Biomedical subjects

Kenji Sugio

Publications and source records attributed to Kenji Sugio.

At least 19 recordsLinked to original sources

PubMed2007

Identification of HLA-A24 restricted shared antigen recognized by autologous cytotoxic T lymphocytes from a patient with large cell carcinoma of the lung.

The aim of the present study was to elucidate the tumor-specific cellular immunological responses occurring in a patient with large cell carcinoma of the lung who had no evidence of recurrence following surgical resections of both a primary lung lesion and a metastatic adrenal lesion. We analyzed an autologous tumor-specific cytotoxic T lymphocytes (CTL clone F2b), which were HLA-A*2402 restricted from regional lymph node lymphocytes. The F2b possessed T cell receptor (TCR) using the Valpha5 and Vbeta7 gene segment. The existence of precursor CTL (pCTL) against autologous tumor cells (A904L) was analyzed using CTL clone-specific PCR. Lymphocytes with the same TCR as F2b were detected in the primary tumor tissue, regional lymph node and the peripheral blood collected from the patient 3 years after the operation. Using the F2b, we identified a cDNA clone encoding the tumor antigen using cDNA expression cloning method. The gene was found to encode splicing variant of the Tara gene. Finally, we identified the 9-mer Ag peptide, using constructions of mini-genes. The F2b recognized 3 out of 7 HLA-A24 positive allogeneic tumor cell lines and in 1 out of 7 HLA-A24 negative allogeneic tumor cell lines when transfected with HLA-A24. This peptide is therefore considered to be potentially useful for performing specific immunotherapy in a significant proportion of lung cancer patients bearing HLA-A24.

Alternative Splicing↗

PubMed2007

Cytochrome P450 expression (CYP) in non-small cell lung cancer.

The cytochrome P450 (CYP) is associated with tumor development and progression as well as activation of anti-cancer prodrugs and their metabolic clearance. In this study, we investigated the expression of aryl-hydrocarbon receptor (AH-R) and four CYPs (CYP1A1, CYP2A6, CYP2E1 and CYP3A) as putative diagnostic markers in 78 non-small cell lung cancers (NSCLC) along with clinical features of the patients. In non-small cell lung cancer, the expression of the five markers was mainly observed in adenocarcinoma but not in the most squamous cell cancers. The expression of them in adenocarcinoma was more frequent in females than in males, suggesting that a higher risk of women for developing lung adenocarcinoma might be associated with the frequent expression of AH-R and the CYPs. These factors were also more frequently expressed in early stage adenocarcinoma and more differentiated adenocarcinoma. Multiple types of CYPs are more frequently expressed in early stage of adenocarcinoma than in advanced stage of adenocarcinoma. There were positive relationships among AH-R, CYP1A1, CYP2E1 and CYP3A expressions in adenocarcinoma, which suggests a metabolite-mediated cross talk in the gene regulation of these markers. However, any of them was unrelated with the expression of CYP2A6, suggesting that the gene regulation of CYP2A6 in adenocarcinoma may be different from the other three CYPs. The expression frequency of CYP1A1 and CYP2E1 in tumors is independent of their genetic polymorphism. The survival of the patients with advanced adenocarcinoma expressing more than one of CYPs was lower rate than the patients with those expressing no CYPs, suggesting that the expression of the CYPs in advanced adenocarcinoma may be associated with poor survival. Our results suggest that AH-R and 4 CYPs may be good markers for the determination of quality of lung cancer. The information could be useful for the better management of lung cancer by molecular targeting therapy and selection of anti-cancer drug based on individual spectrum of the marker proteins. Therefore, the spectrum of CYP proteins in lung cancer could be useful for changing the present "order-made" therapy to the "tailor-made" therapy.

Adenocarcinoma↗

PubMed2006

Resistance to gefitinib.

Subsets of patients with non-small cell lung cancer (NSCLC) who carry somatic mutations in the epidermal growth factor receptor (EGFR) have responded remarkably well to a tyrosine kinase inhibitor (TKI), gefitinib. Despite the dramatic response to this inhibitor, most patients nevertheless ultimately have a relapse. We herein report a case of advanced NSCLC in a patient carrying mutated EGFR (delE746-A750) who had a relapse after dramatic improvement by gefitinib treatment. The DNA sequence of the EGFR gene in a tumor biopsy specimen obtained from the relapse site revealed the presence of a second point mutation, resulting in a threonine-to-methionine amino acid substitution at position 790 of EGFR, which could not be detected in the tumor specimen taken before the treatment. Screening subjects with EGFR mutations therefore allows us to identify patients who can be successfully treated with gefitinib. Such observations should also help us in the search for more effective therapies against a specific subset of NSCLC.

