Japanese Journal Of Cancer Research[JOURNAL]
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200 papers
1-beta-D-arabinofuranosylcytosine is cytotoxic in quiescent normal lymphocytes undergoing DNA excision repair.
Yamauchi T, Kawai Y, Ueda T
Jpn J Cancer Res · 2002 Dec · PMID 12495473 · Full text
We have sought to clarify the potential activity of the S-phase-specific antileukemic agent 1-beta-D-arabinofuranosylcytosine (ara-C), an inhibitor of DNA synthesis, in quiescent cells that are substantially non-sensitiv...
We have sought to clarify the potential activity of the S-phase-specific antileukemic agent 1-beta-D-arabinofuranosylcytosine (ara-C), an inhibitor of DNA synthesis, in quiescent cells that are substantially non-sensitive to nucleoside analogues. It was hypothesized that the combination of ara-C with DNA damaging agents that initiate DNA repair will expand ara-C cytotoxicity to non-cycling cells. The repair kinetics, which included incision of damaged DNA, gap-filling by DNA synthesis and rejoining by ligation, were evaluated using the single cell gel electrophoresis (Comet) assay and the thymidine incorporation assay. When normal lymphocytes were treated with ultraviolet C or with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), the processes of DNA excision repair were promptly initiated and rapidly completed. When the cells were incubated with ara-C prior to irradiation or BCNU treatment, the steps of DNA synthesis and rejoining in the repair processes were both inhibited. The ara-C-mediated inhibition of the repair processes was concentration-dependent, with the effect peaking at 10 microM. The combination of ara-C with these DNA repair initiators exerted subsequent cytotoxicity, which was proportional to the extent of the repair inhibition in the presence of ara-C. In conclusion, ara-C was cytotoxic in quiescent cells undergoing DNA repair. This might be attributed to unrepaired DNA damage that remained in the cells, thereby inducing lethal cytotoxicity. Alternatively, ara-C might exert its own cytotoxicity by inhibiting DNA synthesis in the repair processes. Such a strategy may be effective against a dormant subpopulation in acute leukemia that survives chemotherapy.
Costunolide triggers apoptosis in human leukemia U937 cells by depleting intracellular thiols.
Choi JH, Ha J, Park JH … +7 more , Lee JY, Lee YS, Park HJ, Choi JW, Masuda Y, Nakaya K, Lee KT
Jpn J Cancer Res · 2002 Dec · PMID 12495472 · Full text
We have previously demonstrated that costunolide, a biologically active compound that was isolated from the stem bark of Magnolia sieboldii, induced apoptosis in human cancer cells. In the present study, we investigated...
We have previously demonstrated that costunolide, a biologically active compound that was isolated from the stem bark of Magnolia sieboldii, induced apoptosis in human cancer cells. In the present study, we investigated the underlying mechanisms and suggest that costunolide induces apoptosis in human promonocytic leukemia U937 cells by depleting the intracellular thiols. Costunolide treatment rapidly depleted the intracellular reduced glutathione (GSH) and protein thiols, and this preceded the occurrence of apoptosis. Pretreatment with sulfhydryl compounds such as GSH, N-acetyl-L-cysteine, dithiothreitol and 2-mercaptoethanol almost completely blocked the costunolide-induced apoptosis, highlighting the significance of the intracellular thiol level in the process. Furthermore, overexpression of Bcl-2 also significantly attenuated the effects of costunolide. The apoptosis-inducing activity of costunolide is likely to depend on the exomethylene moiety because derivatives in which this group was reduced, such as dihydrocostunolide and saussurea lactone, did not deplete the cellular thiols and showed no apoptotic activity. Taken together, the present study demonstrates that the costunolide-induced apoptosis depends on intracellular thiols contents, which are modulated by Bcl-2.
Differential mechanisms of constitutive Akt/PKB activation and its influence on gene expression in pancreatic cancer cells.
Matsumoto J, Kaneda M, Tada M … +5 more , Hamada J, Okushiba S, Kondo S, Katoh H, Moriuchi T
Jpn J Cancer Res · 2002 Dec · PMID 12495471 · Full text
Activated Akt/protein kinase B transmits oncogenic signals leading to inhibition of apoptosis, cellular proliferation, and tolerance to hypoxia. Presently, mutational inactivation of PTEN and activation of Ras are consid...
