Japanese Journal Of Cancer Research[JOURNAL]
Sun
200 papers
A statistical study of lung cancer in the annual of pathological autopsy cases in Japan, from 1958 to 1997, with reference to time trends of lung cancer in the world.
Morita T
Jpn J Cancer Res · 2002 Jan · PMID 11802803 · Full text
Lung cancer cases (66650 males and 20890 females) registered in the Annual of Pathological Autopsy Cases in Japan, between 1958 and 1997, were analyzed with regard to sex, age and histology. They were subdivided into dec...
Lung cancer cases (66650 males and 20890 females) registered in the Annual of Pathological Autopsy Cases in Japan, between 1958 and 1997, were analyzed with regard to sex, age and histology. They were subdivided into decades (periods I to IV), and compared with the Japanese mortality statistics, with which they were in good correspondence. Although the autopsy rate is decreasing, more than 10% of the total lung cancer deaths in Japan were registered by 1990. Among autopsied cases, the incidence of lung cancer cases increased from 6% to 12% in males and from 3% to 6% in females. From period III, lung cancer in males became the most frequent, and was the second most frequent cancer in females after gastric cancer. As for the histological distribution, adenocarcinoma was the most frequent and squamous cell carcinoma was the next most frequent in both sexes. Recently, a significant increase in adenocarcinoma and a significant decrease in squamous cell carcinoma have been observed in both sexes. The peak ages shifted from the 60s to the 70s and a significant rise in the mean ages were observed. The male-to-female ratios and the ratio curves by histological and age group were high for squamous cell carcinoma and small cell carcinoma, while they were low for the total and adenocarcinoma. With the recently acquired data on lung cancer in Asian countries, and from the male-to-female ratios and the status of smoking rates, lung cancer in the world at present was divided into three groups; North America, Europe and Asia. The possibility of one group changing to resemble another and of groups converging in the near future is suggested.
Smoking and risk of premature death among middle-aged Japanese: ten-year follow-up of the Japan Public Health Center-based prospective study on cancer and cardiovascular diseases (JPHC Study) cohort I.
Hara M, Sobue T, Sasaki S … +1 more , Tsugane S
Jpn J Cancer Res · 2002 Jan · PMID 11802802 · Full text
To update the evidence on the association between smoking and mortality, we analyzed data from a population-based prospective study in Japan. In total, 19950 men and 21534 women aged 40 - 59 who reported their smoking hi...
To update the evidence on the association between smoking and mortality, we analyzed data from a population-based prospective study in Japan. In total, 19950 men and 21534 women aged 40 - 59 who reported their smoking history and had no serious disease at baseline survey were followed. During 1990 - 1999, 1014 men and 500 women died. Smokers were associated with an unhealthy lifestyle. Relative risks (RRs) for selected cause of death due to smoking were slightly attenuated by adjusting for possible confounding factors. Age- and area-adjusted RRs of male current smokers compared with never smokers were 1.66 (95% confidence intervals (CI): 1.40, 1.95) for all causes, 1.69 (1.31, 2.18) for all cancers, 1.67 (1.20, 2.34) for all circulatory system disease, and 1.63 (1.24, 2.15) for other causes, while those of females were 2.03 (1.52, 2.73), 2.06 (1.35, 3.15), 2.99 (1.75, 5.11), 1.31 (0.69, 2.51), respectively. After adjusting for multivariate variables, the corresponding RRs of male smokers were 1.55 (1.29, 1.86), 1.61 (1.20, 2.15), 1.41 (0.97, 2.03), and 1.61 (1.17, 2.19), against 1.89 (1.36, 2.62), 1.83 (1.14, 2.95), 2.72 (1.45, 5.07), and 1.39 (0.71, 2.73) for females. Twenty-two percent of death from all causes, 25% of all cancer, and 17% of all circulatory system disease deaths, could be attributed to cigarette smoking in males, and 5%, 4%, and 11% in females, respectively. Cumulative dose as indicated by pack-years was clearly associated with cancer death. These findings provided information as to the quantitative risk for premature death due to smoking among middle-aged Japanese men and women, and showed that the elevated risk was not explained by the unhealthy lifestyle of smokers.
L-myc genotype is associated with different susceptibility to lung cancer in smokers.
Kumimoto H, Hamajima N, Nishimoto Y … +4 more , Matsuo K, Shinoda M, Hatooka S, Ishizaki K
Jpn J Cancer Res · 2002 Jan · PMID 11802801 · Full text
We have shown that L-myc genotype is associated with the risk of esophageal cancer from smoking and heavy drinking. In this study, we have analyzed the relationship between the L-myc genotypes and lung cancer risk from s...
