Japanese Journal Of Cancer Research[JOURNAL]
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200 papers
Insulin-like growth factor (IGF)-I, IGF-binding protein-3 and colorectal adenomas in Japanese men.
Teramukai S, Rohan T, Lee KY … +3 more , Eguchi H, Oda T, Kono S
Jpn J Cancer Res · 2002 Nov · PMID 12460458 · Full text
Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage...
Several epidemiological studies have found that high levels of plasma insulin-like growth factor (IGF)-I and low levels of IGF-binding protein (IGFBP)-3 are related to an increased risk of colorectal cancer or late-stage adenomas. We examined the relation of body mass index, fasting and 2-h postload plasma glucose levels and plasma concentrations of IGF-I and IGFBP-3 to colorectal adenomas in middle-aged Japanese men. The study subjects comprised 157 cases of histologically diagnosed colorectal adenomas and 311 controls with normal colonoscopy or non-polyp benign lesions in a consecutive series of 803 men receiving a preretirement health examination at two hospitals of the Self Defense Forces (SDF). After adjustment for rank in the SDF, hospital, smoking and IGFBP-3, a statistically nonsignificant modest increase in the prevalence odds of colorectal adenomas was observed for the highest versus the lowest quartile level of IGF-I. The increase was slightly greater with further adjustment for 2-h glucose concentrations (adjusted odds ratio 1.8, 95% confidence interval 1.0-4.5, trend P=0.06). Men with high levels of IGFBP-3 showed only a minimal decrease in risk after adjustment for IGF-I. The association with IGF-I was less evident for advanced adenomas (>5 mm in size or tubulovillous/villous). Fasting and 2-h glucose and body mass index were more strongly positively associated with colorectal adenomas than IGF-I, especially with advanced adenomas, independently of IGF-I and IGFBP-3. The findings suggest that plasma IGF-I and IGFBP-3 may be involved in colorectal tumorigenesis regardless of the stage in growth of adenoma, but not as a mediator for the effects of being overweight or of hyperglycemia.
Identification of the CAB2/hCOS16 gene required for the repair of DNA double-strand breaks on a core amplified region of the 17q12 locus in breast and gastric cancers.
Nezu M, Nishigaki M, Ishizuka T … +8 more , Kuwahara Y, Tanabe C, Aoyagi K, Sakamoto H, Saito Y, Yoshida T, Sasaki H, Terada M
Jpn J Cancer Res · 2002 Nov · PMID 12460457 · Full text
We previously reported that CAB1 and c-ERBB-2 genes were found to be located in a core amplified region of the 17q12 locus, which is frequently amplified in various cancers. During identification of this core region, CAB...
We previously reported that CAB1 and c-ERBB-2 genes were found to be located in a core amplified region of the 17q12 locus, which is frequently amplified in various cancers. During identification of this core region, CAB2, a human homologue of the yeast COS16 required for the repair of DNA double-strand breaks was cloned. Autofluorescence analysis of cells transfected with its GFP fusion protein demonstrated that CAB2 translocates into vesicles, suggesting that overexpression of CAB2 may decrease intercellular Mn2+ by accumulating it in the vesicles, in the same way as yeast COS16. This is the first report identifying all of the genes on the core amplified region of the 17q12 locus in breast and gastric cancers.
Suppression of lung metastasis by aspirin but not indomethacin in an in vivo model of chemically induced hepatocellular carcinoma.
Futakuchi M, Ogawa K, Sano M … +3 more , Tamano S, Takeshita F, Shirai T
Jpn J Cancer Res · 2002 Oct · PMID 12417048 · Full text
To examine the effect of non-steroidal anti-inflammatory drugs on metastasis formation, aspirin (ASP, 0.5% in diet) and indomethacin (IM, 0.005% in drinking water) were applied to an in vivo highly metastatic rat hepatoc...