Activated Akt/protein kinase B transmits oncogenic signals leading to inhibition of apoptosis, cellular proliferation, and tolerance to hypoxia. Presently, mutational inactivation of PTEN and activation of Ras are considered to be the major causes of Akt activation. Here we report differential mechanisms of constitutive Akt activation in 4 human pancreatic cancer cell lines (KMP-3, KMP-4, PCI-66, and PCI-68). These 4 cell lines displayed phosphorylation and functional activation of Akt both in the presence and absence of serum, while three control cell lines (PCI-79, KMP-8, and PSN-1) did so only in the presence of serum in culture. All the 7 cell lines harbored K-Ras activated by mutations at codon 12 resulting in MAP kinase kinase (MEK1/2) phosphorylation, and all except one (KMP-8) had p53 mutations, indicating that these mutations are not sufficient for constitutive Akt activation. KMP-3 and KMP-4 had lost PTEN function owing to loss of expression or a mutation, but PCI-66 and PCI-68 retained wild-type PTEN. Phosphorylation of Akt was inhibited by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and the tyrosine kinase inhibitor genistein in KMP-3 and KMP-4 cells, indicating that upstream signals are required for Akt activation in these two cell lines. In contrast, neither LY294002 nor genistein inhibited Akt activation in PCI-66 and PCI-68 cells, indicating the involvement of another unknown mechanism of Akt activation independent of PI3K-mediated signaling to Akt. Irrespective of the differential mechanisms, the 4 cell lines showed similar mRNA expression patterns of 49 genes assessed by cDNA array as compared to the 3 cell lines without Akt activation, suggesting that the mechanisms have the same consequences on the downstream signaling of the constitutive Akt activation.
Primary malignant lymphoma of the brain: mutation pattern of rearranged immunoglobulin heavy chain gene.
Endo S, Zhang SJ, Saito T … +4 more , Kouno M, Kuroiwa T, Washiyama K, Kumanishi T
Jpn J Cancer Res · 2002 Dec · PMID 12495470 · Full text
Using reverse transcription-polymerase chain reaction (RT-PCR), six primary brain lymphomas, pathologically diagnosed as diffuse large B-cell lymphoma, were examined for rearranged VH-D-JH sequences of the immunoglobulin...
Using reverse transcription-polymerase chain reaction (RT-PCR), six primary brain lymphomas, pathologically diagnosed as diffuse large B-cell lymphoma, were examined for rearranged VH-D-JH sequences of the immunoglobulin heavy chain gene, focusing on somatic mutations and intraclonal heterogeneity. The reliability of the isolated PCR clones was confirmed by in situ hybridization (ISH) with complementarity-determining region (CDR) 3 oligonucleotide probes. Sequence analysis of the PCR clones revealed a high frequency of somatic mutation, ranging from 8.8 to 27.3% (mean 18.2%) in the VH gene segments in all the lymphomas. A significantly lower frequency of replacement (R) mutations than expected was also seen in their frameworks (FRs) in all cases. These findings suggested that the precursor cells were germinal center (GC)-related cells in these lymphomas. However, despite extensive cloning experiments, intraclonal heterogeneity was not detected in any case except for one in which it could not be ruled out. Thus, it seemed likely that all of our brain lymphomas were derived from GC-related cells and that at least most of them were from post-GC cells.
Effects of antioxidant 1-O-hexyl-2,3,5-trimethylhydroquinone or ascorbic acid on carcinogenesis induced by administration of aminopyrine and sodium nitrite in a rat multi-organ carcinogenesis model.
Yada H, Hirose M, Tamano S … +6 more , Kawabe M, Sano M, Takahashi S, Futakuchi M, Miki T, Shirai T
Jpn J Cancer Res · 2002 Dec · PMID 12495469 · Full text
The effect of antioxidant, 0.25% 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) or 0.25% ascorbic acid (AsA), on carcinogenesis induced by administration of 0.05% aminopyrine (AP) and 0.05% sodium nitrite (NaNO2), was exam...
The effect of antioxidant, 0.25% 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) or 0.25% ascorbic acid (AsA), on carcinogenesis induced by administration of 0.05% aminopyrine (AP) and 0.05% sodium nitrite (NaNO2), was examined using a rat multi-organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with an initiation regimen of N-diethylnitrosamine, N-methyl-N-nitrosourea, N-butyl-N-(4-hydroxybutyl)nitrosamine, N,N'-dimethylhydrazine and 2,2'-dihydroxy-di-n-propylnitrosamine during the first 4 weeks, followed by AP+NaNO2, AP+NaNO2+HTHQ, AP+NaNO2+AsA, NaNO2+HTHQ, NaNO2+AsA, each of the individual chemicals alone or basal diet and tap water as a control. All surviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic lesions. In the AP+NaNO2 group, the incidences of hepatocellular adenomas and hemangiosarcomas were 95% and 35%, respectively. When HTHQ or AsA was simultaneously administered, the incidences decreased to 58% and 11%, or to 80% and 15%, respectively. On the other hand, in the AP+NaNO2 group and the NaNO2-alone group, when HTHQ, but not AsA, was simultaneously administered, the incidence of carcinomas in the forestomach significantly increased. The results suggest that HTHQ can prevent tumor production induced by AP and NaNO2 more effectively than AsA. On the other hand, an enhancing or possible carcinogenic effect of simultaneous administration of HTHQ and NaNO2 only on the forestomach is suggested, while simultaneous treatment with the same dose of AsA and NaNO2 may not be carcinogenic to the forestomach or other organs.