We have shown that L-myc genotype is associated with the risk of esophageal cancer from smoking and heavy drinking. In this study, we have analyzed the relationship between the L-myc genotypes and lung cancer risk from smoking in 191 Japanese lung-cancer patients and 241 non-cancer controls. The odds ratios (ORs) were markedly higher in SS and LS genotypes than in LL genotype; age-sex-adjusted ORs were 3.19, 2.30 and 0.92, respectively. This result suggests that the L-myc polymorphism may affect the induction of lung cancer by smoking. The OR for smoking in SS-genotype patients diagnosed within 2 years was higher than that in other SS patients, suggesting that smoking-related lung cancer in SS genotype might exhibit a poorer prognosis.
A radicicol derivative, KF58333, inhibits expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor, angiogenesis and growth of human breast cancer xenografts.
Kurebayashi J, Otsuki T, Kurosumi M … +3 more , Soga S, Akinaga S, Sonoo H
Jpn J Cancer Res · 2001 Dec · PMID 11749701 · Full text
A novel oxime derivative of radicicol, KF58333, binds to the heat shock protein 90 (Hsp90) and destabilizes its associated signaling molecules. These effects play a critical role in the growth inhibition of tumor cells....
A novel oxime derivative of radicicol, KF58333, binds to the heat shock protein 90 (Hsp90) and destabilizes its associated signaling molecules. These effects play a critical role in the growth inhibition of tumor cells. To further investigate the effects of this agent, it was administered to two human breast cancer cell lines, KPL-1 and KPL-4, both in vitro and in vivo. KF58333 dose-dependently inhibited the growth and vascular endothelial growth factor (VEGF) secretion, concomitantly with a decrease in VEGF mRNA expression, in each cell line. This agent also suppressed the increase of VEGF secretion and expression induced by hypoxia (1% O(2)). Intravenous injections of this agent into nude mice bearing either KPL-1 or KPL-4 xenografts significantly inhibited the tumor growth associated with a decrease in the Ki67 labeling index and microvascular area and an increase in apoptosis and the necrotic area. These findings indicate that the antitumor activity of this radicicol derivative may be partly mediated by decreasing VEGF secretion from tumor cells and inhibiting tumor angiogenesis. To explore the action mechanisms of the anti-angiogenic effect, the expression level of hypoxia-inducible factor (HIF)-1alpha was investigated. KF58333 provided a significant decrease in the HIF-1alpha protein expression under both normoxic and hypoxic conditions. In contrast, the mRNA expression of HIF-1alpha was not decreased by this agent. It is suggested that the post-transcriptional down-regulation of HIF-1alpha expression by this agent may result in a decrease of VEGF expression and tumor angiogenesis.
CPT-11 may provide therapeutic efficacy for esophageal squamous cell cancer and the effects correlate with the level of DNA topoisomerase I protein.
Nakajima Y, Miyake S, Nagai K … +2 more , Kawano T, Iwai T
Jpn J Cancer Res · 2001 Dec · PMID 11749700 · Full text
CPT-11 is a potent anti-cancer drug and a specific inhibitor of DNA topoisomerase I (Topo I). In this study, we aim to evaluate the effects of CPT-11 on esophageal squamous cell cancers (ESCC) and to determine the correl...
CPT-11 is a potent anti-cancer drug and a specific inhibitor of DNA topoisomerase I (Topo I). In this study, we aim to evaluate the effects of CPT-11 on esophageal squamous cell cancers (ESCC) and to determine the correlation between the effects and the levels of Topo I expression. We examined the growth-inhibitory effect caused by SN-38, an active metabolite of CPT-11, in 14 human ESCC cell lines established from 10 primary and 4 metastatic lesions. CPT-11 was considered effective against 5 cell lines from primary lesions and one from metastatic lesions, and thus may show therapeutic efficacy against both primary and metastatic ESCC tumors. Although Topo I mRNA levels in these 14 ESCC cell lines, as quantitated by northern blot analysis, showed no correlation with the IC(50) values, Topo I protein levels, as quantitated by western blot analysis, showed an inverse correlation with the IC(50) values. Topo I protein levels could be an indicator of sensitivity to CPT-11. We also determined Topo I protein levels in 40 ESCC tumors and matched normal mucosae. Thirty-four tumors showed 1.2 - 22.3-fold increases in Topo I levels. Two patients receiving pre-operative chemotherapy and one receiving radiotherapy exhibited increased Topo I protein levels in their tumor lesions. It appeared that CPT-11 could provide selective therapeutic efficacy against ESCC tumors. CPT-11 may be effective for the treatment of metastatic ESCC tumors and as a second-line anti-cancer drug for ESCC.