To examine the effect of non-steroidal anti-inflammatory drugs on metastasis formation, aspirin (ASP, 0.5% in diet) and indomethacin (IM, 0.005% in drinking water) were applied to an in vivo highly metastatic rat hepatocellular carcinoma (HCC) model in F344 male rats. Administration for 8 weeks after induction of highly metastatic HCC by sequential treatment with diethylnitrosamine and N-nitrosomorpholine did not cause any significant change in survival rate or body weight. Multiplicity of HCC in the liver increased during ASP or IM treatment without any significant histological alteration. Although absent in the rats killed at the end of the period of carcinogen exposure, lung metastasis at the end of the experiment was found in 100%, 89% and 100% of rats in the control, ASP and IM groups, respectively. Degree of metastasis was classified into three groups according to the number of metastatic nodules, i.e., slight (1 - 5 nodules), moderate (6 - 50) and severe (more than 51), which amounted to 0%, 43% and 57% in the control group. ASP significantly reduced the degree of metastasis, the incidences being 33%, 44%, and 11%, respectively, whereas IM was without significant influence. Both agents suppressed cell proliferation in HCCs, without any alteration of pan-cadherin expression. However, expression in HCC of mRNAs for intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, both of which are considered to play key roles in attachment of cancer cells to the endothelium, was significantly suppressed by ASP. Thus, the present study demonstrated that ASP, but not IM, has the potential to inhibit lung metastasis of rat HCC in vivo, possibly via reduced attachment of tumor cells to the vascular endothelium. Moreover, these data indicate this in vivo model for induction of rat highly metastatic HCC to be a useful tool for the assessment of the efficacy of therapeutic treatments to block metastasis formation.
Phosphorylation of Fas-associated death domain contributes to enhancement of etoposide-induced apoptosis in prostate cancer cells.
Shimada K, Nakamura M, Ishida E … +3 more , Kishi M, Yonehara S, Konishi N
Jpn J Cancer Res · 2002 Oct · PMID 12417047 · Full text
Fas-associated death domain (FADD) plays an important role as an adapter molecule in Fas (CD95/APO-1)-mediated apoptosis and contributes to anticancer drug-induced cytotoxicity. We treated three human prostate cancer cel...
Fas-associated death domain (FADD) plays an important role as an adapter molecule in Fas (CD95/APO-1)-mediated apoptosis and contributes to anticancer drug-induced cytotoxicity. We treated three human prostate cancer cell lines with etoposide, a toposiomerase II inhibitor with activity against various tumors including prostate cancer. We found that the overexpression of FADD sensitizes etoposide-induced apoptosis through a rapid activation of c-Jun NH(2)-terminal kinase (JNK) and, subsequently, of caspase 3. In addition, phosphorylation of FADD at serine 194 coincided with this sensitization. Treatment with the caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), or overexpression of either mitogen-activated protein kinase kinase (MKK) 7 or Bcl-xL canceled FADD-mediated sensitization to etoposide-induced apoptosis. Moreover, treatment with the caspase 8 inhibitor, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (z-IETD-fmk), or overexpression of viral FLICE/caspase-8-inhibitory protein (FLIP) from equine herpesvirus type 2 E8 also had an inhibitory effect, supporting a major involvement of a caspase 8-dependent mitochondrial pathway. Interestingly, FADD was phosphorylated, and etoposide-induced JNK/caspase activation and apoptosis were enhanced in the cells arrested at G2/M transition, but not in those overexpressing mutant FADD, in which 194 serine was replaced by alanine. Our results demonstrate that phosphorylated FADD-dependent activation of the JNK/caspase pathway plays a pivotal role in sensitization to etoposide-induced apoptosis in prostate cancer cells.
Development of gene therapy using prostate-specific membrane antigen promoter/enhancer with Cre Recombinase/LoxP system for prostate cancer cells under androgen ablation condition.
Ikegami S, Tadakuma T, Suzuki S … +3 more , Yoshimura I, Asano T, Hayakawa M
Jpn J Cancer Res · 2002 Oct · PMID 12417046 · Full text
To enhance the efficacy of suicide gene therapy for prostate cancer under androgen deprivation, we designed a promoter system that consists of the prostate-specific membrane antigen (PSMA) promoter / enhancer (PEPM) and...
To enhance the efficacy of suicide gene therapy for prostate cancer under androgen deprivation, we designed a promoter system that consists of the prostate-specific membrane antigen (PSMA) promoter / enhancer (PEPM) and Cre-loxP DNA recombination system. We constructed two kinds of plasmids. One plasmid contains a Cre recombinase (Cre) under the control of PEPM and the other expresses CMV-lox-luciferase / herpes simplex virus thymidine kinase (TK). In PSMA-positive LNCaP cells, the promoter activity of the PEPM-Cre plus CMV-lox-luciferase demonstrated 800-fold greater activity compared with that of the PSMA promoter alone. However, no enhancement of the promoter activity was observed in the PSMA-negative cells. Furthermore, in contrast to prostate specific antigen promoter / enhancer (PP), the promoter activity of PEPM did not decrease when the LNCaP cells were cultured in charcoal-stripped fetal bovine serum (CFBS). In an in vitro gene therapy model with LNCaP cells, the cell growth inhibition in the presence of ganciclovir (GCV) was more evident in the cells transfected with the PEPM-Cre plus CMV-lox-TK than in the cells with the PP-TK, and the difference in efficacy between the two plasmids was more remarkable when the cells were maintained in CFBS medium. The therapeutic effect of PEPM-Cre plus CMV-lox-TK was also observed in xenografted LNCaP cells on nude mice when the plasmids were directly injected into tumors and GCV was administered intraperitoneally. These findings indicate that the combination of the PSMA promoter / enhancer and the Cre-loxP system can enhance the PSMA promoter activity even under androgen ablation conditions and can exert its anti-tumor effect both in vitro and in vivo.
