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ABSTRACT: PURPOSE: DNA aneuploidy, which is characterized by cells containing an abnormal number of chromosomes, is closely associated with carcinogenesis and malignant progression. Aneuploidy occurs during cell division when the chromosomes do not separate properly. Aurora kinases (Aurora-A, -B, and -C) contribute to accurate cell division, and are candidate molecular targets for mitosis-specific anticancer drugs. METHODS: We determined the expression of Aurora-A and -B in 110 gastric cancer specimens by performing an immunohistochemical analysis. We also determined the DNA content, TP53 gene mutations, and microsatellite instability in the same samples. RESULTS: We found the nuclear expression of Aurora-A and -B to increase in tumor tissue in comparison to that in normal epithelial tissue. A high Aurora-B expression significantly correlated with aneuploidy and TP53 mutations, but not with microsatellite instability. In contrast, the Aurora-A expression did not correlate with either aneuploidy or microsatellite instability. In addition, the expression of Aurora-A or -B was not significantly associated with the clinical outcomes or prognosis. CONCLUSIONS: Our results suggest that an overexpression of Aurora-B, but not of Aurora-A, might contribute to DNA aneuploidy in gastric cancers by promoting chromosomal instability.
Surgery Today 04/2013; · 1.22 Impact Factor
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Masaru Morita,
Hajime Otsu,
Hiroyuki Kawano,
Yuta Kasagi,
Yasue Kimura, Hiroshi Saeki,
Koji Ando,
Satoshi Ida,
Eiji Oki,
Eriko Tokunaga,
Tetsuo Ikeda,
Tetsuya Kusumoto,
Yoshihiko Maehara
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ABSTRACT: PURPOSE: The purpose of this study was to clarify the gender differences in the prognosis, as well as mortality and morbidity, of patients who have undergone esophagectomy for esophageal cancer. METHODS: The clinical results of esophagectomy were compared between 975 male and 156 female patients with esophageal cancer. RESULTS: The male to female ratios of cervical and thoracic esophageal cancer were 1.87 and 7.38, respectively (P < 0.01). The incidence of preoperative comorbidities was 32.4 and 17.4 %, respectively, and the rates of both tobacco and alcohol abuse were significantly lower in the females than in the males. The mortality rate was lower in the females (3.8 %) than in the males (5.7 %), although the differences were not significant. The overall survival was significantly better in the female than in the male patients (P = 0.039). The 5- and 10-year overall survival rates were 32.6 and 20.5 % in the males and 39.5 and 32.5 % in the females, respectively. A multivariate analysis revealed gender to be an independent prognostic factor. However, no significant differences were recognized in disease-specific survival. CONCLUSIONS: These results suggest that the prognosis of females with esophageal cancer is better than that of males after esophagectomy, most likely due to multiple clinical factors, such as a more favorable lifestyle and general status.
Surgery Today 04/2013; · 1.22 Impact Factor
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Masaru Morita,
Hajime Otsu,
Hiroyuki Kawano,
Ryuichi Kumashiro,
Kenji Taketani,
Yasue Kimura, Hiroshi Saeki,
Koji Ando,
Satoshi Ida,
Eiji Oki,
Eriko Tokunaga,
Tetsuo Ikeda,
Tetsuya Kusumoto,
Yoshihiko Maehara
[show abstract]
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ABSTRACT: Aim: To justify esophagectomy for elderly patients.
A total of 1,002 patients with thoracic esophageal cancer who underwent esophagectomy were divided into three groups: I (≤74 years old, n=898); II (75-79 years, n=81); and III (≥80 years, n=23). Historical changes were compared between the first surgical period (1964-1989) and the second period (1990-2011).
The morbidity rates were 40%, 41% and 26% in the respective groups. Pulmonary complications decreased historically in groups II and III (36% to 15% and 43% to 0%, respectively). The mortality was higher in the older groups (4.8%, 8.6% and 13.0%, respectively); however, there was a marked historical decrease in groups II (18.2% to 5.1%) and III (28.6% to 6.3%). The 5-year survival improved from 5% to 35% in group II and from 0% to 17% in group III.
The outcomes of esophagectomy for elderly patients have markedly improved, with acceptable mortality even in octogenarians.