Antineoplastic Agents↗

PubMed2006

Smoking cessation program and CYP2A6 polymorphism.

The relationship between CYP2A6 genotype and smoking status remains unclear although several studies have been reported. In this study, we have investigated the significance of CYP2A6 genotype on smoking habit and treatment of nicotine patch. Sixty-one smokers (1.7%) working in a Japanese company (n = 3585) participated in this smoking cessation program. Forty-four of 61 (72.1%) smokers were treated by nicotine patch. A genotyping analysis was carried out for 41 (40 men and 1 women) of 61 participants (67.2%). The smoking cessation rate at 90 days was 54.1% (33/61). Age and smoking years in re-smoking group are significantly lower than those in smoking cessation group. The smoking cessation rate of participants treated with nicotine patch (63.6%; 28/44) was significantly higher than that of the group non-treated with nicotine patch (29.4%; 5/17) at 90 days (p < 0.05). The incidence of homozygotes of CYP2A6 gene deletion (CYP2A619934/19934) in 41 cases (9.8%; 4/41) could be higher than that in 894 healthy controls (3.7%; 33/894) (p = 0.12), while no other variant alleles (CYP2A619932, CYP2A619933 and CYP2A619936) were found. Age and smoking years of participants with CYP2A619934/19934 are significantly higher than those with CYP2A619931 positive. The scores of Fagerstrom test, an analysis for nicotine-dependence, were slightly different between participants with CYP2A619934/19934 and CYP2A619931 positive. Although treatment of nicotine patch is efficacious to smoking cessation, cases with CYP2A619934/19934 might be more sensitive to nicotine adverse effects and more difficult to quit smoking once they have smoking habit.

Administration, Cutaneous↗

PubMed2006

Immunohistochemical alpha- and beta-catenin and E-cadherin expression and their clinicopathological significance in human lung adenocarcinoma.

The E-cadherin/catenin complex (alpha-catenin, beta-catenin, and E-cadherin) plays a crucial role in cell-cell adhesion and tissue remodeling, and abnormalities in these molecules have been suggested to participate in the proliferation and invasive and metastatic potentials of several human carcinomas. However, in human lung adenocarcinomas, its importance has not yet been sufficiently investigated. We immunohistochemically examined the expressions of E-cadherin/catenin complex in 35 primary lung adenocarinomas, and evaluated their expressions in a semiquantitative manner. Correlations between these expression levels, MIB-1 and nuclear p53 indices, and clinicopathological factors were analyzed by subdividing the cases into high- and low-expression groups for each protein. The reduction in membranous E-cadherin/catenin complex expression correlated significantly with low-grade histological differentiation and with high MIB-1 index. Survival analyses were also performed to clarify which factors potentially affected the prognosis of lung adenocarcinoma patients. The low expression of beta-catenin and the high MIB-1 index had a significantly unfavorable influence on the patients' survival. Moreover, the immunohistochemical expression of beta-catenin by cancer cells and MIB-1 index are considered useful prognostic factors for lung adenocarcinoma.

Adenocarcinoma↗

PubMed2006

The methylation status and protein expression of CDH1, p16(INK4A), and fragile histidine triad in nonsmall cell lung carcinoma: epigenetic silencing, clinical features, and prognostic significance.

BACKGROUND: Aberrant methylation of the promoter CpG island (methylation) is known as a major inactivation mechanism of tumor suppressor and tumor-related genes. In this study, the authors studied the presence of methylation by investigated the inactivation of genes and prognostic factors in patients with nonsmall cell lung carcinoma (NSCLC) by examining resection samples for the presence of methylation. METHODS: Samples were obtained from 224 patients who underwent pulmonary resection for NSCLC. The authors used those samples to study methylation status with methylation-specific polymerase chain reaction analysis and to study protein expression with immunohistochemistry for 3 different genes: CDH1, p16INK4A, and fragile histidine triad (FHIT). RESULTS: The frequency of methylation in NSCLC was determined as 58.0% for CDH1, 21.9% for p16INK4A, and 52.2% for FHIT. The methylation of p16INK4A was observed significantly in heavy smokers compared either with nonsmokers or with patients who had smoked for <20 pack-years (P = .0420); it also was more significant in squamous cell carcinomas than in adenocarcinomas (P = .0343). FHIT methylation also was correlated significantly with lymph node metastasis (P = .0361). Patients who had tumors with both methylation and reduced expression of CDH1 had a significantly poorer prognosis compared with patients who had tumors both without methylation and with positive expression of CDH1 (P = .0259 and P = .0369, respectively; multivariate Cox analysis). For p16INK4A methylation, 63.3% of tumors showed reduced expression; whereas, in p16INK4A-unmethylated tumors, 33.7% showed reduced expression (P = .0002). However, for CDH1 and FHIT, no significant correlation was found for either methylation or reduced expression. CONCLUSIONS: Although protein expression was not inactivated by methylation alone, p16 expression was inactivated strongly by methylation. In addition, the analysis of methylation and expression of CDH1 played a clinically important role in treatment strategies for patients with NSCLC.