Pharmaceutical and biomedical differences between micellar doxorubicin (NK911) and liposomal doxorubicin (Doxil).
Tsukioka Y, Matsumura Y, Hamaguchi T … +3 more , Koike H, Moriyasu F, Kakizoe T
Jpn J Cancer Res · 2002 Oct · PMID 12417045 · Full text
The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposo...
The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of DXR inside micelles or liposomes in an aqueous solution is known to be strongly quenched by the outer shells of the micellar or liposomal formation. Thus, by measuring the fluorescence intensity of DXR released from NK911 or Doxil, we could determine the stability of the micellar or liposomal DXR formation. Furthermore, NK911 was found to be less stable than Doxil in saline solution. In drug distribution experiments using an in vitro solid tumor model, when spheroids formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the spheroids, including their center. On the other hand, when the spheroids were exposed to Doxil, DXR was distributed only to the surface of the spheroids. It has been suggested that Doxil can deliver DXR to a solid tumor more efficiently than NK911 via the EPR (enhanced permeability and retention) effect, because Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in NK911 may be distributed by diffusion to cancer cells distant from the tumor vessel, because NK911 can leak out of the tumor vessel and may be able to release free DXR more easily than Doxil. It has been suggested that drug carrier systems such as liposomes and micelles should be selected appropriately bearing in mind the characteristics of the tumor vasculature and the tumor interstitium.
The intraductal carcinoma component is a significant prognostic parameter in patients with invasive ductal carcinoma of the pancreas.
Kawahira H, Hasebe T, Kinoshita T … +8 more , Sasaki S, Konishi M, Nakagori T, Inoue K, Oda T, Takahashi S, Ochiai T, Ochiai A
Jpn J Cancer Res · 2002 Oct · PMID 12417044 · Full text
We have sometimes encountered invasive ductal carcinomas (IDCs) of the pancreas containing intraductal carcinoma components in the intra- and / or extra-tumor area. The purpose of this study was to investigate whether in...
We have sometimes encountered invasive ductal carcinomas (IDCs) of the pancreas containing intraductal carcinoma components in the intra- and / or extra-tumor area. The purpose of this study was to investigate whether intraductal carcinoma components would be useful for predicting the outcome of IDC patients. Forty-seven surgically treated IDCs were examined, and all histological tumor sections were stained with Elastica to accurately confirm intraductal carcinoma components. Well-known clinicopathological parameters that exhibited a significant correlation in the univariate analyses for predicting disease-free survival (DFS) and overall survival (OS) were entered into the Cox proportional hazard multivariate analysis. Since the lowest P-value predicting DFS or OS periods was observed in IDCs with more than 10% intraductal carcinoma components and those with 10% or less intraductal carcinoma components (P = 0.028 and P = 0.019), we established the cutoff value of intraductal carcinoma components at 10%. In the multivariate analyses for DFS and OS, the presence of more than 10% intraductal carcinoma components showed a marginally significant increase in the hazard rate (HR) of tumor recurrence (P = 0.067) and significantly increased the HR of mortality (P = 0.040). The present study demonstrated that IDCs with more than 10% intraductal carcinoma components were associated with a significantly better patient outcome than those with 10% or less intraductal carcinoma components.
Expression of glycolipids bearing Lewis phenotypes in tissues and cultured cells of human gynecological cancers.
Takehara K, Kubushiro K, Kiguchi K … +4 more , Ishiwata I, Tsukazaki K, Nozawa S, Iwamori M
Jpn J Cancer Res · 2002 Oct · PMID 12417043 · Full text
Transformation-associated expression of Le(b) (Lewis antigen-b) or Le(Y) in human colorectal carcinomas has been well described. To examine the expression of glycosphingolipids (GSLs) bearing Lewis-phenotypes in human gy...