Anticancer research 04/2013; 33(4):1641-7. · 1.73 Impact Factor
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Journal of the American College of Surgeons 03/2013; · 4.55 Impact Factor
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Eiji Oki,
Yasunori Emi,
Yoshito Akagi,
Shoji Tokunaga,
Noriaki Sadanaga,
Takaho Tanaka,
Yutaka Ogata, Hiroshi Saeki,
Yoshihiro Kakeji,
Hideo Baba,
Tadashi Nishimaki,
Shoji Natsugoe,
Kazuo Shirouzu,
Yoshihiko Maehara
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ABSTRACT: Objective: This phase II study examined the efficacy and safety of alternating regimens of mFOLFOX6 and FOLFIRI as a first-line treatment for unresectable or metastatic colorectal cancer. Patients and Methods: Forty-eight patients were enrolled in this study. Patients received an alternating regimen of 4 cycles of mFOLFOX6 followed by 4 cycles of FOLFIRI. Results: The characteristics of the study population were as follows: males/females 34/12, median age 66 years (range 43-75) and Eastern Cooperative Oncology Group performance status 0/1/2 in 37/9/0 patients. The overall response rate was 58.7% [95% confidence interval (CI) 43.9-73.5]. The median progression-free survival was 10.3 months (95% CI 7.5-11.9), and the median overall survival was 28.4 months (95% CI 22.5-35.7). Among the 47 patients evaluated for toxicity, the most common grade 3-4 adverse events were leukopenia (26%), neutropenia (55%), anemia (4%), neurotoxicity (0%), diarrhea (2%), febrile neutropenia (4%), nausea (4%), vomiting (2%), and hypersensitivity (0%). Conclusions: The results of this phase II study indicate that this alternating schedule is effective and well tolerated as a first-line treatment for unresectable or metastatic colorectal cancer. The low rate of grade 3 neurotoxicity is also promising.
Oncology 01/2013; 84(4):233-239. · 2.27 Impact Factor
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Masaru Morita,
Hiroyuki Kawano,
Hajime Otsu,
Yasue Kimura, Hiroshi Saeki,
Koji Ando,
Satoshi Ida,
Eiji Oki,
Tetsuo Ikeda,
Tetsuya Kusumoto,
Jun-Ichi Fukushima,
Torahiko Nakashima,
Yoshihiko Maehara
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ABSTRACT: BACKGROUND: Esophageal cancer is frequently associated with head and neck cancer, and esophagectomy is usually difficult in such a case. The purpose of this study was to clarify the clinical significance of esophagectomy for patients with esophageal cancer associated either synchronously or metachronously with head and neck cancer. METHODS: The clinical outcomes of surgical resections for esophageal cancer were compared between 26 patients with head and neck cancer (double cancer group) and 176 without head and neck cancer (control group). RESULTS: Staged operations were performed in 5 patients in the double cancer group, while microvascular anastomosis as well as a muscle flap was added for 3 and 4 patients, respectively. The mortality and morbidity of the double cancer group were 0 and 35 %, respectively, which were not significantly different from those of the control group (3 and 31 %, respectively). There were no significant differences in overall survival in the double cancer and control groups, which had 5-year survival rates of 59 and 49 %, respectively. CONCLUSIONS: Esophagectomy can be an effective treatment when techniques are adopted that are appropriate for each case, such as staged operations, muscular flaps, and microvascular anastomosis, even in patients with double cancers of the esophagus and the head and neck.