Eradication of Helicobacter pylori restores glutathione S-transferase activity and glutathione levels in antral mucosa.
Oijen AH, Verhulst ML, Roelofs HM … +3 more , Peters WH, de Boer WA, Jansen JB
Jpn J Cancer Res · 2001 Dec · PMID 11749699 · Full text
Glutathione S-transferases (GST) and glutathione peroxidases (GPO) are important in detoxification. GST activity in the mucosa of the gastrointestinal tract is inversely correlated with the development of gastrointestina...
Glutathione S-transferases (GST) and glutathione peroxidases (GPO) are important in detoxification. GST activity in the mucosa of the gastrointestinal tract is inversely correlated with the development of gastrointestinal cancer. Helicobacter pylori (H. pylori) infection has been associated with gastric cancer. We studied GST activity and the substrate glutathione (GSH) in patients with H. pylori-associated gastritis. GST activity and isoenzyme levels, GPO activity and GSH levels were studied in antral biopsies of 38 H. pylori-positive patients, before and after eradication treatment. In 31 patients in whom H. pylori was successfully eradicated, antral GST enzyme activity before therapy was 532 (465 - 598) nmol / mg protein. min (mean and 95% confidence interval) and that after therapy was 759 (682 - 836) nmol / mg protein. min (P < 0.0001). Correspondingly, levels of GST alpha and GST-P1 were higher after eradication (P < 0.001). GSH concentration significantly increased: 21.2 (16.2 - 26.2) nmol / mg protein before and 27.1 (23.6 - 30.6) nmol / mg protein after therapy (P < 0.05). In 7 patients in whom H. pylori was not eradicated, GST activity was 671 (520 - 823) nmol / mg protein. min and 599 (348 - 850) nmol / mg protein before and after treatment respectively (P = 0.32). GSH levels were 17.4 (9.0 - 25.7) nmol / mg protein and 18.2 (9.1 - 27.3) nmol / mg protein, respectively (P = 0.84). No differences in antral GPO enzyme activity, both of selenium (Se)-dependent and total GPO, before and after successful treatment were found. Eradication of H. pylori infection increases GST activity and GSH levels in antral mucosa. Low GST activity and GSH concentration due to H. pylori infection might play a role in gastric carcinogenesis.
The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice.
Minagawa A, Otani Y, Kubota T … +10 more , Wada N, Furukawa T, Kumai K, Kameyama K, Okada Y, Fujii M, Yano M, Sato T, Ito A, Kitajima M
Jpn J Cancer Res · 2001 Dec · PMID 11749698 · Full text
The flavonoid nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, a...
The flavonoid nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK- 1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK-1. The enzymatic activity of MMP-9 expressed in culture medium obtained from a co-culture of TMK-1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration-dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P = 0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3 / body, P = 0.0001). These results suggest that nobiletin may be a candidate anti-metastatic drug for prevention of peritoneal dissemination of gastric cancer.
Phage display cloning and characterization of monoclonal antibody genes and recombinant Fab fragment against the CD98 oncoprotein.
Itoh K, Inoue K, Hirooka K … +8 more , Maruyama K, Ohkawa M, Matsui K, Tada H, Enomoto T, Hashimoto Y, Suzuki T, Masuko T
Jpn J Cancer Res · 2001 Dec · PMID 11749697 · Full text
The Fab gene of anti-CD98 heavy chain (h.c.) monoclonal antibody (mAb) HBJ127 was cloned and expressed as a recombinant Fab (rFab) fragment by means of a phage display system. The variable heavy and light chain genes of...
The Fab gene of anti-CD98 heavy chain (h.c.) monoclonal antibody (mAb) HBJ127 was cloned and expressed as a recombinant Fab (rFab) fragment by means of a phage display system. The variable heavy and light chain genes of HBJ127 were found to be derived from VOx-1 and IgVk8-30 germline, respectively. Extensive somatic mutation was found in the heavy chain complementarity determining region 2. rFab fragment was purified homogeneously from crude bacterial lysates by Ni-chelate chromatography in a yield of 71.4 mg from 100 ml of culture. rFab fragment was reactive with the cell surface of CD98-positive cells irrespective of tissues of origin, but not with CD98-negative cells. The recognition site of the rFab fragment was identical to that of mAb since the binding of rFab fragment to HeLaS(3) cells was completely inhibited by pretreatment with an excess of mAb. The relative affinity values of rFab fragment and mAb were found to be 0.11 x 10(8) and 0.35 x 10(8) M(-1), respectively. Three-fold lower affinity of rFab fragment may be due to the difference of valency of the antibody preparation. Cell growth inhibition in vitro by rFab fragment preincubated with anti-Fab suggests that the rFab fragment produced by cloned gene-bearing Escherichia coli was identical to the Fab part of HBJ127 mAb. These results show that a small fragment with antigen binding activity similar to that of the parent mAb can easily be prepared by using a phage display system. To our knowledge, this is a first report of the production of anti-CD98 h.c. rFab fragment.
