Biomedical subjects

Hisao Ito

Publications and source records attributed to Hisao Ito.

At least 37 records · Page 2Linked to original sources

PubMed2006

Recurrent thymoma: radiological (CT and FDG-PET) and histological (WHO criteria) features.

A 66-year-old man, who had undergone surgical resection of a primary noninvasive thymoma (type B1) in the right anterolateral mediastinum 6 years before, underwent follow-up computed tomography (CT) scanning. The CT scan revealed a few nodules located at the posterior portion of the right thoracic base and just behind the right upper anterior chest wall. Subsequent fluorodeoxyglucose positron emission tomography (FDG-PET) scans showed multiple foci with high [standard uptake value (SUV) 4.3] and low (SUV 2.6) FDG uptake in the right lower posterior area and right upper anterior area of the chest, respectively. The fusion image of the CT and FDG-PET scans demonstrated that the areas of the increased FDG uptake corresponded to those of the nodules on the CT scan. All of the nodules were successfully removed surgically, and the histological features of the nodules indicated that they were type B1 or types B1 plus B2. We regarded the nodule located just behind the right upper anterior chest wall as a type B1 thymoma, whereas those in the posterior area of the right thoracic base as combined thymomas of types B1 plus B2. Our limited experience suggests that the degree of FDG uptake is a reflection of the subtype according to the World Health Organization (WHO) criteria. Furthermore, we showed the role of FDG-PET in the accurate assessment of recurrent thymoma and its therapeutic strategy.

Fluorodeoxyglucose F18↗

PubMed2006

Diagnosis of dementia using perfusion SPECT imaging at the patient's initial visit to a cognitive disorder clinic.

PURPOSE: This study was performed to evaluate the diagnostic accuracy of brain perfusion SPECT in patients visiting the cognitive disorder clinic for initial evaluation using 3D-SSP compared with using standard transaxial section. MATERIALS AND METHODS: Standard transaxial section displays and 3D-SSP z-score maps obtained after administration of Tc-99m ECD or I-123 IMP were randomly interpreted in 315 patients who visited initially to the cognitive disorder clinic (age 46-88 years; 162 women, 153 men). Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were calculated and receiver operating characteristic (ROC) analysis was performed. RESULTS: One hundred thirty-seven patients were clinically diagnosed with Alzheimer disease and 178 patients were diagnosed with other disorders and age-associated cognitive decline. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy calculated using standard transaxial display were 61%, 70%, 61%, 70%, and 66%, respectively, and using the 3D-SSP z-score map were 90%, 74%, 73%, 90%, and 81%, respectively. Particularly, the sensitivity value improved in mild cases compared with severe cases using 3D-SSP. Diagnostic performance with 3D-SSP was superior in both mild dementia (Az = 0.64 [section] vs 0.81 [3D-SSP], P = 0.001) and severe dementia (Az = 0.75 [section] vs 0.90 [3D-SSP], P = 0.002). CONCLUSIONS: Brain perfusion SPECT was useful for diagnosis in patients who come to the cognitive disorder clinic for initial evaluation using 3D-SSP.

Aged↗

PubMed2006

Clinical usefulness of serum telomerase reverse transcriptase (hTERT) mRNA and epidermal growth factor receptor (EGFR) mRNA as a novel tumor marker for lung cancer.

Using a newly developed assay of telomerase reverse transcriptase (hTERT) mRNA in serum by real-time RT-PCR, we previously reported this assay to be superior to other tumor markers for hepatoma. In this study, we aimed to clarify its clinical significance as a biomarker for lung cancer. In 112 patients with lung tumor and 80 individuals without cancer, we measured serum hTERT mRNA and epidermal growth factor receptor (EGFR) mRNA levels, using a quantitative one-step real-time RT-PCR assay. We examined its sensitivity and specificity in lung cancer diagnosis, its clinical significance in comparison with other tumor markers, and its correlation with the clinical parameters using multivariate analyses and correlation relative tests. The copy number of serum hTERT mRNA was independently correlated with tumor size, tumor number, presence of metastasis and recurrence, and smoking (all P < 0.05). EGFR mRNA correlated with tumor number and clinical stage (both P < 0.05). The sensitivity and specificity in lung cancer diagnosis were 89.0% and 72.7% for hTERT mRNA, and 71.3% and 80.0% for EGFR mRNA, respectively. hTERT mRNA was superior to other tumor markers in lung cancer diagnosis. For both mRNAs, serum levels were significantly correlated with levels in lung cancer tissues (both P < 0.05). The copy number of hTERT mRNA significantly decreased after the surgical treatment. The data suggest that hTERT mRNA, especially when combined with EGFR mRNA, is a novel and excellent biomarker for pulmonary malignancies to diagnose and assess the clinical stage.