Earlier Helicobacter pylori infection increases the risk for the N-methyl-N-nitrosourea-induced stomach carcinogenesis in Mongolian gerbils.
Cao X, Tsukamoto T, Nozaki K … +5 more , Tanaka H, Shimizu N, Kaminishi M, Kumagai T, Tatematsu M
Jpn J Cancer Res · 2002 Dec · PMID 12495468 · Full text
Helicobacter pylori (H. pylori) is now well known to be associated with stomach cancer, with infection during childhood rather than as an adult considered to be more important for carcinogenesis. To evaluate the differen...
Helicobacter pylori (H. pylori) is now well known to be associated with stomach cancer, with infection during childhood rather than as an adult considered to be more important for carcinogenesis. To evaluate the difference in susceptibility to stomach carcinogenesis in relation to age of acquisition of H. pylori infection, we designed an experiment involving inoculation of H. pylori ATCC43504 followed by N-methyl-N-nitrosourea (MNU) treatment at different ages. Four-week-old male Mongolian gerbils (MGs) were divided into twelve groups. H. pylori was inoculated at 4, 18 and 32 weeks of age, as representatives of early, middle and late infection, respectively. Two weeks later, the animals were treated with MNU. Groups without H. pylori and/or MNU were included as controls. The incidences of adenocarcinomas at 52 weeks after the inoculation in the early (H. pylori+MNU), middle (H. pylori+MNU), and late (H. pylori+MNU) group were 60% (12/20), 18.4% (2/11), and 10% (2/20), respectively. The corresponding figures were 14.8% (4/27), 0% (0/11), and 0% (0/21) in the MNU-alone groups. A higher titer of serum IgG for H. pylori and higher gastrin level were seen in the early-infected compared to the middle and the late groups (P<0.01). The results clearly demonstrated that early acquisition of H. pylori significantly increases gastric chemical carcinogenesis with MNU, as compared to the case with later infection, possibly because of differences in host gastric mucosal factors and immunologic responses.
Hepatitis B and C viruses infection, lifestyle and genetic polymorphisms as risk factors for hepatocellular carcinoma in Haimen, China.
Yu SZ, Huang XE, Koide T … +11 more , Cheng G, Chen GC, Harada K, Ueno Y, Sueoka E, Oda H, Tashiro F, Mizokami M, Ohno T, Xiang J, Tokudome S
Jpn J Cancer Res · 2002 Dec · PMID 12495467 · Full text
A case-control study was carried out to investigate the impact of factors including virus infection, aflatoxin B1, microcystins, smoking/drinking and dietary habits as well as genetic polymorphisms of aldehyde dehydrogen...
A case-control study was carried out to investigate the impact of factors including virus infection, aflatoxin B1, microcystins, smoking/drinking and dietary habits as well as genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P4502E1 (CYP2E1), on susceptibility to hepatocellular carcinoma (HCC) in Haimen, China. A total of 248 patients with HCC and 248 sex-, age- and residence-matched population-based controls were recruited into the study. Virus infection, and ALDH2 and CYP2E1 gene polymorphisms were assessed in 134 paired cases and controls. By univariate analysis, hepatitis B virus (HBV) infection (odds ratio [OR]=9.75; 95% confidence interval [CI]=4.71-20.2), history of intravenous injection (OR=1.50; 95%CI=1.02-2.22), average income (OR=0.63; 95%CI=0.43-0.92), frequent intake of foods rich in protein, e.g., egg (OR=0.6; 95%CI=0.42-0.87), chicken (OR=0.53; 95%CI=0.35-0.79), pork (OR=0.67; 95%CI=0.46-0.98) and fresh fish (OR=0.58; 95%CI=0.39-0.87) significantly differed between cases and controls. However, peanut intake (OR=0.66; 95%CI=0.43-1.01), source of drinking water, including tap (OR=1.33; 95%CI=0.81-2.20), deep well (OR=0.94; 95%CI=0.56-1.55), shallow well (OR=0.85; 95%CI=0.55=1.30), river (OR=0.95; 95%CI=0.65-1.38), ditch (OR=1.09; 95%CI=0.76-1.55) and pond water (OR=1.0; 95%CI=0.14-7.10) were not significantly associated with risk. Univariate analysis also indicated that the 1-1 genotype of ALDH2 (OR=1.38; 95%CI=0.86-2.23) as well as the Pst1- and Rsa1-digested c1/c1 genotype of CYP2E1 (OR=1.36; 95%CI=0.81-2.28), was slightly more frequent in the case group. On multivariate analysis, HBV infection (OR=13.9; 95%CI=5.78-33.6) and history of intravenous injection (OR=2.72; 95%CI=1.24-6.00) were still associated with significantly increased risk of HCC, while frequent intake of fresh fish (OR=0.32; 95%CI=0.12-0.86) decreased this risk. These findings suggest that whereas peanut intake, water sources as well as genetic polymorphisms in ALDH2 and CYP2E1 do not significantly correlate with the risk of HCC, HBV infection is a main risk factor, and dietary items rich in protein, especially fresh fish, might protect against the risk of HCC in Haimen, China.