Clonality assay of hematopoietic disorders: significance of the buccal epithelium as non-hematopoietic control and of 95% rejection limit as a novel criterion for monoclonality.
Inagaki H, Wakita A, Komatsu H … +4 more , Kikuchi M, Inagaki A, Eimoto T, Ueda R
Jpn J Cancer Res · 2001 Dec · PMID 11749696 · Full text
In clonality assays using X chromosome inactivation patterns (XCIPs), several factors such as constitutive and acquired XCIP skewing, lack of appropriate controls for hematopoietic diseases including multilineage disorde...
In clonality assays using X chromosome inactivation patterns (XCIPs), several factors such as constitutive and acquired XCIP skewing, lack of appropriate controls for hematopoietic diseases including multilineage disorders, and ambiguous criteria for monoclonality, have complicated determination of clonality. To address these issues, we studied the significance of the buccal epithelium as a non-hematopoietic control and the usefulness of the 95% rejection limit as a criterion for monoclonality. Sixty-nine females informative for human androgen receptor gene (HUMARA) were divided into "young," "middle-aged" and "elderly" groups. When XCIP correlation between the buccal epithelium, peripheral granulocytes, and peripheral lymphocytes was analyzed, the buccal epithelium showed a good correlation with granulocytes and lymphocytes in "young" and "middle-aged" groups, whereas the correlation was poor for the "elderly" group. For all age groups, there was an excellent correlation between granulocytes and lymphocytes. When we performed clonality assay for seven "young" and "middle-aged" patients with various leukemic phases using buccal epithelium as a non-hematopoietic control, all cases were accurately evaluated with the aid of a novel criterion, the 95% rejection limit. Our findings suggest that the buccal epithelium may constitute an effective control, especially when a non-hematopoietic control is required, and that the 95% rejection limit may serve as a statistically-defined criterion for monoclonality.
Expression profile of histone deacetylase 1 in gastric cancer tissues.
Choi JH, Kwon HJ, Yoon BI … +4 more , Kim JH, Han SU, Joo HJ, Kim DY
Jpn J Cancer Res · 2001 Dec · PMID 11749695 · Full text
Although histone deacetylases (HDACs) appear to play a crucial role in carcinogenesis, the expression status of HDACs in primary human cancer tissues has not yet been reported. In this study, we investigated the expressi...
Although histone deacetylases (HDACs) appear to play a crucial role in carcinogenesis, the expression status of HDACs in primary human cancer tissues has not yet been reported. In this study, we investigated the expression level of HDAC1 in 25 paired primary human gastric cancer (GC) tissues and corresponding normal tissues through semi-quantitative RT-PCR and immunoblot analysis. The HDAC1 expression pattern was also topologically examined through immunohistochemistry. Overexpression of HDAC1 mRNA was detected in 68% of GC tissues (17 of 25), and the relative density of HDAC1 mRNA in GC tissue was increased 1.8-fold versus the normal counterpart (P < 0.01). Elevated expression of HDAC1 protein was also detected in 61% of GC samples (11 of 18), which also showed an increased mRNA level of HDAC. Immunohistochemically, overexpression of HDAC1 was predominantly localized in the nuclei of most neoplastic cells, including embolic tumor cells, whereas normal glandular epithelial cells revealed only weak HDAC1 expression that was focal in distribution. Thus, the present study clearly demonstrates that HDAC1 is overexpressed in GC and probably plays a significant role in gastric carcinogenesis.
Aberrations of the p14(ARF) and p16(INK4a) genes in renal cell carcinomas.
Kawada Y, Nakamura M, Ishida E … +6 more , Shimada K, Oosterwijk E, Uemura H, Hirao Y, Chul KS, Konishi N
Jpn J Cancer Res · 2001 Dec · PMID 11749694 · Full text
The INK4a / ARF locus on chromosome 9p21, which encodes two distinct genes, p14(ARF) and p16(INK4a), is frequently altered in human neoplasms. To investigate the potential roles of p14(ARF) and p16(INK4a) genes in human...