Acid Anhydride Hydrolases↗

PubMed2006

Identification of a new cancer/germline gene, KK-LC-1, encoding an antigen recognized by autologous CTL induced on human lung adenocarcinoma.

The purpose of our present study is to identify a tumor-specific antigen capable of inducing a specific cellular immune response in lung cancer patients. We established a lung adenocarcinoma cell line, designated as F1121L, and induced tumor-specific CTL clone H1 from regional lymph node lymphocytes of patient F1121. CTL clone H1 lysed autologous tumor cells in an HLA-B*1507-restricted manner, but not autologous EBV-B, phytohemagglutinin-blast cells, and K562. The CTL clone also recognized allogeneic HLA-B*1501- or 1507-positive lung cancer cell lines in the HLA-restricted manner. Using the CTL clone, we identified an antigen-coding gene by cDNA expression cloning technique. The gene consisted of 556 bp, including an open reading frame consisted of 113 amino acids, designated as Kita-kyushu lung cancer antigen 1 (KK-LC-1). A 9-mer peptide (KK-LC-1(76-84); RQKRILVNL) was identified as an epitope peptide. The genomic DNA of this antigen was located in chromosome Xq22. A reverse transcription-PCR analysis revealed that the mRNA of this gene was only expressed in the testis among normal tissues. It was expressed in 9 of 18 (50%) allogeneic non-small-cell lung cancer cell lines and in 40 of 100 (40%) non-small-cell lung cancer tissues. We thus identified a new tumor antigen-coding gene categorized as a cancer/germline gene by an autologous lung cancer and CTL system. The new cancer/germline gene was located in Xq22, which is apparently different from the locations of previously reported cancer/germline genes.

Adenocarcinoma↗

PubMed2006

A point mutation in the NFYC gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human squamous cell lung carcinoma.

We have identified an antigen recognized by cytolytic T lymphocytes (CTL) on the autologous tumor cells of a nonsmall cell lung cancer patient. The antigenic peptide, presented by HLA-B*5201 molecules, was encoded by a mutated sequence in the gene coding for the C subunit of transcription factor NF-Y. The mutation was present in the tumor sample from which the cell line was derived, and appeared to be unique to the tumor of this patient. In a lymph node draining the tumor, precursors of CTL recognizing the autologous tumor cells were detected at a frequency of about 1/30,000 of the CD8 cells, and 85% of them recognized the mutated NF-YC peptide, suggesting that the patient mounted a T cell response against this antigen. These results strengthened the notion that unique tumor-specific antigens are highly represented not only in melanoma but also in other types of tumors, like nonsmall cell lung cancer.

Antigens, Neoplasm↗

PubMed2005

Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in Japanese.

The protein-kinase family is the most frequently mutated gene family found in human cancer. Gefitinib, an ATP-competitive inhibitor of epidermal growth factor receptor (EGFR), also appears to be particularly effective in adenocarcinoma of the lung and in patients without smoking history. To determine whether lung tumors sensitive to gefitinib contained mutations within the tyrosine kinase (TK) domain of EGFR, we screened exons 18-23 of EGFR of tumors in 20 patients with non-small cell lung cancer (NSCLC) who had been treated with gefitinib. Nine (45%) tumors had TK domain mutations. All mutations were observed in adenocarcinoma. Seven (77.8%) of 9 cases with mutated types showed sensitivity to gefitinib, while no cases of 11 with wild type showed gefitinib sensitivity. Such mutations were more frequently observed in patients who had never smoked (5/8 or 62.5%) than in smokers (4/12 or 33.3%). The patients with mutations of EGFR to have a more favorable prognosis than those with wild type (p=0.033). These data show that adenocarcinomas from patients who had never smoked comprise a specific subset of patients with NSCLC sensitive to gefitinib treatment.

Adult↗

PubMed2005

Expression of aldehyde dehydrogenase 2 in the normal esophageal epithelium and alcohol consumption in patients with esophageal cancer.

Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.

Alcohol Drinking↗

PubMed2005

Identification of the HLA-Cw*0702-restricted tumor-associated antigen recognized by a CTL clone from a lung cancer patient.