Transformation-associated expression of Le(b) (Lewis antigen-b) or Le(Y) in human colorectal carcinomas has been well described. To examine the expression of glycosphingolipids (GSLs) bearing Lewis-phenotypes in human gynecological carcinoma-derived cells, we determined the concentrations of all GSLs. Although neither Le(b) nor Le(Y) was present in HEC-108 cells established from the poorly differentiated type of endometrial adenocarcinoma, other cell lines from moderately or well-differentiated types expressed either Le(b) or Le(Y), or both, at concentrations of 0.01 to 0.03 microg per mg of dry cells, which comprised 0.3 to 1.3% of the total GSLs. In the cervical and ovarian carcinoma-derived cell lines, Lewis phenotypes tended to be carried by nLc(4)Cer, which was accumulated in the cells without sialylation or fucosylation. These results indicated that expression of Le(b)- or Le(Y)-phenotypes was strongly dependent on the metabolic ability to supply the precursor GSLs. Both Le(b) and Le(Y) were successfully detected by monoclonal antibody MSN-1, which was a useful probe for the simultaneous detection of Le(b) and Le(Y). On application of MSN-1, either Le(b) or Le(Y) was detected in tissues from patients with well- and moderately differentiated types of endometrial adenocarcinoma at concentrations of 0.01 to 0.04 microg per mg of dry tissues, but not in the tissues of poorly differentiated type. Normal endometria at the follicular and luteal phases also contained the antigens, but the concentrations and the frequency of antigen expression were lower than those in the well- and moderately differentiated types of endometrial adenocarcinoma.
Clinical significance of glucose transporter 1 (GLUT1) expression in human breast carcinoma.
Kang SS, Chun YK, Hur MH … +6 more , Lee HK, Kim YJ, Hong SR, Lee JH, Lee SG, Park YK
Jpn J Cancer Res · 2002 Oct · PMID 12417042 · Full text
Glucose uptake and glycolytic metabolism are enhanced in cancer cells compared to normal cells and tissues. Increased expression of glucose transporter 1 (GLUT1) has been reported in human malignant cells. The aim of thi...
Glucose uptake and glycolytic metabolism are enhanced in cancer cells compared to normal cells and tissues. Increased expression of glucose transporter 1 (GLUT1) has been reported in human malignant cells. The aim of this study is to determine the expression of the facilitative glucose transporter protein GLUT1 in human breast carcinomas and a possible correlation between GLUT1 expression and clinical outcome including disease-free or overall survival. One hundred consecutive formalin-fixed, paraffin-embedded sections of invasive breast carcinomas were evaluated by means of immunohistochemical staining of GLUT1. Forty-seven (47%) of 100 breast carcinomas showed positive staining for GLUT1. Expression of GLUT1 correlated significantly with nuclear grade (P < 0.001), estrogen receptor status (P = 0.002), and progesterone receptor status (P = 0.001). The mean disease-free survival periods of GLUT1-positive and -negative patients were 47 +/- 2.4 months and 54.3 +/- 1.3 months, respectively (P = 0.017). The mean overall survival periods of GLUT1-positive and -negative patients were 48.7 +/- 2.2 and 56.1+/- 1.3 months, respectively (P = 0.043). In the multivariate analysis, disease-free survival correlated significantly with GLUT1, tumor size, and lymph node involvement (P = 0.043, P = 0.014, and P = 0.045, respectively). In analysis of overall survival, however, lymph node involvement, tumor size, and nuclear grade were statistically significant (P = 0.024, P = 0.023, and P = 0.003, respectively). Our data suggest that absence of GLUT1 expression significantly increases disease-free survival. These findings demonstrate that GLUT1 expression in breast carcinoma can be a marker of aggressive biological behavior and identifies a worse prognosis in breast carcinoma patients.
Differentially regulated genes as putative targets of amplifications at 20q in ovarian cancers.
Watanabe T, Imoto I, Katahira T … +6 more , Hirasawa A, Ishiwata I, Emi M, Takayama M, Sato A, Inazawa J
Jpn J Cancer Res · 2002 Oct · PMID 12417041 · Full text
Frequent amplification of DNA at 20q or part of 20q has been demonstrated by comparative genomic hybridization in ovarian cancer (OC), but the genetic target(s) of these amplification events remain unknown. We examined c...