Annals of Surgical Oncology 01/2013; · 4.17 Impact Factor
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ABSTRACT: Hyperthermia is widely used to treat patients with cancer, especially in combination with other treatments such as radiation therapy. Heat treatment per se activates DNA damage responses mediated by the ATR-Chk1 and ATM-Chk2 pathways but it is not fully understood how these DNA damage responses are activated and affect heat tolerance. By performing a genetic analysis of human HeLa cells and chicken B lymphoma DT40 cells, we found that heat-induced Chk1 Ser345 phosphorylation by ATR was largely dependent on Rad9, Rad17, TopBP1 and Claspin. Activation of the ATR-Chk1 pathway by heat, however, was not associated with FancD2 monoubiquitination or RPA32 phosphorylation, which are known as downstream events of ATR kinase activation when replication forks are stalled. Downregulation of ATR, Rad9, Rad17, TopBP1 or Claspin drastically reduced clonogenic cell viability upon hyperthermia, while gene knockout or inhibition of ATM kinase reduced clonogenic viability only modestly. Suppression of the ATR-Chk1 pathway activation enhanced heat-induced phosphorylation of Chk2 Thr68 and simultaneous inhibition of ATR and ATM kinases rendered severe heat cytotoxicity. These data indicate that essential factors for activation of the ATR-Chk1 pathway at stalled replication forks are also required for heat-induced activation of ATR kinase, which predominantly contributes to heat tolerance in a non-overlapping manner with ATM kinase.
PLoS ONE 01/2013; 8(2):e55361. · 4.09 Impact Factor
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Ryota Nakanishi,
Jun Harada,
Munkhbold Tuul,
Yan Zhao,
Koji Ando, Hiroshi Saeki,
Eiji Oki,
Takefumi Ohga,
Hiroyuki Kitao,
Yoshihiro Kakeji,
Yoshihiko Maehara
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ABSTRACT: BACKGROUND: Mutations of the KRAS or BRAF genes are now recognized as prognostic markers for colorectal cancer (CRC). They are also important predictive markers for resistance to the monoclonal antibodies that target the epidermal growth factor receptor. METHODS: In this retrospective study, KRAS and BRAF mutations were analyzed using a direct sequence method in 254 Japanese CRC patients, and the associations between KRAS or BRAF mutations and clinicopathological characteristics or outcome were evaluated. RESULTS: KRAS and BRAF mutations were detected in 33.5 and 6.7 % of all patients, respectively. Consistent with previous reports, BRAF mutations were significantly correlated with the anatomical site of the tumor (P < 0.001), tumor grade (P = 0.001) and high frequency of microsatellite instability (P < 0.001). BRAF mutations were correlated with poor overall survival in the full patient cohort (P = 0.009). KRAS mutations were significantly correlated with poor recurrence-free survival (P = 0.03), particularly in patients with stage II CRC (P = 0.007). Cox regression analysis showed that KRAS mutations were a negative predictor of recurrence-free survival in patients with stage II CRC. CONCLUSION: KRAS mutation status could be a novel biomarker for predicting disease recurrence in Japanese patients with stage II CRC.
International Journal of Clinical Oncology 11/2012; · 1.41 Impact Factor
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Masaru Morita,
Yasushi Toh, Hiroshi Saeki,
Masahiko Sugiyama,
Kippei Ohgaki,
Shin-Ichiro Maehara,
Kazuhito Minami,
Yasuharu Ikeda,
Yoshihisa Sakaguchi,
Takeshi Okamura,
Satoru Uehara,
Yoshihiko Maehara
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ABSTRACT: To clarify the clinical significance of definitive chemoradiotherapy (CRT) and CRT followed by esophagectomy for cT4 esophageal cancer.
The treatment results for cT4 esophageal cancer were examined in 81 patients who received definitive CRT [radiation 50-70 Gy, cisplatin and 5-fluorouracil; group I] and 19 patients who underwent esophagectomy after preoperative CRT [40Gy, Group II].
Among the 81 patients in group I, toxicities (grade 3 or 4) were observed in 32 patients, while partial response and complete response were recognized in 8 and 47 patients, respectively. Of the 19 group II patients, an R0 resection was performed in 16 patients, and the mortality rate was 5%. The 5-year survival rates were 19% and 42% in groups I and II, respectively.
Long-term survival can be expected after multimodal therapy, even for patients with cT4 esophageal cancer. Esophagectomy is therefore a valid treatment option when down-staging can be achieved.
Anticancer research 08/2012; 32(8):3275-82. · 1.73 Impact Factor
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Toshiro Okuyama,
Takahiro Higashi,
Ai Edagawa,
Shigeyuki Nagata,
Kenkichi Hashimoto, Hiroshi Saeki,
Eiji Oki,
Hideaki Uchiyama,
Hirofumi Kawanaka,
Masaru Morita,
Masahiro Tateishi,
Daisuke Korenaga,
Hidemichi Yaita,
Kenji Takenaka
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ABSTRACT: The prognosis of gastric cancer patients undergoing curability B surgery was retrospectively examined to determine the effectiveness of the administration of oral anti-cancer drugs as postoperative adjuvant chemotherapy.