The INK4a / ARF locus on chromosome 9p21, which encodes two distinct genes, p14(ARF) and p16(INK4a), is frequently altered in human neoplasms. To investigate the potential roles of p14(ARF) and p16(INK4a) genes in human renal cell carcinomas (RCCs), we analyzed 6 human RCC cell lines and 91 primary RCCs for homozygous deletion, promoter hypermethylation and expression of the p14(ARF) and p16(INK4a) gene products using differential PCR, methylation-specific PCR, and immunohistochemistry, respectively. Five cell lines showed homozygous co-deletion of both genes and one demonstrated promoter hypermethylation of the p16(INK4a) gene only. Eight of 91 RCCs showed aberrations of p14(ARF) or p16(INK4a) status and six of these featured gross extension into the renal vein. The results suggest that p14(ARF) and p16(INK4a) aberrations may play roles in the relatively late stage of renal tumorigenesis associated with tumor progression.
Possible involvement of interferon regulatory factor 4 (IRF4) in a clinical subtype of adult T-cell leukemia.
Imaizumi Y, Kohno T, Yamada Y … +4 more , Ikeda S, Tanaka Y, Tomonaga M, Matsuyama T
Jpn J Cancer Res · 2001 Dec · PMID 11749693 · Full text
Interferon regulatory factor (IRF) 4 is the lymphoid-specific transcription factor that is required for the proliferation of mitogen-activated T cells. IRF4 has been suggested to be involved in tumorigenesis because the...
Interferon regulatory factor (IRF) 4 is the lymphoid-specific transcription factor that is required for the proliferation of mitogen-activated T cells. IRF4 has been suggested to be involved in tumorigenesis because the overexpression of IRF4 caused the transformation of Rat-1 fibroblasts in vitro. Here, we show that IRF4 is constitutively expressed in adult T-cell leukemia (ATL)-derived cell lines, which were infected with human T-cell leukemia virus type-I, but hardly expressed the trans-activator protein, Tax. Similarly, constitutive expression of IRF4 was demonstrated in freshly isolated peripheral blood mononuclear cells (PBMC) from patients with either acute or chronic ATL. However, the high-level expression of IRF4 was specifically associated with acute ATL. With mitogen-activated PBMC from healthy donors, cell cycle analyses revealed that the induction of IRF4 occurred prior to cell cycle progression and the cells that had entered the cell cycle were predominantly IRF4-positive cells. In addition, ectopic expression of IRF4 in Rat-1 fibroblasts increased the S and G2 / M phase population significantly. Taken together, our results indicate that IRF4 is involved in the pathogenesis of ATL through its positive effect on the cell cycle, and that IRF4 can be used as a molecular marker of clinical subtype in ATL.
p53 and H-ras mutations and microsatellite instability in renal pelvic carcinomas of NON / Shi mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine: different genetic alteration from urinary bladder carcinoma.
Gen H, Yamamoto S, Morimura K … +9 more , Min W, Mitsuhashi M, Murai T, Mori S, Hosono M, Oohara T, Makino S, Wanibuchi H, Fukushima S
Jpn J Cancer Res · 2001 Dec · PMID 11749692 · Full text
We previously reported p53 mutations to be frequent (greater than 70%), whereas both H-ras mutations and microsatellite instability (MSI) were infrequent (about 10%), in urinary bladder carcinomas (UBCs) and their metast...
We previously reported p53 mutations to be frequent (greater than 70%), whereas both H-ras mutations and microsatellite instability (MSI) were infrequent (about 10%), in urinary bladder carcinomas (UBCs) and their metastatic foci in the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse urothelial carcinogenesis model. In the present study, an analysis of p53 and H-ras mutations as well as MSI was performed on 12 renal pelvic carcinomas (RPCs) and 8 metastatic or invading foci produced by the same experimental procedure. Histologically, 10 of the RPCs were transitional cell carcinomas and the remaining 2 were squamous cell carcinomas. p53 mutations were infrequent and only found in one primary RPC (8%), its metastatic foci and an invading lesion in another animal (in a total 2 of 12; 17%). H-ras mutations were slightly more frequent (found in 3 of 12 animals; 25%), 4 of 5 involving codon 44, GTG to GCG, not a hot-spot reported for human cancers. In two cases, H-ras mutations were confined to lung metastasis and not detectable in their primary RPCs. MSI analysis was available for 6 pairs of primary RPCs and their metastatic foci, and 4 animals (67%) had MSI at one or more microsatellite loci. Overall, the distribution of genetic alterations differed from that in UBCs produced by the same experimental protocol. The results thus suggest that different genetic pathways may participate in carcinogenesis of the upper and lower urinary tract due to BBN.