Frequent amplification of DNA at 20q or part of 20q has been demonstrated by comparative genomic hybridization in ovarian cancer (OC), but the genetic target(s) of these amplification events remain unknown. We examined copy-number changes with respect to six candidate genes, E2F1 (20q11.2), TGIF2 (20q11.2), AIB1 (20q12), PTPN1 (20q13.1), ZNF217 (20q13.2), and BTAK (20q13), and then measured transcription levels of each candidate in 18 OC cell lines. Three distinct cores of amplification were identified: 20q11.2, harboring E2F1 and TGIF2 (region I; 1 of 18 cell lines, 5.6%); 20q13.1, harboring PTPN1 (region II; 5 lines, 27.8%); and 20q13.2, harboring ZNF217 and BTAK (region III; 6 lines, 33.3%). Among the six genes examined, expression levels of PTPN1 and ZNF217 were significantly correlated with absolute copy-number, and those of PTPN1 and TGIF2 were significantly correlated with copy-number relative to the centromere of chromosome 20 (20cen). Among 19 primary OCs examined, moreover, we observed amplification of TGIF2, PTPN1 and ZNF217 in five (26.3%), ten (52.6%), and twelve (63.2%) tumors, respectively. Expression levels of PTPN1 and ZNF217 were significantly correlated with their copy-numbers in those primary OCs. Our results suggest that 20q amplifications in OCs can be extensive and complex, probably due to synergistic or non-synergistic amplification of separate regions of 20q, involving multiple, independently amplified targets.
Frequent epigenetic silencing of the p16 gene in non-small cell lung cancers of tobacco smokers.
Yanagawa N, Tamura G, Oizumi H … +3 more , Takahashi N, Shimazaki Y, Motoyama T
Jpn J Cancer Res · 2002 Oct · PMID 12417040 · Full text
Epidemiological studies have demonstrated a causal link between tobacco smoking and lung cancer. We investigated the association between inactivation of the p16 gene and tobacco smoking in 51 non-small cell lung cancers...
Epidemiological studies have demonstrated a causal link between tobacco smoking and lung cancer. We investigated the association between inactivation of the p16 gene and tobacco smoking in 51 non-small cell lung cancers (NSCLCs). Aberrations of the p16 gene were studied by PCR single-strand conformation polymorphism analysis, followed by direct sequencing, microsatellite analysis, methylation-specific PCR, and immunohistochemistry. Mutations were detected in 3.9% (2/51) of the tumors; the tumors carrying mutations were from smokers. The incidences of loss of heterozygosity, homozygous deletion, and promoter methylation in 37 smokers vs. 14 non-smokers were; 45.9% vs. 28.6%, 16.2% vs. 7.1%, and 35.1% vs. 7.1%, respectively. Among these, only the association between promoter methylation and tobacco smoking was statistically significant (P < 0.05). Therefore, epigenetic aberration is considered to be a major causative event in p16 silencing by tobacco smoking. Loss of p16 protein expression was apparent in 49% (25/51) of the tumors, and was associated with tobacco smoking (P < 0.05) and with histological type (P < 0.05). These findings suggest that tobacco smoking leads to inactivation of the p16 gene mainly through the epigenetic mechanism, ultimately increasing the risk of NSCLC, especially the squamous cell histological type.
Cloning of the 5' upstream region of the rat p16 gene and its role in silencing.
Abe M, Okochi E, Kuramoto T … +4 more , Kaneda A, Takato T, Sugimura T, Ushijima T
Jpn J Cancer Res · 2002 Oct · PMID 12417039 · Full text
Hypermethylation of the 5' upstream region (5' region) of the human p16(CDKN2A) (p16) gene is known to cause silencing, which is involved in a wide range of human cancers. For the rat p16 gene, its 5' region has not been...
Hypermethylation of the 5' upstream region (5' region) of the human p16(CDKN2A) (p16) gene is known to cause silencing, which is involved in a wide range of human cancers. For the rat p16 gene, its 5' region has not been cloned, and it is uncertain whether surrogate use of exon 1 alpha is adequate for analysis of p16 silencing. In this study, we observed that methylation analysis of exon 1 alpha gave false positive results in three samples of normal rat mammary epithelia and in two of six primary mammary carcinomas. Therefore, we determined the nucleotide sequence of the 5' region of the rat p16 gene. To confirm that methylation status of the 5' region is correlated with p16 expression, the methylation status was analyzed by bisulfite sequencing and methylation-specific PCR in three samples of normal mammary glands, six samples of mammary carcinomas and four cell lines. The 5' region was demethylated in all of the three normal and six carcinoma samples that fully expressed p16. On the other hand, the 5' region was highly methylated in the 3Y1 cell line, which lacked p16 expression, but without deletion. These results showed that the methylation status of the 5' region was more closely correlated with p16 expression than that of the exon 1 alpha and analysis of the methylation status is useful in examining p16 silencing in various rat tumors.
Enhanced expression of type IV collagen-binding protein (p29) in Fyn-transfected murine fibrosarcoma cells.
Koike K, Kogawa K, Takayama T … +5 more , Yoshizaki N, Muramatsu H, Nakamura K, Sakamaki S, Niitsu Y
Jpn J Cancer Res · 2002 Oct · PMID 12417038 · Full text
We investigated the mechanism of the enhancement of metastatic potential induced by transfection of the fyn gene, a member of the src family. We employed two murine fyn cDNA-transfected clones, ML-SN1 and ML-SN2, which w...