This study was based on the outcomes of 86 potentially curative patients who had undergone curability B resection of gastric cancer with or without the subsequent administration of oral 5-fluorouracil analogue. There were 21 patients who underwent surgery alone with no oral anti-cancer agents (group A) and 65 patients who were treated postoperatively, mainly with UFT (Tegafur and uracil; group B). This study compared the ten-year survival times of these two groups using univariate and multivariate analyses.
The amount of UFT in group B was 354.2 +/- 122.0 mg and the administration period was 11.7 +/- 7.2 months. The backgrounds showed significantly more older patients in group A compared than group B (P = 0.0002). A univariate analysis showed the ten-year survival rate in group B to be higher than group A (P = 0.0079). A multivariate analysis showed that the postoperative administration of UFT was an independent factor associated with prolongation of survival times as well as the extent of lymph nodes metastasis and pathological stage (P = 0.0096).
This study provided conventional evidence that postoperative administration of oral 5-fluorouracil analogue is associated with better long-term prognoses in patients undergoing curability B resection for gastric carcinoma.
Fukuoka igaku zasshi = Hukuoka acta medica 07/2012; 103(7):138-44.
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Tetsuo Ikeda,
Hiroyuki Kawano,
Yuichi Hisamatsu,
Koji Ando, Hiroshi Saeki,
Eiji Oki,
Takefumi Ohga,
Yoshihiro Kakeji,
Shunichi Tsujitani,
Shunji Kohnoe,
Yoshihiko Maehara
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ABSTRACT: BACKGROUND: Billroth I (B-I) gastroduodenostomy is an anastomotic procedure that is widely performed after gastric resection for distal gastric cancer. A circular stapler often is used for B-I gastroduodenostomy in open and laparoscopic-assisted distal gastrectomy. Recently, totally laparoscopic distal gastrectomy (TLDG) has been considered less invasive than laparoscopic-assisted gastrectomy, and many institutions performing laparoscopic-assisted distal gastrectomy are trying to progress to TLDG without markedly changing the anastomosis method. The purpose of this report is to introduce the technical details of new methods of intracorporeal gastroduodenostomy using either a circular or linear stapler and to evaluate their technical feasibility and safety. METHODS: Seventeen patients who underwent TLDG with the intracorporeal double-stapling technique using a circular stapler (n = 7) or the book-binding technique (BBT) using a linear stapler (n = 10) between February 2010 and April 2011 were enrolled in the study. Clinicopathological data, surgical data, and postoperative outcomes were analyzed. RESULTS: There were no intraoperative complications or conversions to open surgery in any of the 17 patients. The usual postoperative complications following gastroduodenostomy, such as anastomotic leakage and stenosis, were not observed. Anastomosis took significantly longer to complete with DST (64 ± 24 min) than with BBT (34 ± 7 min), but more stapler cartridges were needed with BBT than with DST. CONCLUSIONS: TLDG using a circular or linear stapler is feasible and safe to perform. DST will enable institutions performing laparoscopic-assisted distal gastrectomy with circular staplers to progress to TLDG without problems, and this progression may be more economical because fewer stapler cartridges are used during surgery. However, if an institution has already been performing δ anastomosis in TLDG but has been experiencing certain issues with δ anastomosis, converting from δ anastomosis to BBT should be beneficial.
Surgical Endoscopy 06/2012; · 4.01 Impact Factor
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Eiji Oki,
Yoshihisa Sakaguchi,
Kippei Ohgaki, Hiroshi Saeki,
Yoshiki Chinen,
Kazuhito Minami,
Yasuo Sakamoto,
Yasushi Toh,
Testuya Kusumoto,
Takeshi Okamura,
Yoshihiko Maehara
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ABSTRACT: Since a patient's obesity can affect the mortality and morbidity of the surgery, less drastic surgeries may have a major benefit for obese individuals. This study evaluated the feasibility of performing a totally laparoscopic distal gastrectomy, with intracorporeal anastomosis, in obese patients suffering from gastric cancer.