PURPOSE: A large number of tumor-associated antigens have been used in vaccination trials for mainly melanomas. Our purpose of this study is to identify a novel tumor antigen useful for immunotherapy of lung cancer patients. EXPERIMENTAL DESIGN: Analysis of an autologous tumor-specific CTL clone F2a that was established from regional lymph node lymphocytes of a patient with lung cancer (A904) by a mixed lymphocyte-tumor cell culture. RESULTS: F2a recognized and killed autologous tumor cells (A904L), whereas it did not respond to autologous EBV-transformed B cells, phytohemagglutinin-blastoid T cells, and K562 cells. cDNA clone 31.2 was isolated by using cDNA expression cloning method as a gene encoding antigen. This gene was identical to the reported gene whose function was unknown. The antigen encoded by the cDNA was recognized by the CTL in a HLA-Cw*0702-restricted manner. Furthermore, a 9-mer peptide at positions 659 to 685 in cDNA clone 31.2 was identified as a novel epitope peptide. The CTL recognized some allogeneic cancer cell lines with HLA-Cw*0702 as well as some HLA-Cw*0702-negative cell lines when transfected with HLA-Cw*0702, thus indicating that the identified antigen was a cross-reactive antigen. CONCLUSIONS: Although exact mechanism to process the encoded protein and present the antigen in the context of HLA class I remains to be elucidated, the CTL recognized some of tumor cells in the context of HLA-Cw*0702 but did not recognize a variety of normal cells and also autologous EBV-transformed B cells. These results indicated that the antigen identified in this study may therefore be a possible target of tumor-specific immunotherapy for lung cancer patients.

Antigen Presentation↗

PubMed2005

Haplotype loss of HLA class I antigen as an escape mechanism from immune attack in lung cancer.

One of tumor escape mechanisms from the host's immunosurveillance system (i.e., a haplotype loss of HLA class I antigens) has been detected in various tumor cells. We hypothesize that the majority of tumor cells with normal HLA class I expression were attacked and eradicated by CTLs, and only a minority with an abnormal expression of HLA class I antigens could escape the host's immunosurveillance system. Using HLA class I-transfected tumor variants as stimulators in A904L lung cancer cell line, which has a haplotype loss of HLA class I antigens, both the transfected HLA-A26 and HLA-B39-restricted CTL lines were induced from autologous lymphocytes. However, only one HLA-B39-restricted CTL clone (CTL G3b) was established, and it was then used to identify the antigen. SGT1B [suppressor of G2 allele of SKP1 (SGT1), suppressor of kinetochore protein (SKP1)] was identified as the antigen recognized by CTL G3b. Further experiments using 13 subclones from a primary culture of A904L were found to confirm our above-mentioned hypothesis. Tumor cells with a normal HLA class I expression may thus be killed by CTL at an early stage of carcinogenesis, and only tumor cells with a haplotype loss of HLA class I antigens can escape an immune attack and develop into clinical cancer.

Amino Acid Sequence↗

PubMed2005

Immunohistochemical evaluation of cytochrome P450 (CYP) and p53 in breast cancer.

In breast cancer, cytochrome P450 (CYP) metabolizes both endogenous substrates (i.e. estradiol) and exogenous substrates (i.e. anticancer drugs), which is associated not only with tumor development and progression but also with efficacy of cancer treatment. Therefore, we examined the expression of CYPs (CYP2A6, CYP1B1 and CYP3A) and p53 in specimens from 34 Japanese patients with breast cancer by immunohistochemistry. The expression of CYP3A was not detected in the 34 cases. CYP2A6 was detected only in one specimen (2.9%). Twenty-eight specimens (82.4%) showed positive signals for CYP1B1 expression. Eight of 34 (23.5%) were positive for p53 expression. Positive rate of CYP1B1 in stage I disease (100%) was statistically higher than that in stage II - IV disease (70.0%). Positive rate of p53 was 21.4% (6/28) in CYP1B1-positive cases and 33.3% (2/6) in CYP1B1-negative cases. There was no significant relationship between CYP1B1 expression and p53 expression. In conclusion, the expression of CYP3A in breast cancer may be less frequent in Japanese population although the expression of CYP3A has been reported in 20% of breast cancer in Caucasian, suggesting that the CYP3A expression in breast cancer may be dependent on ethnic groups. Since CYP3A is involved in the conversion of tamoxifen to its metabolites, the variation of the CYP3A expression in breast cancer tissues among ethnic groups might cause differences in the efficacy of tamoxifen.