We investigated the mechanism of the enhancement of metastatic potential induced by transfection of the fyn gene, a member of the src family. We employed two murine fyn cDNA-transfected clones, ML-SN1 and ML-SN2, which were previously established from an ML-01 low-metastatic clone of Meth A sarcoma of BALB / c mice and were proven to have higher metastatic ability than ML-01 and the mock-transfected clone ML-MT-neo (Takayama et al., 1993). Our present investigation revealed that the two transfectants showed higher metastatic ability and higher rates of adherence to type IV collagen than ML-MT-neo. However, no difference was found in in vitro or in vivo growth rates, attachment to laminin or endothelial cells or cell motility through a reconstituted basement membrane. Analysis of surface membrane proteins labeled with (125)I on SDS-PAGE showed that a 29 kD band specifically bound to type IV collagen-coupled beads was more intense in ML-SN2 than in ML-MT-neo. Genistein, a protein tyrosine kinase inhibitor, dramatically reduced protein tyrosine kinase (PTK) activity of ML-SN2 in a dose-dependent fashion, corresponding to the reduction of adhesiveness to type IV collagen. The expression of the type IV collagen-binding protein (p29) of ML-SN2 was also reduced significantly by genistein treatment. These results suggested that the fyn product in Meth A cells augments the expression of a type IV collagen-binding protein through elevation of the PTK activity of the membrane fraction and thus facilitates the metastasis of Meth A.
Synergistic promoting effects of Helicobacter pylori infection and high-salt diet on gastric carcinogenesis in Mongolian gerbils.
Nozaki K, Shimizu N, Inada K … +7 more , Tsukamoto T, Inoue M, Kumagai T, Sugiyama A, Mizoshita T, Kaminishi M, Tatematsu M
Jpn J Cancer Res · 2002 Oct · PMID 12417037 · Full text
Helicobacter pylori (Hp) infection and high-salt diet administration are both considered to be important factors in gastric carcinogenesis in man. To investigate the interaction of these two factors on gastric carcinogen...
Helicobacter pylori (Hp) infection and high-salt diet administration are both considered to be important factors in gastric carcinogenesis in man. To investigate the interaction of these two factors on gastric carcinogenesis, an experimental study of the carcinogenesis model was performed. Mongolian gerbils were treated with 20 ppm of N-methyl-N-nitrosourea (MNU) in their drinking water for alternate weeks for a total of 5 weeks' exposure (groups 1, 2, 3 and 4) or were maintained as controls (groups 5, 6, 7 and 8). At week 11, the animals were inoculated with Hp (groups 1, 2, 5 and 6) or the vehicle alone (groups 3, 4, 7 and 8), and after week 12, animals were fed a 10% high salt diet (groups 1, 3, 5 and 7) or the control diet (groups 2, 4, 6 and 8). At week 50, the incidence of adenocarcinomas in group 1 (32.1%, 6 well-differentiated, 2 poorly-differentiated adenocarcinomas, and one signet-ring cell carcinoma) was significantly higher than in groups 3 (0%) (P < 0.005) and 4 (0%) (P < 0.01). The incidence of adenocarcinomas in group 2 (11.8%, one well-differentiated adenocarcinoma, and one signet-ring cell carcinoma) was also higher than in groups 3 and 4. A high-salt diet enhanced the effects of Hp infection on gastric carcinogenesis, and these two factors acted synergistically to promote the development of stomach cancers. Moreover, Hp infection promoted gastric carcinomas more than the high-salt diet.
Lack of a dose-response relationship for carcinogenicity in the rat liver with low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N-nitrosodiethylamine.
Fukushima S, Wanibuchi H, Morimura K … +13 more , Wei M, Nakae D, Konishi Y, Tsuda H, Uehara N, Imaida K, Shirai T, Tatematsu M, Tsukamoto T, Hirose M, Furukawa F, Wakabayashi K, Totsuka Y
Jpn J Cancer Res · 2002 Oct · PMID 12417036 · Full text
For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged w...
For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. Here we show that a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts at low doses, but does not induce glutathione S-transferase placental form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy-2'-deoxyguanosine in rat liver. Moreover a N-nitroso compound, N-nitrosodiethylamine, at low doses was also found not to induce GST-P-positive foci in rat liver. These results imply that there is a no-observed effect level for hepatocarcinogenesis by these genotoxic carcinogens.
