Li ZZ, Kondo T, Murata T
… +6 more, Ebersole TA, Nishi T, Tada K, Ushio Y, Yamamura K, Abe K
Jpn J Cancer Res
· 2002 Feb · PMID 11856480
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The quaking gene family encodes single KH domain RNA-binding proteins that play vital roles in cell differentiation, proliferation, and apoptotic processes. The human quaking gene, Hqk, maps to 6q25-q26, where cytogeneti...The quaking gene family encodes single KH domain RNA-binding proteins that play vital roles in cell differentiation, proliferation, and apoptotic processes. The human quaking gene, Hqk, maps to 6q25-q26, where cytogenetic alterations associated with a variety of human malignancies, including gliomas have been reported. To assess possible relationships of Hqk with human diseases such as glial tumors, we first isolated the Hqk gene, characterized its structure and expression pattern, and carried out mutational analysis of Hqk in primary tumor samples. The Hqk gene contains 8 exons spanning a approximately 200 kb genomic region, and generating at least four alternatively spliced transcripts, Hqk-5, Hqk-6, Hqk-7 and Hqk-7B, of which Hqk-7 is abundantly expressed in brain. Analysis of primary tumors demonstrated a high incidence of expression alterations of Hqk in gliomas (30%; 6/20), but not in other tumors such as schwannomas (0/3), or meningiomas (0/8). Among the tumor samples showing expression alterations, two were devoid of all three major transcripts, one was missing only the Hqk-5 message, and only the Hqk-7 message was absent in two cases. Our results thus imply the involvement of Hqk in human glial tumor progression.
Deguchi A, Segawa K, Hosaka K
… +2 more, Weinstein IB, Umezawa K
Jpn J Cancer Res
· 2002 Feb · PMID 11856479
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Phosphatidylinositol (PI) turnover is thought to play an important role in the regulation of cell growth. PI synthase (PIS, cytidine diphosphate (CDP)-diacylglycerol (DG): myo-inositol 3-phosphatidyltransferase, EC 2.7.8...Phosphatidylinositol (PI) turnover is thought to play an important role in the regulation of cell growth. PI synthase (PIS, cytidine diphosphate (CDP)-diacylglycerol (DG): myo-inositol 3-phosphatidyltransferase, EC 2.7.8.11) acts at the last step in the de novo biosynthesis of PI by catalyzing the condensation of CDP-DG and myo-inositol. To study the physiological role of PIS, we established murine NIH3T3 fibroblasts that stably overexpress PIS, by transfection with PIS cDNA (NIH-PIS cells). In immunofluorescence assays, the constitutively overexpressed PIS was found to be localized in the endoplasmic reticulum, as previously reported for the native enzyme activity. NIH-PIS cells showed an increase in PI synthesis in vitro and in vivo, as well as increased cellular levels of PI-4,5-P2 and PI-3,4,5-P3. They also displayed a decrease in their doubling time and accelerated G1 progression. Overexpression of PIS increased cellular levels of the cyclin D1 and E proteins and Akt kinase activity in serum-stimulated quiescent NIH3T3 cells. Moreover, PIS overexpression potentiated the colony formation of NIH3T3 cells in soft agar. These results suggest that PIS accelerates G1 progression and stimulates growth by increasing cellular levels of cyclins D1 and E.
Choi YK, Yoon BI, Kook YH
… +7 more, Won YS, Kim JH, Lee CH, Hyun BH, Oh GT, Sipley J, Kim DY
Jpn J Cancer Res
· 2002 Feb · PMID 11856478
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The significance of urokinase-type plasminogen activator (uPA) expression in gastric cancer development was tested by using a human uPA cDNA transfection approach and an in vivo severe combined immunodeficient (SCID) mou...The significance of urokinase-type plasminogen activator (uPA) expression in gastric cancer development was tested by using a human uPA cDNA transfection approach and an in vivo severe combined immunodeficient (SCID) mouse model. The AGS gastric cancer cell line, which has urokinase-type plasminogen-activator receptor (uPAR) but lacks uPA, was transfected with a plasmid containing human uPA cDNA and injected into the backs of SCID mice. Compared with the parent AGS cells, uPA protein secretion in AGS-2-, AGS-4-, and AGS-8-transfected cells increased by 26.1-, 34.6-, and 4.8-fold, respectively (P < 0.05). mRNA expression levels of uPA in the AGS-4 clone were much stronger than those in AGS-2 and AGS-8 clones. After the cancer cells (2 x 10(6)) were injected s.c. into the SCID mice, a palpable mass was observed at the injection site at around 140 days post-injection, followed by accelerated growth of the xenograft up to 180 days post-injection only in the high uPA-producing clone (AGS-4). These results suggest that continuous and high production of uPA by tumor cells is one of the important factors reflecting the malignancy of gastric cancer cells.