Adult↗

PubMed2005

A different pattern of cytotoxic T lymphocyte recognition against primary and metastatic tumor cells in a patient with nonsmall cell lung carcinoma.

BACKGROUND: Lung carcinoma represents the most frequent cause of cancer death worldwide because of tumor metastases. The objective of the current study was to analyze the immunologic response during the progress of lung carcinoma metastasis. METHODS: The authors established two tumor cell lines that were derived from primary and metastatic lesions in a patient with lung carcinoma (Patient G603). One cell line (G603L) was established from the primary lesion, and the other cell line (G603AD) was established from a metastatic lesion in the right adrenal gland 7 months after the patient underwent surgery for the primary lesion. Autologous regional lymph node lymphocytes were stimulated with CD80-transfected G603L cells, then cytotoxic T lymphocytes (CTLs) were induced against both lung carcinoma cell lines. RESULTS: Both G603L cells and G603AD cells expressed Class I human leukocyte antigen, intracellular cell adhesion molecule 1, and lymphocyte-associated antigen type 3 (LFA-3), but not Fas or Fas ligand on their surfaces. By stimulation with CD80-transfected G603L cells, 2 CTL clones (H2/17 and H2/36) were established from the bulk CTLs. CTL clone H2/17 lysed G603L cells but not G603AD cells, suggesting that the antigen recognized by CTL clone H2/17 was abrogated during the process of metastasis. In contrast, CTL clone H2/36 lysed both G603L cells and G603AD cells, indicating that the antigen recognized by CTL clone H2/36 was maintained in the tumor cells throughout tumor progression. CONCLUSIONS: The results demonstrated the possibility that some tumor-associated antigens may be abrogated during the process of metastasis, although others are maintained. The identification of these antigens will lead to a better understanding of their immunologic role during disease progression in patients with lung carcinoma.

Aged↗

PubMed2005

Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism.

In alcohol metabolism, acetaldehyde, a highly reactive intermediate that may cause cellular and DNA damages, is converted to acetate by mitochondrial aldehyde dehydrogenase ALDH2. Although the majority of ingested alcohol is eliminated in the liver, the first-pass metabolism of ethanol in the upper digestive tract is also important for prevention and management of ethanol-related gastrointestinal diseases. However, the tissue-distribution of Aldh2 in mice has been poorly investigated. In this study, therefore, we investigated the tissue-distribution of Aldh2 as well as Aldh1, Cyp1a1, Cyp2e1, and Cyp4b1 in wild type and Aldh2-null mice by immuno-histochemical analysis. The human liver and esophageal tissues were also examined. In mice, the Aldh2 protein was detected in the liver, lung, heart, kidney, testis, esophagus, stomach, colon, and pancreas, suggesting that the tissue-distribution of Aldh2 in mice is similar to that in humans. Therefore, Aldh2-null mice may be useful model animals for the investigation of alcohol metabolism and related diseases. Compared with the wild type, the expression level of Cyp2e1 was increased in the liver from Aldh2-null mice based on Western blot analysis, whereas the levels of Aldh1, Cyp1a1, and Cyp4b1 were indistinguishable. This observation suggests that a metabolite(s) of Aldh2 might down-regulate the expression of Cyp2e1 gene.

Alcohols↗

PubMed2005

Iris metastasis of esophageal cancer.

Ocular metastasis in patients with esophageal cancer is quite rare. Several cases have been reported in the literature, but no successful treatments for such metastases have ever been described. We herein report a case of esophageal cancer in which the ocular metastasis was controlled by systemic chemotherapy.

Carcinoma, Squamous Cell↗

PubMed2005

Primary pulmonary collision cancer consisting of large cell carcinoma and adenocarcinoma.

A case of pulmonary collision tumor is herein reported. An abnormal shadow was discovered in the right lung of a 53-year-old man. A right upper lobectomy with a mediastinal lymph node dissection was performed. Based on the findings of a postoperative pathologic examination, this tumor was considered to be a collision tumor of large cell carcinoma and adenocarcinoma, as the distribution of each tumor was clearly separated. This case is the first report of a primary pulmonary collision tumor consisting of large cell carcinoma and adenocarcinoma.

Adenocarcinoma↗

PubMed2005

Tracheobronchopathia osteochondroplastica occurring in a subsegmental bronchus and causing obstructive pneumonia.

A 59-year-old man was referred to the University of Occupational and Environmental Health hospital because a chest roentgenogram obtained at an annual medical examination showed an abnormal shadow. We treated the patient for tracheobronchopathia osteochondroplastica, which caused segmental obstructive pneumonia that proved to be difficult to accurately diagnose before surgery.

Humans↗