Serum copper/zinc superoxide dismutase (Cu/Zn SOD) and gastric cancer risk: a case-control study.
Lin Y, Kikuchi S, Obata Y … +2 more , Yagyu K, Tokyo Research Group on Prevention of Gastric Cancer
Jpn J Cancer Res · 2002 Oct · PMID 12417035 · Full text
We conducted a case-control study to evaluate the association between serum levels of copper/zinc superoxide dismutase (Cu/Zn SOD) and the risk of gastric cancer. Cases were 214 patients who had been diagnosed with gastr...
We conducted a case-control study to evaluate the association between serum levels of copper/zinc superoxide dismutase (Cu/Zn SOD) and the risk of gastric cancer. Cases were 214 patients who had been diagnosed with gastric cancer and controls were 120 persons who underwent medical checkups. Serum levels of Cu/Zn SOD were determined by enzyme-linked immunosorbent assay (ELISA). Compared with the lowest quartile, the OR (odds ratio) was 4.54 (95% CI (confidence interval), 1.62 - 12.66) for the third quartile and 15.75 (95% CI, 5.84 - 42.46) for the highest quartile. With both early and advanced cancers, as well as with the intestinal and diffuse types, a significant increase in risk was observed with increasing levels of serum Cu/Zn SOD. Our case-control study showed that serum levels of Cu/Zn SOD were significantly elevated in gastric cancer patients compared with apparently healthy controls, and higher Cu/Zn SOD levels may be associated with an increased risk of gastric cancer.
Dose-response trial of lactoferrin in patients with chronic hepatitis C.
Okada S, Tanaka K, Sato T … +6 more , Ueno H, Saito S, Okusaka T, Sato K, Yamamoto S, Kakizoe T
Jpn J Cancer Res · 2002 Sep · PMID 12359061 · Full text
Hepatitis C virus (HCV) is one of the most common causes of chronic hepatitis. Interferon is presently the only effective treatment for chronic hepatitis C (CH-C), though its effectiveness is limited. Lactoferrin (LF), w...
Hepatitis C virus (HCV) is one of the most common causes of chronic hepatitis. Interferon is presently the only effective treatment for chronic hepatitis C (CH-C), though its effectiveness is limited. Lactoferrin (LF), which is an 80-kDa, iron-binding glycoprotein, has several biological activities including anti-viral activity, and it was recently reported to inhibit HCV infection in cultured human hepatocytes. The present trial was designed to assess the relationship between the dose of bovine LF (bLF) and the effect of bLF on serum alanine aminotransaminase (ALT) and HCV RNA levels in patients with CH-C. Forty-five patients entered at each of the three dose levels (bLF of 1.8, 3.6, and 7.2 g/day) received orally an 8-week course of bLF. There was no significant relation between the dose of bLF and the effect of bLF on serum ALT or HCV RNA levels. Biochemical (a 50% or greater decrease in the serum ALT level) and virological (a 50% or greater decrease in HCV RNA level) responses were observed in two and four patients, respectively, but all responders relapsed during the follow-up period after bLF treatment. The bLF treatment was generally well tolerated, and no patient had any serious adverse event. In conclusion, the excellent tolerance and potential anti-HCV activity of bLF shown in this trial suggest that further trials using a large number of patients are mandatory. We are currently conducting a double-blind randomized controlled trial comparing bLF with placebo to clarify the anti-HCV activity of bLF in patients with CH-C.
A role for survivin in radioresistance of pancreatic cancer cells.
Asanuma K, Kobayashi D, Furuya D … +3 more , Tsuji N, Yagihashi A, Watanabe N
Jpn J Cancer Res · 2002 Sep · PMID 12359060 · Full text
Using gene-transduced pancreatic cancer cells, we examined whether survivin expression is directly involved in regulation of radiosensitivity. Ordinarily radiosensitive MIAPaCa-2 cells transduced with wild-type survivin...
Using gene-transduced pancreatic cancer cells, we examined whether survivin expression is directly involved in regulation of radiosensitivity. Ordinarily radiosensitive MIAPaCa-2 cells transduced with wild-type survivin gene (MS cells) proliferated more rapidly than cells transduced with control vector. MS cells were significantly less radiosensitive than control vector-transduced cells. Radiation-induced activity of caspase-3, but not caspase-7, was significantly inhibited in MS cells. On the other hand, transduction of a dominant-negative mutant survivin gene into radioresistant PANC-1 cells augmented radiosensitivity. Further, the radiation-induced increase in caspase-3 activity was enhanced, indicating that survivin function was truly inhibited. These results indicate that survivin expression directly down-regulates radiosensitivity.