Narisawa T, Fukaura Y, Takeba N
… +1 more, Nakai K
Jpn J Cancer Res
· 2002 Feb · PMID 11856477
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Bile acids enhance colon carcinogenesis in animal models, whereas ursodeoxycholic acid (UDCA) suppresses it. Nonsteroid anti-inflammatory drugs prevent colon cancer development in animals and humans. The aim of the prese...Bile acids enhance colon carcinogenesis in animal models, whereas ursodeoxycholic acid (UDCA) suppresses it. Nonsteroid anti-inflammatory drugs prevent colon cancer development in animals and humans. The aim of the present study was to explore the inhibitory effect of UDCA conjugate with 5-aminosalicylic acid (5-ASA), UDCA-5-ASA conjugate (UDCA-5-ASA), against colon carcinogenesis in rats. One-hundred-and-twenty-nine 7-week-old F344 rats received an intrarectal instillation of 2 mg of N-methylnitrosourea 3 times a week for 3 weeks, and were fed a 0% (control), 0.11% or 0.02% UDCA-5-ASA-, 0.08% UDCA- or 0.03% 5-ASA-supplemented diet for the next 27 weeks. The test diets contained an equimolar amount of a test agent, 2.0 mmol/kg diet, except for the 0.02% UDCA-5-ASA diet. The tumor incidence and the mean number of tumors/rat at week 30 were significantly lower and smaller in the UDCA-5-ASA diet groups, 48% and 0.7 in both, and marginally lower in the UDCA and 5-ASA diet groups, 56% and 0.9, and 64% and 0.8, compared to the control group, 83% and 1.3. All the tumors were polypoid in shape, and most of them were differentiated adenocarcinomas restricted to the mucosa or submucosa. An analysis by HPLC for bile acids and 5-ASA in the feces and serum collected at week 30 showed that one-half of ingested UDCA-5-ASA was cleaved into UDCA and 5-ASA in the colon. Thus, the two moieties may have independently affected the promotion stage of carcinogenesis.
Kohno H, Suzuki R, Noguchi R
… +3 more, Hosokawa M, Miyashita K, Tanaka T
Jpn J Cancer Res
· 2002 Feb · PMID 11856476
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The modifying effects of dietary feeding of conjugated linolenic acid (CLN) isolated from the seeds of bitter gourd (Momordica charantia) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF)...The modifying effects of dietary feeding of conjugated linolenic acid (CLN) isolated from the seeds of bitter gourd (Momordica charantia) on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats to predict its possible cancer chemopreventive efficacy. The effect of CLN on the proliferating cell nuclear antigen (PCNA) index in colonic ACF was also examined. Rats were given subcutaneous injections of AOM (20 mg/kg body weight) once a week for 2 weeks to induce ACF. They also received the experimental diet containing 0.01%, 0.1% or 1% CLN for 5 weeks, starting one week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (108 +/- 21/rat) at the end of the study (week 4). Dietary administration of CLN caused a significant reduction in the frequency of ACF: 87 +/- 14 (19.4% reduction, P < 0.05) at a dose of 0.01%, 69 +/- 28 (36.1% reduction, P < 0.01) at a dose of 0.1% and 40 +/- 6 (63.0% reduction, P < 0.001) at a dose of 1%. Also, CLN administration lowered the PCNA index and induced apoptosis in ACF. These findings might suggest possible chemopreventive activity of CLN in the early phase of colon tumorigenesis through modulation of cryptal cell proliferation activity and/or apoptosis.