Serum insulin-like growth factors, insulin-like growth factor-binding protein-3, and risk of lung cancer death: a case-control study nested in the Japan Collaborative Cohort (JACC) Study.
Wakai K, Ito Y, Suzuki K … +9 more , Tamakoshi A, Seki N, Ando M, Ozasa K, Watanabe Y, Kondo T, Nishino Y, Ohno Y, JACC Study Group
Jpn J Cancer Res · 2002 Dec · PMID 12495466 · Full text
To elucidate the roles of insulin-like growth factors (IGFs) in the development of lung cancer, we conducted a case-control study nested within the Japan Collaborative Cohort Study. Serum samples were collected at baseli...
To elucidate the roles of insulin-like growth factors (IGFs) in the development of lung cancer, we conducted a case-control study nested within the Japan Collaborative Cohort Study. Serum samples were collected at baseline from 39140 men and women between 1988 and 1990. We measured serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in 194 case subjects who subsequently died from lung cancer during an 8-year follow-up and in 9351 controls. The odds ratios (ORs), adjusted for smoking and other covariates, were smaller with higher levels of IGF-II and IGFBP-3. The ORs across quartiles were 0.41 (95% confidence interval [CI], 0.27-0.63), 0.47 (0.31-0.71), and 0.67 (0.46-0.98) for IGF-II (trend P=0.018), and 0.55 (95% CI, 0.37-0.81), 0.54 (0.36-0.82), and 0.67 (0.45-1.01) for IGFBP-3 (trend P=0.037). These peptides were not independently related to lung cancer risk when mutually adjusted. The risk was increased in the highest vs. the lowest quartile of IGF-I only after controlling for IGFBP-3 (OR, 1.74; 95% CI, 1.08-2.81). Limiting subjects to those followed for 3 years strengthened the negative associations of IGF-II and IGFBP-3, whereas the ORs for IGF-I generally decreased. A higher level of circulating IGFBP-3 and / or IGF-II may decrease lung cancer risk. Elevated serum IGF-I may increase the risk, but this could partly be attributable to latent tumors.
Molecular analysis of oncogenes, ras family genes (N-ras, K-ras, H-ras), myc family genes (c-myc, N-myc) and mdm2 in natural killer cell neoplasms.
Sugimoto KJ, Kawamata N, Sakajiri S … +1 more , Oshimi K
Jpn J Cancer Res · 2002 Nov · PMID 12460470 · Full text
Natural killer (NK) cell neoplasms are rare diseases. Frequent abnormalities of the tumor suppressor genes Rb, p53, p15INK4B, p16INK4A and p14ARF have been reported. However, no oncogenes associated with tumorigenesis of...
Natural killer (NK) cell neoplasms are rare diseases. Frequent abnormalities of the tumor suppressor genes Rb, p53, p15INK4B, p16INK4A and p14ARF have been reported. However, no oncogenes associated with tumorigenesis of NK cell neoplasms have been reported so far. We analyzed the status of oncogenes including N-ras, K-ras, H-ras, c-myc, N-myc and mdm2 by Southern blot, PCR-SSCP, western blot analysis and immunohistochemical staining. We analyzed four cell lines derived from NK cell neoplasms and 31 clinical samples with five subclasses of NK cell neoplasms. We found no point mutations of the ras family genes. We detected no mutations in the c-myc and N-myc genes. No overexpression of c-Myc protein was detected by western blot analysis. Although we found neither amplification nor rearrangement of the mdm2 gene, we found high expression of MDM2 protein in some cases by western blot analysis. Immunohistochemical staining confirmed the overexpression of MDM2 protein. We found 14 cases with overexpression of MDM2 protein out of 15 cases (93%) with four subclasses of NK cell neoplasms except chronic NK lymphocytosis. Our previous and these results suggested that the expression level of MDM2 protein is independent of the status of the p14ARF, p53, Rb genes. MDM2 protein might independently contribute to carcinogenesis of NK cell neoplasms. Although the number of the cases we analyzed was not large, alterations of ras and myc family genes may rarely contribute to tumorigenesis in NK cell neoplasms. In contrast, overexpression of MDM2 might be associated with tumorigenesis of NK cell neoplasms, especially aggressive subclasses.
Detection of tumor DNA in serum of colorectal cancer patients.