Decreased expression of Bcl-x protein during hepatocarcinogenesis induced exogenously and endogenously in rats.
Hatanaka Y, Nakae D, Mutai M … +8 more , Hashizume K, Kamihara Y, Kinoshita N, Tani Y, Danno Gi G, Ohta S, Konishi Y, Ashida H
Jpn J Cancer Res · 2001 Dec · PMID 11749691 · Full text
Dysregulations of apoptosis have been widely recognized as important events in multi-stage carcinogenesis. Bcl-x, a member of the Bcl-2 family, is known to act as a regulator of apoptosis. The present study was conducted...
Dysregulations of apoptosis have been widely recognized as important events in multi-stage carcinogenesis. Bcl-x, a member of the Bcl-2 family, is known to act as a regulator of apoptosis. The present study was conducted to assess the role of altered Bcl-x protein expression in exogenous and endogenous hepatocarcinogenesis in rats. In the short-term exogenous models, male Fischer 344 rats, 6 weeks old, were given a single intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 200 mg / kg body weight, partially hepatectomized at the end of week 3, administered phenobarbital at a concentration of 0.05% from the end of week 2 for 6 weeks, and sacrificed. In the livers, glutathione S-transferase (GST-P)-positive, putative preneoplastic lesions were induced, and Bcl-x protein expression was decreased in 24.7% of such lesions. The incidence of GST-P-positive lesions with decreased Bcl-x increased depending on the size of the lesions; 18.9%, 32.4% and 86.5% in the lesions smaller than 0.03, between 0.03 and 0.3, and larger than 0.3 mm(2), respectively. In GST-P-positive lesions larger than 0.3 mm(2), both apoptosis induction and cell proliferation activity were enhanced when Bcl-x protein expression was decreased. In the long-term exogenous models, rats were given 10 mg / kg of DEN, partially hepatectomized 4 h after treatment, administered 0.5 mg / kg of colchicine at the end of days 1 and 3, subjected to a selection procedure, and sacrificed at the end of week 45. Hepatocellular carcinomas were induced with the decreased Bcl-x protein expression. In the endogenous model, rats were fed a choline-deficient, L-amino acid-defined diet for 16 or 80 weeks and sacrificed. Bcl-x protein expression was decreased both in GST-P-positive lesions and hepatocellular carcinoma. These results suggest that this decrease of Bcl-x protein might serve as an indicator of the advanced form of preneoplastic lesions, and that this decrease could also be associated with a potential to progress into carcinoma in both exogenous and endogenous hepatocarcinogenesis of rats.
Dietary habits and risk of lung cancer death in a large-scale cohort study (JACC Study) in Japan by sex and smoking habit.
Ozasa K, Watanabe Y, Ito Y … +8 more , Suzuki K, Tamakoshi A, Seki N, Nishino Y, Kondo T, Wakai K, Ando M, Ohno Y
Jpn J Cancer Res · 2001 Dec · PMID 11749690 · Full text
Lung cancer has increased and is the leading cause of cancer death among Japanese males. The associations of dietary habits with the risk of lung cancer death were evaluated by sex and smoking habits in this study. In th...
Lung cancer has increased and is the leading cause of cancer death among Japanese males. The associations of dietary habits with the risk of lung cancer death were evaluated by sex and smoking habits in this study. In the Japan Collaborative Cohort (JACC) Study, a cohort established in 1988 - 90 and consisting of 42 940 males and 55 308 females was observed for lung cancer deaths up to the end of 1997. During the observation period, 446 males and 126 females died of lung cancer. A self-administered food frequency questionnaire was used as the baseline survey. Hazard ratios for dietary factors were calculated by Cox's proportional hazards model. Among males, a high intake of ham and sausages, cheese, green-leafy vegetables, oranges, and other fruits significantly and dose-dependently decreased the risk of lung cancer death. Among females, a high intake of miso-soup, ham and sausages, and liver significantly and almost dose-dependently increased the risk. Vegetables and fruits rich in antioxidative and carcinogenic agents reduced the risk of lung cancer deaths among male smokers more than among female nonsmokers. The results among female nonsmokers were partially consistent with the hypothesis that high fat consumption increases the risk of lung cancer, especially that of adenocarcinoma.