Adenocarcinoma↗

PubMed2006

Induction of efficient apoptosis and cell-cycle arrest in tumor cells by adenovirus-mediated p53 A4 mutant.

p53 is an effective tumor suppressor and is inactivated in numerous cancer cells. In the present study, p53 mutant A4, which carries mutations in C-terminus of the protein and is resistant to murine double minute 2-mediated degradation, was exploited to introduce p53 function in tumor cells. The effect of p53 A4 mutant with recombinant adenovirus vector (Ad-p53 A4) was examined. Ad-p53 A4 infection at a low multiplicity of infection showed significant accumulation of p53 protein and strongly induced a killing effect on osteosarcoma cell line MG-63 that is less sensitive to transduction of wild-type p53. DNA fragmentation assay and caspase assay showed that the cell death induced by Ad-p53 A4 was more rapid and higher than that by Ad-p53 wild-type infection. It is also showed Ad-p53 A4 induces cell-cycle arrest in G1 phase. Moreover, a similar effect was observed in some human cancer cell lines (HeLa, HepG2, KATO III and Saos-2) in various status of endogenous p53 expression. These results suggest that Ad-p53 A4 has the ability to strongly suppress tumor cells and is a promising, novel tool for cancer gene therapy.

Adenoviridae↗

PubMed2006

Protective effects of melatonin against low- and high-LET irradiation.

To investigate the protective effects of melatonin against high-LET ionizing radiation, V79 Chinese hamster cells were irradiated with 100 keV/microm carbon beam. Parallel experiments were performed with 200 kV X-rays. To avoid the impact from extra solvents, melatonin was dissolved directly in culture medium. Cells were cultured in melatonin medium for 1 hr before irradiation. Cell inactivation was measured with conventional colony forming assay, medium containing 6-thioguanine was used for the selection of mutants at hprt locus, and the cell cycle was monitored by flow cytometry. Both carbon beam and X-rays induced cell inactivation, hprt gene mutation and cell cycle G2 block dose-dependently. But carbon beam showed stronger effects as indicated by all three endpoints and the relative biological effectiveness (RBE) was 3.5 for cell killing (at 10% survival level) and 2.9 for mutation induction (at 5 x 10(-5) mutants/cell level). Melatonin showed protective effects against ionizing radiation in a dose-dependent manner. In terms of cell killing, melatonin only increased the survival level of those samples exposed to 8Gy or larger of X-rays or 6 Gy or larger of carbon beam. In the induction of hprt mutation and G2 block, melatonin reduced such effects induced by carbon beam but not by X-rays. The results suggest that melatonin reduces the direct interaction of particles with cells rather than an indirect interaction. Further studies are required to disclose the underlying mechanisms.

Animals↗

PubMed2006

Effects of methamphetamine on cortisone concentration, NK cell activity and mitogen response of T-lymphocytes in female cynomolgus monkeys.

As a model for studying methamphetamine (MAP) abuse, which has become a social problem in Japan, we investigated the changes in serum cortisone, NK cell activity and mitogenic response of T-lymphocytes after a single injection of MAP (3.0 mg/kg) in female cynomolgus monkeys. Serum cortisol concentration was significantly elevated to 2.66 times pre-injection levels at 6 h post-injection, and the effect was still observed 24 h later. NK cell activity was significantly elevated at 6 h after MAP injection, but at 24 h after injection had dropped markedly to 49.5% of baseline. Mitogen (PHA) response of lymphocytes was elevated when MAP was injected, and this increased level continued up to 24 h. We speculate that the transient increase in NK cell activity followed by a distinct drop, as well as the changes in T-lymphocytes, may be strongly related to the cortisone concentration.

Animals↗

PubMed2006

CoCl2-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway.