Ito S, Hibi K, Nakayama H … +4 more , Kodera Y, Ito K, Akiyama S, Nakao A
Jpn J Cancer Res · 2002 Nov · PMID 12460469 · Full text
We previously found p16 promoter methylation in DNA in the sera of 13 colorectal cancer patients out of 44 (30%) whose tumor DNA exhibited the methylation, using methylation-specific PCR (MSP). To examine whether the can...
We previously found p16 promoter methylation in DNA in the sera of 13 colorectal cancer patients out of 44 (30%) whose tumor DNA exhibited the methylation, using methylation-specific PCR (MSP). To examine whether the cancer detection rate could be improved by using a different tumor marker, we examined the K-ras status in 90 colorectal cancer patients using a mismatch ligation assay. Among the 31 patients showing K-ras gene mutations in their tumors, the same mutations were observed in serum DNA of 11 patients (35%). Among the 90 patients, 63 showed tumors positive for K-ras mutation or p16 promoter methylation, or both, and 22 had serum DNA positive for one or both. K-ras mutation was found even in serum DNA of patients with Dukes A cancer, suggesting that colorectal cancer might be detected even in patients without symptoms by using this ligation assay.
Multiparametric in situ mRNA hybridization analysis of gastric biopsies predicts lymph node metastasis in patients with gastric carcinoma.
Takahashi Y, Kitadai Y, Ellis LM … +3 more , Bucana CD, Fidler IJ, Mai M
Jpn J Cancer Res · 2002 Nov · PMID 12460468 · Full text
We examined the expression level of several genes that regulate different steps in metastasis formation in formalin-fixed, paraffin-embedded biopsies of 189 primary human gastric carcinomas prior to surgical resection in...
We examined the expression level of several genes that regulate different steps in metastasis formation in formalin-fixed, paraffin-embedded biopsies of 189 primary human gastric carcinomas prior to surgical resection in patients in whom lymph node metastasis was not evident by endoscopic ultrasound or computed tomography (CT) scan. The expressions of epidermal growth factor receptor (EGF-R), vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2 and E-cadherin were examined by a colorimetric in situ mRNA hybridization technique. The integrity of the mRNAs was verified, leaving 161 (85.2%) patients for study. After gastrectomy, 82 patients had positive lymph nodes and 79 patients had negative lymph nodes. The concurrent expression levels of MMP-2 and E-cadherin mRNAs were significantly higher and lower, respectively, in the metastatic tumors than the non-metastatic tumors. Expression of EGF-R and VEGF was not different between the metastatic and non-metastatic tumors. However, when only the intestinal-type of gastric cancer was evaluated, the level of VEGF mRNA was significantly higher in tumors associated with lymph node metastasis than in those without metastasis. However, a high MMP-2:E-cadherin ratio significantly correlated with lymph node metastasis in both types of gastric cancer. These results suggest that multiparametric in situ hybridization analysis for several metastasis-related genes may allow the preoperative prediction of lymph node metastasis from gastric cancer.
HER2 is frequently over-expressed in ovarian clear cell adenocarcinoma: possible novel treatment modality using recombinant monoclonal antibody against HER2, trastuzumab.
Fujimura M, Katsumata N, Tsuda H … +5 more , Uchi N, Miyazaki S, Hidaka T, Sakai M, Saito S
Jpn J Cancer Res · 2002 Nov · PMID 12460467 · Full text
Ovarian clear cell adenocarcinoma (CCA) is generally chemo-resistant. Recently the poor prognosis and resistance to chemotherapeutic agents of HER2/neu over-expressing tumors have become clear. Thus, we investigated the...
Ovarian clear cell adenocarcinoma (CCA) is generally chemo-resistant. Recently the poor prognosis and resistance to chemotherapeutic agents of HER2/neu over-expressing tumors have become clear. Thus, we investigated the expression level of HER2 in surgically resected CCA and ovarian serous adenocarcinoma, endometrioid adenocarcinoma, and mucinous adenocarcinoma specimens, as well as CCA cell lines, by an immunohistochemical method. HER2 was over-expressed in 42.9% of CCA (P=0.026, vs. ovarian serous adenocarcinoma), 20.8% of ovarian serous adenocarcinoma, 23.1% of ovarian endometrioid adenocarcinoma, and 30.0% of mucinous adenocarcinoma specimens. Three CCA cell lines, RMG-1, HAC-II and KK were also positively stained for HER2. A flow-cytometric study of HER2 revealed 7.2-, 6.4- and 4.5-fold greater expression of HER2 than that of normal mammary gland, respectively. Trastuzumab, a humanized recombinant monoclonal antibody against HER2 significantly and dose-dependently reduced the growth of CCA cell lines in vitro. The extent of the inhibitory effect of trastuzumab was dependent on the expression level of HER2. Trastuzumab also dose-dependently inhibited the growth of xenografted RMG-1 tumor. The survival period of trastuzumab-treated mice was longer than that of the control group. From these findings, trastuzumab appears to be a candidate as a treatment modality for HER2 over-expressing ovarian CCA.