Macrophage colony-stimulating factor prevents febrile neutropenia induced by chemotherapy.
Hidaka T, Fujimura M, Sakai M … +1 more , Saito S
Jpn J Cancer Res · 2001 Nov · PMID 11714451 · Full text
There are very few studies describing the preventive effect of macrophage colony-stimulating factor (M-CSF/CSF-1) on chemotherapy-induced infection. In this study, we evaluated the changes in superoxide anion production...
There are very few studies describing the preventive effect of macrophage colony-stimulating factor (M-CSF/CSF-1) on chemotherapy-induced infection. In this study, we evaluated the changes in superoxide anion production by granulocytes before and after chemotherapy in ovarian cancer patients and investigated the preventive effect of M-CSF on chemotherapy-induced febrile neutropenia. Three courses of chemotherapy [paclitaxel 180 mg/m(2) and carboplatin (area under the curve; AUC 5)] were administered to 32 ovarian cancer patients, and seven patients presented febrile neutropenia. In the 25 afebrile patients, the percentage of superoxide anion production by granulocytes was significantly decreased from 86.5 +/- 7.7 (%) to 75.1 +/- 8.8 (%) at day 7 and 71.0 +/- 6.3 (%) at day 14 without administration of CSF. However, in the patients who presented febrile neutropenia, it was more severely decreased from 86.8 +/- 6.8 (%) to 60.0 +/- 9.9 (%) at day 7 and 56.8 +/- 5.0 (%) at day 14 without administration of CSF. When M-CSF was administered to all patients in the next course with the same dose of chemotherapy, the incidence of febrile neutropenia was significantly decreased (P = 0.0195), and the duration of fever (>or= 38.0 degrees C) and high serum C-reactive protein (CRP) (>or= 2.0 mg/dl) were also significantly shortened (P = 0.0023, P = 0.0051). Moreover, in these M-CSF-treated patients, the percentage of superoxide anion production by granulocytes was maintained at the level before chemotherapy. These findings indicate that severe impairment of granulocyte function leads to febrile neutropenia, and that M-CSF reduces the incidence of febrile neutropenia by maintaining or improving granulocyte function.
Paclitaxel and SN-38 overcome cisplatin resistance of ovarian cancer cell lines by down-regulating the influx and efflux system of cisplatin.
Komuro Y, Udagawa Y, Susumu N … +3 more , Aoki D, Kubota T, Nozawa S
Jpn J Cancer Res · 2001 Nov · PMID 11714450 · Full text
Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effectiv...
Cisplatin (DDP) is one of the key drugs used to treat patients with ovarian cancer, although resistance to DDP can occur. Paclitaxel and SN-38 (an active metabolite of irinotecan (CPT-11)) are two drugs that are effective in patients with DDP-resistant ovarian cancer. To study how these drugs may overcome the intrinsic and / or acquired resistance of cancer cells to DDP, we investigated the effect of a combination of DDP with paclitaxel and a combination of DDP with SN-38 on three ovarian cancer cell lines, RTSG (intrinsically resistant cell line), KF (DDP-sensitive cell line), and KFra (acquired resistant cell line obtained from KF). We found that these combinations showed additive to synergistic antitumor activity. A time-dependent platinum (Pt) accumulation was observed in the DDP-sensitive KF cell line, while a decrease occurred in the KFra cell line. Little accumulation was observed in RTSG. Intracellular Pt accumulation was increased in all three cell lines by exposure to paclitaxel or SN-38. Ouabain, a Na(+),K(+)-ATPase inhibitor, decreased Pt accumulation in KF and KFra cell lines and inhibited the paclitaxel- and SN-38-induced increases in Pt accumulation in these cell lines. When we assessed the mRNA levels of the multidrug resistance-associated protein (MRP), which may be an efflux pump for DDP, the combination of paclitaxel or SN-38 with DDP down-regulated these levels, which are up-regulated by DDP alone. These results suggest that paclitaxel and SN-38 overcome DDP resistance of ovarian cell lines by controlling intracellular accumulation of DDP via both the influx and efflux systems.
Reversal of multidrug resistance by novel nitrophenyl pyrones, SNF4435C and D.
Kurosawa K, Takahashi K, Tsuda E … +2 more , Tomida A, Tsuruo T
Jpn J Cancer Res · 2001 Nov · PMID 11714449 · Full text
SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various multidrug-resistant (MDR) tumor cells overexpressing P-glycoprotein...
SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various multidrug-resistant (MDR) tumor cells overexpressing P-glycoprotein. These two compounds in the range of 3-10 microM completely reversed the resistance of MDR variant cells, mouse leukemia P388 cells [vincristine (VCR)-resistant P388/VCR and adriamycin (ADM)-resistant P388/ADM], human myelogenous leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM) and human ovarian cancer A2780 cells (ADM-resistant AD(10)), against VCR. Both compounds moderately potentiated the sensitivity of the MDR cells to ADM but the reversal was not complete. SNF4435C and D significantly increased the intracellular accumulation of VCR in AD(10) cells as potently as verapamil, cyclosporin A (CysA) and FK506, whereas the compounds exerted no effect on the accumulation of VCR in the drug-sensitive parent cells. Moreover, SNF4435C improved the chemotherapeutic efficacy of VCR in the treatment of P388/VCR-bearing mice. When 10 mg/kg SNF4435C was administered intraperitoneally to the mice concurrently with 0.2 mg/kg VCR for every 5 days, a treated/control (T/C) value of 143% was obtained. These results suggest that the compounds are useful candidates or tools for MDR modification in cancer chemotherapy.
A potential use of a synthetic retinoid TAC-101 as an orally active agent that blocks angiogenesis in liver metastases of human stomach cancer cells.
Oikawa T, Murakami K, Sano M … +3 more , Shibata J, Wierzba K, Yamada Y
Jpn J Cancer Res · 2001 Nov · PMID 11714448 · Full text
TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521...
TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) is a novel, synthetic retinoid that is effective against liver metastases of human gastrointestinal cancer cells such as the human stomach carcinoma line AZ-521 in animal models, and is currently in use in phase I cancer trials. However, the mechanism of its antimetastatic action is still poorly understood. Tumor metastasis depends on angiogenesis, and various retinoids have been found to exhibit antiangiogenic activity. Based on these findings we here examined the antiangiogenic effects of TAC-101. Oral administration of TAC-101 (2-8 mg/kg/day) resulted in a drastic suppression of the AZ-521 cell-induced angiogenesis in a mouse dorsal air sac assay system, compared to the vehicle alone. Immunohistochemical analysis with antibody against the endothelial marker CD31 revealed a significant reduction in microvessel density in liver metastases from animals treated with TAC-101 (8 mg/kg p.o.), compared to liver metastases from the untreated control animals. The ability of TAC-101 (8 mg/kg p.o.) to prevent experimental liver metastasis of AZ-521 cells in athymic nude mice was comparable with that of the known angiogenesis inhibitor TNP-470 (30 mg/kg s.c.). TAC-101 also affected angiogenesis in chorioallantoic membranes and some functions of endothelial cells associated with angiogenesis, whereas the retinoid failed to suppress AZ-521 cell proliferation directly. These data suggest that the TAC-101 is an orally active antiangiogenic agent and that this antiangiogenic property may contribute to its efficacy against liver metastasis of human stomach cancer cells.
Introduction of clusterin gene into human renal cell carcinoma cells enhances their resistance to cytotoxic chemotherapy through inhibition of apoptosis both in vitro and in vivo.
Hara I, Miyake H, Gleave ME … +1 more , Kamidono S
Jpn J Cancer Res · 2001 Nov · PMID 11714447 · Full text
Recent studies have revealed the powerful antiapoptotic activity of clusterin in various malignant tumors; however, the significance of clusterin expression in the acquisition of a resistant phenotype against several kin...
Recent studies have revealed the powerful antiapoptotic activity of clusterin in various malignant tumors; however, the significance of clusterin expression in the acquisition of a resistant phenotype against several kinds of treatment in human renal cell carcinoma (RCC) has not been well characterized. We, therefore, transfected the clusterin cDNA into RCC ACHN cells, that scarcely express clusterin protein, to examine whether overexpression of clusterin inhibits chemotherapy-induced apoptosis both in vitro and in vivo. Although no significant differences were observed in the in vitro growth rates between clusterin-transfected ACHN (ACHN/CL) and the vector only-transfected cell line (ACHN/Co), ACHN/CL exhibited high resistance to cisplatin treatment compared with ACHN/Co, with a greater than 5-fold higher IC(50) through the inhibition of apoptotic cell death, which was demonstrated by DNA fragmentation analysis and western blotting of PARP protein. Moreover, intravenous administration of cisplatin into athymic nude mice bearing ACHN/CL tumors resulted in 2- to 3-times faster tumor growth compared with ACHN/Co tumors. These findings suggest that clusterin overexpression helps confer a chemoresistant phenotype through inhibition of apoptosis in human RCC cells.
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