The exact mechanism behind the effect of hypoxia-inducible factor-1alpha (HIF-1alpha) on the proliferation and/or apoptosis of carcinoma cells is still a matter of debate. We treated a human gastric carcinoma cell line, MKN-1 (mutant P53), with 500 microM CoCl(2). A dual-phase pattern of HIF-1alpha expression with an increase until 4 h followed by a decrease until 36 h was observed. Immunocytochemistry showed that nuclear translocation was maximal at 4 h of treatment, while trypan blue staining showed a dual-phase pattern. Instead of G1/S arrest, FACS showed an increase in the pre-G1 fraction and G(2)/M arrest that correlated with Cyclin-B1, SKP-2 and P27 expression. Starting at 6 h, the apoptotic index increased in a time-dependent manner, in correlation with the expression of HIF-1alpha, Bcl-2, Bcl-xL, Bax and cleaved-Caspase-9. Phosphorylation of Akt was inhibited by CoCl(2) treatment and LY294002 treatment inhibited HIF-1alpha expression in a dose-dependent manner. These results suggested that the alteration of CoCl(2)-induced HIF-1alpha expression correlated with proliferation and apoptosis in MKN-1 cells. A possible role for the PI3K/Akt pathway was indicated in this model of hypoxia.

Antimutagenic Agents↗

PubMed2005

Geranylgeranylacetone protects against acetaminophen-induced hepatotoxicity by inducing heat shock protein 70.

Geranylgeranylacetone (GGA), an anti-ulcer drug, has been reported to induce heat shock protein (HSP) 70 in several animal organs. The present study was performed to determine whether GGA protects mouse liver against acetaminophen (APAP)-induced injury and whether it has potential as a therapeutic agent for APAP overdose. Hepatic damage was induced by single oral administration of APAP (500 mg/kg). GGA at 400 mg/kg was given orally 4 or 8h before, or 0.5h after APAP administration. Treatment of mice with GGA 4h before or 0.5h after APAP administration suppressed increases in transaminase activities and ammonia content in blood as well as hepatic necrosis. Such GGA treatment significantly increased hepatic HSP70 accumulation after APAP administration. Furthermore, GGA inhibited increases in hepatic lipid peroxide content and hepatic myeloperoxidase activity after APAP administration. In contrast, GGA neither inhibited hepatic cytochrome P450 2E1 activity nor suppressed hepatic glutathione depletion after APAP administration. The protective effect of GGA treatment 4h before APAP on hepatotoxicity induced by APAP was completely inhibited with quercetin, known as an HSP inhibitor. In conclusion, GGA has been identified as a new antidote to APAP injury, acting by induction of HSP70. The potential of GGA as a therapeutic tool is strongly supported by its ability to inhibit hepatic injury even when administered after ingestion of APAP.

Acetaminophen↗

PubMed2005

Preoperative chemotherapy and radiation therapy for squamous cell carcinoma of the maxillary sinus.

OBJECTIVE: This study was undertaken to assess the prognostic factors for the management of squamous cell carcinoma (SCC) of the maxillary sinus, who received preoperative chemotherapy and radiation therapy (RT). We also elucidated the appropriate sequence of chemotherapy. METHODS: A total of 124 patients (median age 62 years) with SCC of the maxillary sinus were analysed retrospectively. T3 or T4 disease was found in 93% of the patients. Thirty-nine patients received neoadjuvant chemotherapy (NA), 38 patients received concurrent chemoradiotherapy (CRT) and 47 patients received NA followed by CRT. The median dose of RT was 60 Gy. Maxillectomy was undertaken in 98 patients. RESULTS: The 5 year overall survival (OAS) and local control probability (LCP) were 56.6 and 73.7%, respectively. On univariate analysis, surgery (P < 0.0001) and T classification (P < 0.04) were significant prognostic factors for OAS and LCP. Histological grade and nodal status were also related to OAS. However, any chemotherapy sequence was not associated with the treatment outcome. On multivariate analysis, surgery (P < 0.0005) and T classification (P < 0.05) were identified as significant prognostic factors for LCP and OAS. CONCLUSIONS: This study suggests that both surgery and T stage are important prognostic factors for LCP and OAS in the management of SCC of the maxillary sinus. The appropriate sequence of chemotherapy remains to be elucidated in the future study.

Adult↗

PubMed2005

Toxicities and effects of involved-field irradiation with concurrent cisplatin for unresectable carcinoma of the pancreas.