This was a retrospective analysis of the 138 patients, who underwent a totally laparoscopic distal gastrectomy from April 2005 to March 2009, at the National Kyushu Cancer Center. The body mass index of 20 patients was ≥25, and in 118 patients, it was <25 kg/m(2).
The mean values of body mass index in the 2 groups were 27.3±2.2 and 21.4±2.3. Hypertension was significantly more frequent in the obese patients than in the non-obese patients. The intraoperative blood loss, duration of surgery, post-operative complication rate, post-operative hospital stay, and a number of retrieved lymph nodes were not significantly different between the two groups.
Intracorporeal anastomosis seemed to have a benefit for obese individuals. Totally laparoscopic gastrectomy is, therefore, considered to be a safe and an effective modality for obese patients.
Journal of gastric cancer. 06/2012; 12(2):108-12.
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ABSTRACT: Esophageal perforation with mediastinal abscess formation is a potentially life-threatening complication after chemoradiotherapy
(CRT) in patients with esophageal cancer. We present the case of a 64-year-old woman with cervico-thoracic esophageal cancer
who had previously undergone distal gastrectomy. Definitive CRT was initially performed since the patient refused laryngectomy.
However, she developed an esophageal fistula and a subsequent cervico-mediastinal abscess, which made oral intake impossible.
In order to address the fistula, abscess, and cancer, we decided to perform a staged operation. The patient first underwent
total pharyngo-laryngo-esophagectomy and abscess drainage. She next underwent esophageal reconstruction with an ileocolonic
conduit through a subcutaneous route. The patient is currently alive and well after surgery. This case suggests that surgical
resection may be performed in high-risk patients with cervico-thoracic esophageal cancer via a two-stage operation.
KeywordsSalvage operation–Esophageal cancer with fistula–Two-stage operation–Curative chemoradiotherapy
Esophagus 04/2012; 8(3):197-201. · 0.66 Impact Factor
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ABSTRACT: The biological characteristics of cancers depend mostly on genetic alterations in the cancer cells of individuals. Gastric cancers show a high frequency of DNA aneuploidy, a phenotype of chromosomal instability. Compared to diploid tumors, gastric carcinomas with aneuploidy have been shown to have high proliferative activity and high metastatic or invasive potential; these characteristics lead to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. This review, in order to determine whether gastric carcinomas that display aneuploidy are associated with a poorer prognosis than diploid tumors, and to discuss the biological mechanisms that induce aneuploidy, summarizes the results of studies on DNA ploidy in gastric cancer published in the English literature. Analysis of DNA ploidy in gastric cancer may provide clinically useful information from diagnostic, therapeutic, and prognostic standpoints. Further investigations may be needed to clarify the relationship between chromosome instability and DNA ploidy.
Journal of Gastroenterology 03/2012; 47(4):351-8. · 4.16 Impact Factor
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Masahiko Sugiyama,
Masaru Morita,
Rintaro Yoshida,
Koji Ando,
Akinori Egashira,
Ohga Takefumi, Hiroshi Saeki,
Eiji Oki,
Yoshihiro Kakeji,
Yoshihisa Sakaguchi,
Yoshihiko Maehara
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ABSTRACT: The results and outcomes of surgical resection for esophageal carcinoma have improved remarkably in recent years; however, recurrence still frequently develops, even after complete resection. The purpose of this study is to clarify the characteristics of recurrence in this patient population.
Among 208 patients, who underwent R0 resection for esophageal carcinoma, recurrence developed in 61. Clinical data were available for 56 of these patients, who were the subjects of this study. We evaluated the time, patterns, and treatment of recurrence in these patients.
Recurrence developed within 1 and 2 years after esophagectomy in 71 and 84% of the patients, respectively, and was classified as loco-regional (54%), hematogenous (36%), or mixed type (10%). The prognosis of patients with loco-regional recurrence tended to be better than that of those with distant metastasis, although the difference was not significant (P = 0.088). Patients with recurrence treated by chemotherapy alone or multimodal therapy, such as radiation or surgery combined with systemic chemotherapy, survived significantly longer than those with untreatable recurrence (P = 0.016).