Denda A, Kitayama W, Kishida H
… +5 more, Murata N, Tsutsumi M, Tsujiuchi T, Nakae D, Konishi Y
Jpn J Cancer Res
· 2002 Feb · PMID 11856475
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Development of hepatocellular carcinomas in rats caused by a choline-deficient, L-amino acid-defined (CDAA) diet, usually associated with fatty liver, fibrosis, cirrhosis and oxidative DNA damage, has been recognized as...Development of hepatocellular carcinomas in rats caused by a choline-deficient, L-amino acid-defined (CDAA) diet, usually associated with fatty liver, fibrosis, cirrhosis and oxidative DNA damage, has been recognized as a useful model of hepatocarcinogenesis caused by endogenous factors. In the present study, in order to further explore involved factors and genes, we established an equivalent model in spontaneous liver tumor-resistant C57BL/6J mice. Six-week-old males and females were continuously fed the CDAA diet and histological liver lesions and oxidative DNA damage due to 8-hydroxydeoxyguanosine (8-OHdG) were examined after 22, 65 and 84 weeks. In male mice, fatty change and fibrosis were evident at 22 weeks, and preneoplastic foci of altered hepatocytes were seen at an incidence of 8/8 (100%) and a multiplicity of 6.6 +/- 4.0 per mouse at 65 weeks. Hepatocellular adenomas and carcinomas developed at incidences of 16/24 (66.7%) and 5/24 (20.8%), and multiplicities of 1.42 +/- 1.32 and 0.29 +/- 0.62, respectively, at 84 weeks. The female mice exhibited resistance to development of these lesions. The CDAA diet also increased 8-OHdG levels in male but not female mice. These results indicate that a CDAA diet causes hepatocellular preneoplastic foci, adenomas and carcinomas associated with fibrosis and oxidative DNA damage in mice, as in rats, providing a hepatocarcinogenesis model caused by endogenous factors in mice.
Katsuda S, Yoshida M, Kuroda H
… +6 more, Ando J, Takahashi M, Kurokawa Y, Watanabe G, Taya K, Maekawa A
Jpn J Cancer Res
· 2002 Feb · PMID 11856474
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Since many risk factors are associated with the development of uterine adenocarcinomas in humans, the etiology is unclear in most cases, although it has been pointed out that estrogen may play essential roles. To clarify...Since many risk factors are associated with the development of uterine adenocarcinomas in humans, the etiology is unclear in most cases, although it has been pointed out that estrogen may play essential roles. To clarify the effects of exposure to p-tert-octylphenol (OP), an environmental xenoestrogen, on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and exposed thereafter to 100 mg / kg OP by s.c. injection until 15 months of age. Adult ovariectomized (OVX) rats were also treated in a similar way. OP had no effect on occurrence of persistent estrus in middle age, although uterotrophic effects were obvious in OVX rats. At the termination, development of uterine adenocarcinomas was significantly increased in animals exposed to OP during adulthood. No tumors, but a few focal hyperplasias, developed in OVX rats. These findings suggest that OP has tumor-promoting effects on ENNG-treated endometrium of rats, possibly due to direct action on the uterus, as indicated by the uterotrophic effect when a high dose of OP was given. The results provide clues to the mechanisms of influence of hormonal disrupters on uterine carcinogenesis.
Nakamura Y, Sakagami T, Yamamoto N
… +7 more, Yokota Y, Koizuka H, Hori K, Fukuda Y, Tanida N, Kobayashi T, Shimoyama T
Jpn J Cancer Res
· 2002 Feb · PMID 11856473
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Helicobacter pylori (H. pylori) infection has been acknowledged as a promoter and an initiator for gastric carcinogenesis in experimental models using Mongolian gerbils with H. pylori strains TN2GF4 and ATCC 43504, which...Helicobacter pylori (H. pylori) infection has been acknowledged as a promoter and an initiator for gastric carcinogenesis in experimental models using Mongolian gerbils with H. pylori strains TN2GF4 and ATCC 43504, which have + ve cagA and vacA phenotype s1 / m1. To get more insight into the role of H. pylori in gastric carcinogenesis, we studied the effect of H. pylori SS1, which has + ve cagA and vacA phenotype s2 / m2, on N-methyl-N-nitrosourea (MNU)-induced chemical gastric carcinogenesis using SPF C57BL / 6 mice. Thus, H. pylori SS1 was inoculated 1 week after the completion of MNU treatment to examine the promoting effect of this bacterium. The incidences of polypoid lesions, differentiated adenocarcinomas, and adenomatous hyperplasias were 67% (10 / 15), 47% (7 / 15) and 80% (12 / 15), respectively, in the MNU-alone group. The corresponding figures were 31% (8 / 26), 23% (6 / 26) and 35% (9 / 26) in the MNU + H. pylori group. The incidences of polypoid lesions and adenomatous hyperplasia were significantly different between the groups. Thus, the results indicate that H. pylori SS1 infection reduced susceptibility to chemical gastric carcinogenesis in this model. The discrepancy between the present result and previous results is likely to have been caused by differences in host factors and bacterial factors. Further study of the relationship between gastric carcinogenesis and H. pylori infection is needed.