PURPOSE: To evaluate local effects and acute toxicities of involved field irradiation with concurrent cisplatin (CDDP) for unresectable pancreatic carcinoma. MATERIALS AND METHODS: Thirty-three patients with unresectable pancreatic carcinoma were treated with chemoradiotherapy. Sixteen were Stage IVA; 17 were Stage IVB. The total prescribed dose of radiotherapy was 50 Gy/25 fractions or 50.4 Gy/28 fractions, using a three-dimensionally determined involved-field that included only the primary tumor and clinically enlarged lymph nodes. Twelve patients received a daily i.v. infusion of CDDP; 21 patients received a combination of CDDP and 5-fluorouracil either i.v. or through the proper hepatic artery. RESULTS: Twenty-seven (82%) patients completed planned chemoradiotherapy. Nausea was the most frequent complaint. No patient experienced Grade 4 toxicities. More than half achieved pain relief. As for the primary site, only 4 patients (12%) achieved a partial response at 4 weeks; however, 3 additional patients attained >50% tumor reduction thereafter. The most frequent site of disease progression was the liver, and only 3 patients developed local progression alone. No regional lymph nodal progression outside the treatment field was seen. Median survival time and survival at 1 year were 7.1 months and 27%, respectively, for the entire group. Difference in overall survival between patients with and without distant metastases was significant (p = 0.01). CONCLUSIONS: Involved-field irradiation with concurrent daily CDDP was well tolerated without compromising locoregional effects.

Abdominal Pain↗

PubMed2005

Therapeutic effect of adenoviral-mediated hepatocyte growth factor gene administration on TNBS-induced colitis in mice.

Inflammatory bowel disease is incurable and relapsing disease. In order to clarify the effect of HGF gene therapy for inflammatory bowel disease, the adenoviral-mediated HGF gene was intrarectally administered into TNBS-colitis-induced Balb/c mice. Adenoviral-mediated gene delivery targetted its expression mainly to intestinal epithelial cells. Mucosal damage of HGF-treated intestine was significantly improved, and compared with LacZ-treated and saline administered mice (P<0.05, each). The mice treated with intrarectal administration of pAxCAHGF showed an increased average of body weight in comparison with that of pAxCALacZ-treated and saline-treated mice (P<0.05, each). The PCNA-positive cells in pAxCALacZ-treated mice were 44.7+/-4.9%, 51.7+/-6.6%, and 53.9+/-4.5% at 10, 15, and 21 days after TNBS administration, however those in pAxCAHGF-treated mice were increased to 74.3+/-5.1%, 67.1+/-2.6%, and 69.2+/-4.6% (P<0.05, each). The TUNEL-positive cells in pAxCALacZ-treated mice were 13.3+/-5.2%, 11.5+/-2.1%, and 7.2+/-5.2%, respectively. However, those in pAxCAHGF-treated mice at 10, 15, and 21 days were significantly decreased to 5.4+/-1.8%, 3.8+/-1.3%, and 5.7+/-2.8% (P<0.05, respectively). Expression of ERK1/2 was stronger in pAxCAHGF mice than in pAxCALacZ. These data suggest that adenoviral-mediated HGF gene therapy via an intrarectal route is a promising therapy for inflammatory bowel disease.

Adenoviridae↗

PubMed2005

Proteomic identification of differentially-expressed genes in human gastric carcinomas.

Although genetic alterations in proto-oncogenes, tumor-suppressor genes, cell cycle regulators, and cell growth factors have been implicated in the process of human gastric carcinogenesis, the principle carcinogenic mechanisms are not fully understood. In this study, we used a proteomic approach to search for genes that may be involved in gastric carcinogenesis and that might serve as diagnostic markers. We identified nine proteins with increased expression and 13 proteins with decreased expression in gastric carcinomas. The two most notable groups included proteins involved in mitotic checkpoint (MAD1L1 and EB1) and mitochondrial functions (CLPP, COX5A, and ECH1). This suggested that there are links between dysfunctions in these processes and gastric carcinogenesis. We also observed the differential expression of HSP27 and CYR61 proteins in gastric carcinoma, whose expression is known to be altered in other types of tumors. Furthermore, the study identified proteins whose function in gastric carcinomas was previously unsuspected and that may serve as new molecular markers for gastric carcinomas. Importantly, immunohistochemical analyses confirmed that the levels of expression of MAD1L1, HSP27, and CYR61 were altered in gastric carcinoma tissues. Therefore, our study suggested not only that the proteins identified in this study can be useful diagnostic markers but also that a proteomics-based approach is useful for developing a more complete picture of the pathogenesis and function of gastric carcinomas.

Blotting, Western↗

PubMed2005

Weekly cisplatin administration concurrent with radiation therapy for locoregionally advanced nasopharyngeal carcinoma.