These findings reinforce the importance of careful follow-up for both loco-regional and hematogenous recurrence after esophagectomy, particularly during the first 2 years.
Surgery Today 02/2012; 42(8):752-8. · 1.22 Impact Factor
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Yasuo Sakamoto,
Yoshihisa Sakaguchi,
Hisafumi Akimoto,
Yoshiki Chinen,
Miyako Kojo,
Masahiko Sugiyama,
Kazutoyo Morita, Hiroshi Saeki,
Kazuhito Minami,
Yuji Soejima,
Yasushi Toh,
Takeshi Okamura
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ABSTRACT: Laparoscopic gastrectomy is commonly performed for gastrointestinal stromal tumors (GISTs). Partial gastrectomy is usually achieved with a wedge resection to preserve gastric function; however, performing a wedge resection to excise a large tumor located close to the esophagogastric junction (EGJ) can result in deformation of the stomach and/or the stenosis of the EGJ if the gastric wall resection is excessive. We describe our procedure, in which the whole layer of the gastric wall was cut, maintaining a sufficient margin and confirming the distance between the tumor and the EGJ, by endoscopy and laparoscopy. The defect in the gastric wall was closed using linear staplers by hanging up the stay sutures. Five patients with GIST close to EGJ underwent this procedure, followed by a good postoperative course. Thus, we consider our procedure to be safe and effective for gastric GISTs close to the EGJ.
Surgery Today 01/2012; 42(7):708-11. · 1.22 Impact Factor
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ABSTRACT: Both squamous cell carcinomas and adenocarcinomas can develop in the esophagogastric junction. To clarify the appropriate lymph node dissection range, lymph node metastases from cancers in the esophagogastric junction were investigated.
The nodal metastases were analyzed in 64 patients with squamous cell carcinoma and 129 with adenocarcinoma according to Siewert's classification, which is based on topographic anatomical criteria for adenocarcinoma.
The squamous cell carcinomas located above the esophagocardial junction had more frequent metastasis to the lower and middle mediastinal lymph nodes in proportion to the depth of the tumor. Nodal metastasis was also often detected in the abdominal lymph nodes. In contrast, adenocarcinomas metastasized less frequently to the mediastinal lymph nodes, and the metastatic rates in the abdominal nodes were higher than those from squamous cell carcinoma.
Esophagectomy with mediastinal and abdominal lymph node dissection is considered to be an appropriate approach for surgical resection of squamous cell carcinomas, whereas transhiatally extended gastrectomy with lower mediastinal and abdominal lymph node dissection is recommended for the treatment of adenocarcinomas.
Surgery Today 01/2012; 42(4):351-8. · 1.22 Impact Factor
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Yasunori Emi,
Yoshihiro Kakeji,
Eiji Oki, Hiroshi Saeki,
Koji Ando,
Masaki Kitazono,
Yoshihisa Sakaguchi,
Masaru Morita,
Hironori Samura,
Yutaka Ogata,
Yoshito Akagi,
Shoji Natsugoe,
Kazuo Shirouzu,
Shoji Tokunaga,
Florin Sirzen,
Yoshihiko Maehara
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ABSTRACT: BACKGROUND: A prospective feasibility study was planned to clarify the proportion of compliance and adverse events in the administration of capecitabine as adjuvant chemotherapy for colon cancer in Japanese patients. METHODS: We aimed initially to register 92 cases of R0 stage III colon cancer. Capecitabine (2,500 mg/m(2)/day) was given orally on days 1-14 every 3 weeks for 8 cycles. The proportion of treatments completed as planned was selected as the primary endpoint. RESULTS: Ninety-seven cases were registered and treated between September 2008 and August 2009. The proportion of treatments completed in the full analysis set was 64/97 [66.0%; 95% confidence interval (CI), 55.7-75.3%] and in the per protocol set was 64/91 (70.3%; 95% CI, 59.8-79.5%). Adverse events which led to treatment discontinuation included hand-foot syndrome (HFS) (7), haematotoxicity (5) and increased hepatic damage (4). The proportions of patients with major grade 3/4 adverse events were HFS 22.7%, neutropenia 7.2%, diarrhoea 2.1%, and increased bilirubin 0.0%. CONCLUSIONS: This collaborative multi-facility study, the first of its kind in Japan, presented results of a safety confirmation experiment on capecitabine as adjuvant chemotherapy for stage III colon cancer. The results suggest that capecitabine may be administered safely to Japanese patients.