Liposome formulations for effective administration of lipophilic malonatoplatinum(II) complexes.
Han I, Jun MS, Kim MK … +2 more , Kim JC, Sohn YS
Jpn J Cancer Res · 2002 Nov · PMID 12460466 · Full text
For effective administration of lipophilic trans(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of malonate derivatives [(dach)PtL, L=allylmalonate (AM), diallylmalonate (DAM), allylbenzylmalonate (ABM), or dibenzylma...
For effective administration of lipophilic trans(+/-)-1,2-diaminocyclohexaneplatinum(II) complexes of malonate derivatives [(dach)PtL, L=allylmalonate (AM), diallylmalonate (DAM), allylbenzylmalonate (ABM), or dibenzylmalonate (DBM)] in aqueous solution, we have applied three different liposome formulations and evaluated their physical and chemical properties, along with their in vitro cytotoxicity. The liposome formulations were composed of DMPC / DMPG [DMPC=1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPG=1,2-dimyristoyl-sn-glycero-3-(phospho-rac-1-glycerol) (sodium salt)] in different molar ratios (7/3 or 3/7) or an equimolar DOTAP/DOPE formulation (DOTAP=1,2-dioleoyl-3-trimethylammonium propane, DOPE=1,2-dioleoyl-sn-glycero-3-phosphoethanolamine). Preliposomal powders of the platinum complexes were prepared by lyophilization, and reconstituted in aqueous solution to obtain the final liposomal platinum complexes. Due to the lipophilicity of the malonatoplatinum complexes, the entrapment efficiency of drugs within the liposomes was over 90% except for the AM complex, and platinum drug stability was also satisfactory (>90%) in these liposomal systems. In vitro cytotoxicity was tested in human ovarian carcinoma cells sensitive (A2780) and resistant to cisplatin (A2780/PDD). In both cell lines, the liposomal DBM complex was much more cytotoxic than the corresponding DAM and ABM complexes, which means that the more hydrophobic benzyl substituent affords higher cytotoxicity than the allyl substituent in the malonato leaving group. Furthermore, the DBM complex in DMPC/DMPG formulations was effective against both sensitive and resistant A2780 cells (resistance indexes (RI)=1.10-1.49), showing lack of cross-resistance to cisplatin. Therefore, the liposomal DBM complex in the DMPC/DMPG formulations is a promising candidate for stable pharmaceutical liposomal platinum complexes.
Incorporation of the anticancer agent KRN5500 into polymeric micelles diminishes the pulmonary toxicity.
Mizumura Y, Matsumura Y, Yokoyama M … +4 more , Okano T, Kawaguchi T, Moriyasu F, Kakizoe T
Jpn J Cancer Res · 2002 Nov · PMID 12460465 · Full text
KRN5500 is a highly active new semi-synthetic water-insoluble anticancer agent. The only mechanism of anticancer activity of KRN5500 described so far is an inhibitory effect on protein synthesis. At the time of writing,...
KRN5500 is a highly active new semi-synthetic water-insoluble anticancer agent. The only mechanism of anticancer activity of KRN5500 described so far is an inhibitory effect on protein synthesis. At the time of writing, a phase I clinical trial is under way at the National Cancer Center Hospital, Tokyo, and at the National Cancer Institute in the USA. Although preclinical data did not indicate lung toxicity, some cases of severe pulmonary disorder were reported in the phase I clinical trials. This study has been conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce the toxic effects caused by the current formulation of KRN5500. The in vitro and in vivo antitumor activities of KRN5500 and KRN/m were compared. Pulmonary toxicity of KRN5500 and KRN/m was studied using a bleomycin (BLM)-induced lung injury rat model. In BLM-rats, extensive pulmonary hemorrhage with diapedesis was observed with KRN5500 i.v. bolus injection at the dose of 3 mg/kg, which is equivalent to 21.0 mg/m2 (level 5) of the Japanese phase I trial. However, toxicity was not observed when rats were administered KRN / m at the equivalent dose to KRN5500 in potency. Electron microscopy of the lung treated with KRN5500 showed disruption of the alveolar type II membrane with release of lamellar debris. Furthermore, in vivo, KRN/m showed similar antitumor activity to KRN5500. These results indicate that KRN/m may be useful for reducing the pulmonary toxicity associated with the current formulation of KRN5500, while fully maintaining its antitumor activity.
Quantitative analysis of multidrug-resistance mdr1 gene expression in head and neck cancer by real-time RT-PCR.
Tseng CP, Cheng AJ, Chang JT … +5 more , Tseng CH, Wang HM, Liao CT, Chen IH, Tseng KC
Jpn J Cancer Res · 2002 Nov · PMID 12460464 · Full text
Progression of head and neck cancer is always associated with changes of gene expression profile. In this study, we characterized the expression of multidrug-resistance mdr1 gene, which may play a role in tumorigenesis a...