Radiation therapy (RT) with concurrent and adjuvant chemotherapy has been a widely accepted treatment for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We administered 40 mg/m2 cisplatin (CDDP) weekly, concurrently with RT, to six consecutive patients with locoregionally advanced NPC to evaluate its toxicity and efficacy. The median number of courses of CDDP administration was 4.5 and the median radiation dose was 69.7 Gy. Grade 3 leukopenia was observed in three patients. All but one patient experienced grade 3 or 4 skin reactions, pharyngitis, or dysphagia. All but one patient achieved a complete response, and the remaining patient received radical neck dissection for persistent cervical lymphadenopathies, which contained no cancer cells. All six patients were disease-free at last contact, with a median follow up of 23.5 months. This regimen is well tolerated in patients with locoregionally advanced NPC.

Adult↗

PubMed2005

Immunohistochemical analysis of a muscle ankyrin-repeat protein, Arpp, in paraffin-embedded tumors: evaluation of Arpp as a tumor marker for rhabdomyosarcoma.

Arpp, a protein including an ankyrin-repeat, P EST motif, and p roline-rich region, is a recently identified protein that is exclusively expressed in striated muscles. This study comprehensively analyzed its expression among soft tissue sarcomas of various histological types and evaluated its potential use for the differential diagnosis of rhabdomyosarcoma (RMS). Formalin-fixed, paraffin-embedded tissues, including 37 RMS cases, 88 non-RMS sarcomas, and 38 carcinomas, were analyzed for Arpp expression. Arpp was detected in 33 (89.2%) of 37 RMS cases by immunohistochemistry. Western blot analysis revealed expression of Arpp in all RMS cases tested. High expression of Arpp was generally associated with morphological evidence of skeletal muscle differentiation of tumor cells. In contrast, Arpp displayed 6.3% (8/126) positivity among the non-RMS tumors. Focal or weak expression was seen in malignant fibrous histiocytoma (2/27), synovial sarcoma (1/11), Ewing sarcoma (1/5), and epithelioid sarcoma (3/5), whereas one epithelioid sarcoma displayed strong expression for Arpp. A comparative analysis of the Arpp profile with that of myogenic markers in RMS revealed that the sensitivity of Arpp (89.2%) was higher than that of myoglobin (59.6%) and comparable with that of myogenin (88.2%), MyoD (80.6%), muscle-specific actin (83.8%), and desmin (89.2%). These results suggested that Arpp is sensitive to and specific for RMS. Thus, we proposed that Arpp is a novel skeletal muscle-specific marker, which is useful for differential diagnosis of RMS.

Biomarkers, Tumor↗

PubMed2005

Cyclo-oxygenase-1 and -2 expression in human oral mucosa, dysplasias and squamous cell carcinomas and their pathological significance.

Cyclo-oxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostanoids. The expression of its isoforms, COX-1 and -2 is found in many human malignancies. This study analyzed the correlation between COX expression and the pathobiological nature of human oral mucosa, dysplasias and squamous cell carcinomas (SCCs). We examined 9 specimens of normal oral epithelia, 65 lesions with dysplasias and 50 SCCs. Labeling indices (LIs) for COX-1, COX-2, Ki-67 and P53, microvessel density (MVD) and apoptotic index (AI) were evaluated using immunohistochemistry and TUNEL methods. Western blot analysis of COX-1 and -2 was performed on four human oral SCC cell lines, all of which showed expression. The LIs for COX-1 and -2 were higher for the dysplasias than the SCCs. LIs of COX-2 but not COX-1 correlated with the histological grade of dysplasia, being highest for the severe dysplasias (p < 0.05). In contrast, the COX-2 LIs as well as COX-1 were significantly (p < 0.05) inversely correlated with the histological differentiation of the SCCs. COX-2 expression was significantly correlated with LIs of COX-1 for dysplasia (p < 0.05), but not for the SCCs. In addition no significant relationship was noted between COX-2 expression and the Lis of Ki-67, P53, AI as well as MVD for the dysplasias and SCCs. The expression of COX-1 and -2 is correlated with early stage tumorigenesis and cellular differentiation of SCCs in the oral dysplasia-carcinoma sequence.

Apoptosis↗

PubMed2005

Phase I study of daily cisplatin and concurrent radiotherapy in patients with cervical carcinoma.