Significance of nuclear glutathione S-transferase pi in resistance to anti-cancer drugs.
Goto S, Kamada K, Soh Y … +2 more , Ihara Y, Kondo T
Jpn J Cancer Res · 2002 Sep · PMID 12359059 · Full text
Recent study has shown that nuclear glutathione S-transferase (GST) pi accumulates in cancer cells resistant to doxorubicin hydrochloride (DOX) and may function to prevent nuclear DNA damage caused by DOX (Goto et al., F...
Recent study has shown that nuclear glutathione S-transferase (GST) pi accumulates in cancer cells resistant to doxorubicin hydrochloride (DOX) and may function to prevent nuclear DNA damage caused by DOX (Goto et al., FASEB J., 15, 2702 - 2714 (2001)). It is not clear if the amount of nuclear GSTpi increases in response to other anti-cancer drugs and if so, what is the physiological significance of the nuclear transfer of GSTpi in the acquisition of drug-resistance in cancer cells. In the present study, we employed three cancer cell lines, HCT8 human colonic cancer cells, A549 human lung adenocarcinoma cells, and T98G human glioblastoma cells. We estimated the nuclear transfer of GSTpi induced by the anti-cancer drugs cisplatin (CDDP), irinotecan hydrochloride (CPT-11), etoposide (VP-16) and 5-fluorouracil (5-FU). It was found that: (1) Nuclear GSTpi accumulated in these cancer cells in response to CDDP, DOX, CPT-11, VP-16 and 5-FU. (2) An inhibitor of the nuclear transport of GSTpi, edible mushroom lectin (Agaricus bisporus lectin, ABL), increased the sensitivity of the cancer cells to DOX and CDDP, and partially to CPT-11. Treatment with ABL had no apparent effect on the cytotoxicity of VP-16 and 5-FU. These results suggest that inhibitors of the nuclear transfer of GSTpi have practical value in producing an increase of sensitivity to DOX, CDDP and CPT-11.
Reversal of P-glycoprotein-mediated paclitaxel resistance by new synthetic isoprenoids in human bladder cancer cell line.
Enokida H, Gotanda T, Oku S … +9 more , Imazono Y, Kubo H, Hanada T, Suzuki S, Inomata K, Kishiye T, Tahara Y, Nishiyama K, Nakagawa M
Jpn J Cancer Res · 2002 Sep · PMID 12359058 · Full text
We isolated a paclitaxel-resistant cell line (KK47/TX30) from a human bladder cancer cell line (KK47/WT) in order to investigate the mechanism of and reversal agents for paclitaxel resistance. KK47/TX30 cells exhibited 7...
We isolated a paclitaxel-resistant cell line (KK47/TX30) from a human bladder cancer cell line (KK47/WT) in order to investigate the mechanism of and reversal agents for paclitaxel resistance. KK47/TX30 cells exhibited 700-fold resistance to paclitaxel and cross-resistance to vinca alkaloids and topoisomerase II inhibitors. Tubulin polymerization assay showed no significant difference in the ratio of polymerized alpha- and beta-tubulin between KK47/WT and KK47/TX30 cells. Western blot analysis demonstrated overexpression of P-glycoprotein (P-gp) and lung resistance-related protein (LRP) in KK47/TX30 cells. Drug accumulation and efflux studies showed that the decreased paclitaxel accumulation in KK47/TX30 cells was due to enhanced paclitaxel efflux. Cell survival assay revealed that verapamil and cepharanthine, conventional P-gp modulators, could completely overcome paclitaxel resistance. To investigate whether new synthetic isoprenoids could overcome paclitaxel resistance, we synthesized 31 isoprenoids based on the structure of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB), which could reverse multidrug resistance (MDR), as shown previously. Among those examined, trans-N,N'-bis(3,4-dimethoxybenzyl)-N-solanesyl-1,2-diaminocyclohexane (N-5228) could completely reverse paclitaxel resistance in KK47/TX30 cells. N-5228 inhibited photoaffinity labeling of P-gp by [(3)H]azidopine, suggesting that N-5228 could bind to P-gp directly and could be a substrate of P-gp. Next, we investigated structural features of these 31 isoprenoids in order to determine the structural requirements for the reversal of P-gp-mediated paclitaxel resistance, suggesting that the following structural features are important for overcoming paclitaxel resistance: (1) a basic structure of 8 to 10 isoprene units, (2) a cyclohexane ring or benzene ring within the framework, (3) two cationic sites in close proximity to each other, and (4) a benzyl group with 3,4-dimethoxy functionalities, which have moderate electron-donating ability. These findings may provide valuable information for the development of P-gp-mediated MDR-reversing agents.
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