Progression of head and neck cancer is always associated with changes of gene expression profile. In this study, we characterized the expression of multidrug-resistance mdr1 gene, which may play a role in tumorigenesis and multidrug resistance in head and neck cancer. A TaqMan one-step RT-PCR with a linear range for quantification across at least a 5 log scale of concentration of mdr1 mRNA was designed to determine the level of mdr1 expression in 50 pairs of normal vs. malignant head and neck tissues. Both the absolute level of mdr1 mRNA in tumor (T) and the relative mdr1 expression between tumor and its normal counterpart (T/N) were measured and their associations with several clinical variables were analyzed. Among the clinical variables analyzed, only the clinical stage of tumor was found to be associated with mdr1 expression. The distribution of clinical stages differed significantly (P<0.01) among the 27 specimens that had a T/N>1, with 59.3%, 22.2%, 14.8% and 3.7% in stage IV, III, II, and I, respectively. In addition, 76% of stage IV and 75% of stage III tumors had a T/N>1 compared to 25% of stage II and 20% of stage I tumors (P=0.004). Multivariate logistic regression analysis also indicated a significant difference of mdr1 expression between the early (I and II) and advanced (III and IV) stages tumors. The adjusted odds ratios (95% confidence intervals) were 1.477 (1.084 - 2.012) and 1.001 (1.000-1.002) for T/N (P<0.05) and T (P<0.05) treated as continuous variables, and 15.521 (3.414-70.550) and 5.074 (1.154-22.311) for T/N (P<0.001) and T (P<0.05) treated as binary variables, respectively. Taken together, the data presented here indicated that real-time RT-PCR provides a quantitative way to monitor mdr1 gene expression. The differential expression of mdr1 between early and advanced stages of head and neck cancer may shed light on the process of tumorigenicity and offer clues to the planning of new treatments.
Functional polymorphism of the thymidylate synthase gene in colorectal cancer accompanied by frequent loss of heterozygosity.
Kawakami K, Ishida Y, Danenberg KD … +3 more , Omura K, Watanabe G, Danenberg PV
Jpn J Cancer Res · 2002 Nov · PMID 12460463 · Full text
The thymidylate synthase (TS) gene has a polymorphic repeated sequence in its 5'-untranslated region. The repeat length is associated with TS protein expression, which suggests that we may be able to predict the efficacy...
The thymidylate synthase (TS) gene has a polymorphic repeated sequence in its 5'-untranslated region. The repeat length is associated with TS protein expression, which suggests that we may be able to predict the efficacy of 5-fluorouracil (5-FU)-based chemotherapy from a patient's TS genotype determined through analysis of normal tissue obtained non-invasively. However, it is not yet elucidated whether the TS genotype is identical in tumor and normal tissue. In this study, we investigated the TS genotype in 151 matched tumor and normal DNA samples isolated from colorectal cancer and adjacent normal tissues by PCR analysis. The results showed that TS genotypes are identical in normal and tumor tissues of homozygous individuals, suggesting that the repeat sequence is stable through carcinogenesis. However, in heterozygous samples, an imbalance between the 2R and 3R alleles in the tumor DNA was frequently observed, suggesting loss of heterozygosity (LOH) at the TS locus. Detailed LOH analysis revealed that 62% (31 of 50) of 2R/3R-heterozygous samples had LOH. Frequent LOH at the TS locus was confirmed by RT-PCR of TS mRNA and microsatellite analysis using the marker D18S59, located on 18p11.3. There was no difference in the expressions of TS mRNA and TS protein between LOH and non-LOH samples. However, when the heterozygous genotype bearing LOH was subdivided according to the number of repeats, the cancer tissue with 2R/loss genotype expressed a significantly lower level of TS protein than did that with 3R/loss genotype. The results suggest that the difference in TS genotype between tumor and normal tissue due to LOH should be considered when the genotype is analyzed with normal tissue, such as peripheral blood cells, because it is important for TS protein expression.
Analysis of the beta-catenin/T cell factor signaling pathway in 36 gastrointestinal and liver cancer cells.
Ikenoue T, Ijichi H, Kato N … +8 more , Kanai F, Masaki T, Rengifo W, Okamoto M, Matsumura M, Kawabe T, Shiratori Y, Omata M
Jpn J Cancer Res · 2002 Nov · PMID 12460462 · Full text
We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift...
We investigated the frequency and mechanism of beta-catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the beta-catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or beta-catenin, and Tcf-4 was highly expressed in these cell lines with upregulated signaling. Nuclear beta-catenin was observed not only in the signaling-activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling-upregulated gastric cancer cell lines with intact APC and beta-catenin suggests the involvement of other mechanisms than mutations of APC or beta-catenin.