OBJECTIVE: Chemoradiation based on cisplatin is the standard treatment for locally advanced cervical carcinoma; however, the optimal scheduling and dosing have still not been established. This study was conducted to determine the maximum-tolerated dose (MTD) of cisplatin for daily administration during pelvic radiotherapy (RT). METHODS: Fourteen patients with locally advanced cervical carcinoma and 13 who required postoperative RT were registered. A low dose of cisplatin was given daily concurrently with RT. Cisplatin dosing was started at 6.0 mg/m(2)/day, which was incremented by 0.5 mg/m(2)/day. RT was delivered at 2 Gy/day to a total dose of 50 Gy. The MTD was defined as the dose level immediately below that causing dose-limiting toxicity (DLT) in over one-third of treated patients. RESULTS: Twenty-five patients were treated with a maximum of six escalating dose levels. In 22/25 patients (88%), cisplatin was administered continuously as planned without interruption. The MTD was determined to be 8 mg/m(2) and the DLT was indicated by the onset of neutropenia. CONCLUSION: Daily cisplatin, at 8 mg/m(2)/day, is a well-tolerated radiosensitizer in cervical carcinoma patients.

Adult↗

PubMed2005

Postoperative pelvic radiotherapy for cervical cancer patients with positive parametrial invasion.

OBJECTIVE: To evaluate patterns of failure in cervical cancer patients with histopathologic parametrial invasion treated with postoperative pelvic radiation therapy. METHODS: Records of 117 stages IB-IIB cervical cancer patients with parametrial invasion treated with postoperative radiation therapy from 1985 to 2002 were retrospectively reviewed. Patients were divided into two groups based on status of pelvic lymph nodes. Patterns of recurrence and prognosis by status of pelvic lymph nodes were statistically analyzed. RESULTS: Status of pelvic lymph nodes had significant impact on both recurrence and survival. Extrapelvic recurrence was observed in 23 of 66 node-positive patients compared with 6 of 51 node-negative patients (P = 0.005). Of 66 patients with a positive pelvic lymph node, 18 developed visceral metastases, whereas only three visceral metastases were noted in the 51 node-negative patients (P = 0.003). Five-year overall survival in node-positive and -negative patients was 52% and 89%, respectively (P = 0.0005). Corresponding rates for recurrence-free survival were 44% and 83%, respectively (P = 0.0002). The correlation between nodal metastasis and prognosis was enhanced when node-positive patients were stratified into two groups based on number of positive nodes (n = 1 and n > or = 2). Five-year recurrence-free survival rates for patients with negative, one positive, and two or more positive nodes were 83%, 61%, and 31%, respectively (P = 0.0001). CONCLUSIONS: Extrapelvic recurrence was uncommon in node-negative patients with parametrial invasion. These findings do not support use of systemic therapy for cervical cancer patients with parametrial invasion if pelvic lymph node metastasis is negative.

Adult↗

PubMed2005

COX-2 inhibitor, NS398, enhances Fas-mediated apoptosis via modulation of the PTEN-Akt pathway in human gastric carcinoma cell lines.

A variety of human cancer cells are resistant to Fas ligand and anti-Fas antibody induced apoptosis. Previously, we reported that human gastric carcinoma cell lines were resistant to the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. Cyclooxygenase (COX)-2 is known to be expressed in many human malignancies, and is correlated with tumor progression and resistance to apoptosis. This study examined whether NS398, a COX-2 inhibitor, inhibited cell proliferation and increased Fas-mediated apoptosis in human gastric carcinoma cell lines. Treatment of NS398 inhibited cell proliferation in MKN-45, which expressed the highest level of COX-2 among seven human gastric carcinoma cell lines, in a dose- and time-dependent manner, in contrast to less prominent effects in KATO-III, which expresses no COX-2. Although the treatment of CH-11 induced apoptosis in both cells, the simultaneous treatment of NS398 and CH-11 remarkably induced apoptosis, as confirmed by Hoechst 33258 staining and the terminal deoxynucleotidyl transferase- mediated dUTP-digoxigenin nick-end labeling (TUNEL) method in MKN-45. Flow cytometric analysis also revealed the increased pre-G1 fraction by the simultaneous treatment. The treatment of NS398 induced upregulation of Bad and PTEN, and downregulation of phosphorylated Akt (Thr308). These findings suggest that COX-2 might inhibit Fas-mediated apoptosis in human gastric carcinoma cell lines, especially MKN-45, by modulating PTEN and Akt.

Antibodies↗