International Journal of Clinical Oncology 01/2012; · 1.41 Impact Factor
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Yoshihiko Fujinaka,
Kazuaki Matsuoka,
Makoto Iimori,
Munkhbold Tuul,
Ryo Sakasai,
Keiji Yoshinaga, Hiroshi Saeki,
Masaru Morita,
Yoshihiro Kakeji,
David A Gillespie,
Ken-Ichi Yamamoto,
Minoru Takata,
Hiroyuki Kitao,
Yoshihiko Maehara
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ABSTRACT: 5-Fluorouracil (5-FU) has long been a mainstay antimetabolite chemotherapeutic drug for the treatment of major solid tumors, particularly colorectal cancer. 5-FU is processed intracellularly to yield active metabolites that compromise RNA and DNA metabolism. However, the mechanisms responsible for its cytotoxicity are not fully understood. From the phenotypic analysis of mutant chicken B lymphoma DT40 cells, we found that homologous recombinational repair (HRR), involving Rad54 and BRCA2, and the ATR-Chk1 signaling pathway, involving Rad9 and Rad17, significantly contribute to 5-FU tolerance. 5-FU induced γH2AX nuclear foci, which were colocalized with the key HRR factor Rad51, but not with DNA double-strand breaks (DSBs), in a dose-dependent manner as cells accumulated in the S phase. Inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX and enhanced 5-FU cytotoxicity not only in wild-type cells but also in Rad54- or BRCA2-deficient cells, suggesting that HRR and Chk1 kinase have non-overlapping roles in 5-FU tolerance. 5-FU-induced Chk1 phosphorylation was significantly impaired in Rad9- or Rad17-deficient cells, and severe γH2AX nuclear foci and DSBs were formed, which was followed by apoptosis. Finally, inhibition of Chk1 kinase by UCN-01 increased 5-FU-induced γH2AX nuclear foci and enhanced 5-FU cytotoxicity in Rad9- or Rad17-deficient cells. These results suggest that Rad9- and Rad17-independent activation of the ATR-Chk1 signaling pathway also significantly contributes to 5-FU tolerance.
DNA repair 12/2011; 11(3):247-58. · 4.20 Impact Factor
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ABSTRACT: BRCA1 and BRCA2 are two major tumor suppressor genes for hereditary breast and ovarian cancer. In sporadic breast cancer, although somatic mutations of these genes are rare, loss of heterozygosity (LOH) at BRCA1 and BRCA2 loci is common.
LOH at BRCA1 and BRCA2 loci were investigated in 202 Japanese invasive breast cancer patients. The relationships between LOH at these gene loci and clinicopathologic characteristics were analyzed.
Among 166 informative cases for both BRCA1 and BRCA2 loci, 69 (41.6%) and 52 (31.3%) tumors revealed LOH at BRCA1 and BRCA2 loci, respectively. LOH at BRCA1 LOH or BRCA2 locus was associated with higher nuclear grade (P < 0.0001, P = 0.0187). LOH at BRCA1 locus was associated with estrogen receptor and progesterone receptor negativity (P = 0.001 and P = 0.015) and significantly shorter disease-free survival (P < 0.0001), distant metastasis-free survival (P < 0.0001), and overall survival (P < 0.0001). In contrast, LOH at BRCA2 locus had no associations with estrogen receptor or progesterone receptor status and prognosis. LOH at BRCA1 locus was independently associated with poor prognosis in terms of disease-free survival (hazard ratio 3.08, 95% confidence interval [CI] 1.58-6.18, P = 0.0009), distant metastasis-free survival (hazard ratio 5.18, 95% CI 2.35-12.19, P < 0.0001), and overall survival (hazard ratio 4.97, 95% CI 1.84-15.1, P = 0.0013).
LOH at BRCA1 locus could be an independent prognostic biomarker useful in identifying a subgroup of patients with poor prognosis.
Annals of Surgical Oncology 12/2011; 19(5):1499-507. · 4.17 Impact Factor