Fuzzy neural network applied to gene expression profiling for predicting the prognosis of diffuse large B-cell lymphoma.
Ando T, Suguro M, Hanai T … +3 more , Kobayashi T, Honda H, Seto M
Jpn J Cancer Res · 2002 Nov · PMID 12460461 · Full text
Diffuse large B-cell lymphoma (DLBCL) is the largest category of aggressive lymphomas. Less than 50% of patients can be cured by combination chemotherapy. Microarray technologies have recently shown that the response to...
Diffuse large B-cell lymphoma (DLBCL) is the largest category of aggressive lymphomas. Less than 50% of patients can be cured by combination chemotherapy. Microarray technologies have recently shown that the response to chemotherapy reflects the molecular heterogeneity in DLBCL. On the basis of published microarray data, we attempted to develop a long-overdue method for the precise and simple prediction of survival of DLBCL patients. We developed a fuzzy neural network (FNN) model to analyze gene expression profiling data for DLBCL. From data on 5857 genes, this model identified four genes (CD10, AA807551, AA805611 and IRF-4) that could be used to predict prognosis with 93% accuracy. FNNs are powerful tools for extracting significant biological markers affecting prognosis, and are applicable to various kinds of expression profiling data for any malignancy.
Analysis of Fas gene mutations on laser capture microdissected specimens from renal cell carcinoma.
Takayama H, Takakuwa T, Tsujimoto Y … +3 more , Nonomura N, Okuyama A, Aozasa K
Jpn J Cancer Res · 2002 Nov · PMID 12460460 · Full text
Renal cell carcinoma (RCC) expresses Fas antigen on the cell surface, and thus could be sensitive to apoptosis induced by the binding of Fas ligand. Fas gene mutations might be involved in the development of RCC. Fas gen...
Renal cell carcinoma (RCC) expresses Fas antigen on the cell surface, and thus could be sensitive to apoptosis induced by the binding of Fas ligand. Fas gene mutations might be involved in the development of RCC. Fas gene mutations were examined in genomic DNA extracted from RCC lesions. With use of laser capture methods, one RCC and one non-neoplastic lesion per case were microdissected from 15 patients with RCC. Polymerase chain reaction-amplified products were directly sequenced. Loss of heterozygosity (LOH) was examined at four sites of known polymorphism. Mutations of the Fas gene were detected in 3 RCC lesions from 3 (20%) of 15 cases. All mutations were point mutations, 2 missense and one silent, in exons 7 and 9. Non-neoplastic tissues never showed Fas gene mutations. Nine of 15 cases (60.0%) were heterozygous for one or more sites of the known biallelic polymorphisms, i.e., at nucleotides -1377, -670, 416, and 836. Two of these 9 cases showed LOH at promoter region -670. Mouse T-cell lymphoma cells transfected with missense mutated genes were resistant to apoptosis induced by anti-Fas antibody, indicating these to be loss-of-function mutations. The results of the present study suggest that Fas gene mutations play a role in the pathogenesis of RCC.
Reduced expression and promoter methylation of p16 gene in Epstein-Barr virus-associated gastric carcinoma.
Osawa T, Chong JM, Sudo M … +6 more , Sakuma K, Uozaki H, Shibahara J, Nagai H, Funata N, Fukayama M
Jpn J Cancer Res · 2002 Nov · PMID 12460459 · Full text
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a unique type of gastric carcinoma (GC), which is considered to develop in a different pathway from EBV-negative GC. To evaluate a possible role of p16, a...
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a unique type of gastric carcinoma (GC), which is considered to develop in a different pathway from EBV-negative GC. To evaluate a possible role of p16, an inhibitor of G1/S transition of the cell cycle, in the carcinogenesis of EBVaGC, p16-immunohistochemistry and methylation-specific PCR analysis (MSP) were applied to surgically resected gastric carcinomas. When the percentage of p16-positive cells in more than 1000 carcinoma cells was expressed as p16 labeling index (p16-LI), it ranged from 2.5 to 88.1 (mean 42.9+/-24.4) in 70 gastric carcinomas. EBVaGC showed significantly lower values (n=15, 26.1+/ -22.1) than EBV-negative GC (n=55, 47.5+/-23.2) (P=0.0036). Fresh frozen tissues of 55 gastric carcinomas (16 EBVaGC and 39 EBV-negative GC) were further subjected to MSP, to evaluate abnormal methylation of the promoter region of the p16 gene. The frequency of methylation was significantly higher in EBVaGC (14/16) than in EBV-negative GC (9/39) (<0.0001). The methylation-positive carcinomas showed significantly lower p16-LI (35.9+/-21.6) than the unmethylated ones (55.2+/-22.7) (P=0.0014). Thus, a marked decrease of p16 expression, caused by the aberrant methylation of the p16 gene promoter, is closely associated with the development of EBVaGC.
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