in Ireland showed that, when compared with patients younger than 60 years of age, the likelihood for resection was significantly lower among older cohorts by 33%, 74% and 93% for patients aged 60-69, 70-79 and 80+, respectively (7).Chemoradiotherapy (CRT) has been accepted nowadays as the standard nonsurgical treatment for locally advanced esophageal cancer. The Radiation Therapy Oncology Group (RTOG) phase III intergroup trial RTOG 85-01 demonstrated that CRT with 5-fluorouracil (5-FU) and cisplatin (CDDP) provided a significant survival advantage over RT alone (8,9). However, the toxicity of CRT was substantial. 64% of patients treated with CRT experienced severe or life threatening adverse events comparing to 28% of patients treated with RT alone (9). And only 23% of patients enrolled in this study were over age 70, which brought a question about the suitability of CRT for elderly patients. Recently, several retrospective studies suggested that elderly patients with esophageal cancer may also benefit from CRT with 5-FU and CDDP (10-12). The clinical complete response (CR) rate was found at a range of 57.8-63.6% and survival time of 8.6-15.2 months. However, only 9-38.5% of patients finished the scheduled treatment because of the ...

show abstract

“…To explicate the molecular mechanisms of sensitization of effects of CPT and 5-FU by gimeracil, we examined whether gimeracil affects the radiosensitivity of cells deficient in DNA-PK activity. We previously demonstrated that gimeracil enhances the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways [23]. DNA is the principal target for the biologic effects of radiation.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that gimeracil does in fact have a radiosensitizing effect by inhibiting homologous recombination (HR) in the mechanism of DNA double strand breaks (DSB) [23]. Because HR plays a key role in the repair of DNA DSB caused by radiotherapy, gimeracil may enhance the efficacy of radiotherapy through the suppression of HR-mediated DNA repair pathways.…”

mentioning

confidence: 99%

The combination of hyperthermia or chemotherapy with gimeracil for effective radiosensitization

et al. 2012

View full text Add to dashboard Cite

show abstract

Gimeracil sensitizes cells to radiation via inhibition of homologous recombination

Cited by 36 publications

References 25 publications

Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

Phase I/II Study of Preoperative Concurrent Chemoradiotherapy with S-1 for Locally Advanced, Resectable Rectal Adenocarcinoma

A phase I dose escalation study of S-1 with concurrent radiotherapy in elderly patients with esophageal cancer

The combination of hyperthermia or chemotherapy with gimeracil for effective radiosensitization

Contact Info

Product

Resources

About