Shinkai M, Ueda K, Ohtsu S
… +3 more, Honda H, Kohri K, Kobayashi T
Jpn J Cancer Res
· 2002 Jan · PMID 11802814
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Specific heating of magnetic particles in radiofrequency (RF) capacitive hyperthermia and its hyperthermic effect were investigated in an in vivo study. Magnetite cationic liposomes (MCLs) were injected into a rat tumor...Specific heating of magnetic particles in radiofrequency (RF) capacitive hyperthermia and its hyperthermic effect were investigated in an in vivo study. Magnetite cationic liposomes (MCLs) were injected into a rat tumor on the femur and 8 MHz-RF capacitive heating was applied to the rat under "mild heating" conditions. Although the input power of RF capacitive heating was low under the same power conditions, the MCLs-injected tumor was heated over 43 degrees C, whereas it was only heated to 41 degrees C in the case of the rats not injected with MCLs. A necrotic area in the tumor was observed in the heated rats. From the results of histological observation of the removed tissue, the necrotic area in the MCLs-injected tumor was wider than that in MCLs-free tumor. Complete tumor suppression was observed in 71% (5 / 7) of MCLs-injected rats, and the hyperthermic effect was greatly improved by the MCLs.
Okamoto R, Takano H, Okamura T
… +7 more, Park JS, Tanimoto K, Sekikawa T, Yamamoto W, Sparreboom A, Verweij J, Nishiyama M
Jpn J Cancer Res
· 2002 Jan · PMID 11802813
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The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O(6)-methylguanine-DNA methyltransferase (...The precise mechanisms of resistance to camptothecin (CPT)-derived DNA topoisomerase (topo I) inhibitors and the determinants remain unclear. We found that a DNA repair protein, O(6)-methylguanine-DNA methyltransferase (MGMT), participated in resistance to irinotecan hydrochloride (CPT-11), its active metabolite SN-38, and a novel CPT derivative, DX-8951f. In 17 human cancer cell lines, MGMT gene expression level closely correlated with sensitivity to the CPT derivatives, and inhibition of MGMT activity by nontoxic 5 microM O(6)-benzylguanine augmented the drug activity in relation to the MGMT expression levels in 8 cell lines examined. Transfection of pCR / MGMT-sense into U-251MG and pCR / MGMT-antisense into T98G and HEC-46 cells revealed that increased MGMT expression decreased the sensitivity to CPT-11, SN-38, and DX-8951f, whereas repressed MGMT expression sensitized cells to the drugs. Western analysis revealed that treatment of MGMT-expressing T98G cells with the drugs caused a decrease of both MGMT and topo I in a dose-dependent manner. Although, in the transfectants, MGMT expression did not so closely correlate with the sensitivity to drugs as to nimustine hydrochloride (ACNU), MGMT is probably an important resistance determinant to CPT derivatives, and may play some role in the topo I-mediated DNA damage and / or the repair process.
Sahara H, Hanashima S, Yamazaki T
… +12 more, Takahashi S, Sugawara F, Ohtani S, Ishikawa M, Mizushina Y, Ohta K, Shimozawa K, Gasa S, Jimbow K, Sakaguchi K, Sato N, Takahashi N
Jpn J Cancer Res
· 2002 Jan · PMID 11802812
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We recently reported that 3'-sulfonoquinovosyl-1'-monoacylglycerol (designated A-5) extracted from sea urchin intestine was effective in suppressing the growth of solid tumors. Although the major fatty acid component of...We recently reported that 3'-sulfonoquinovosyl-1'-monoacylglycerol (designated A-5) extracted from sea urchin intestine was effective in suppressing the growth of solid tumors. Although the major fatty acid component of A-5 was a saturated C(16) acid, there were five other fatty acids, 14:0, 18:0, 14:1, 16:1, and 18:1, which constitute minor components of A-5. Therefore, it remains unclear as to which of these six fatty acid components of A-5 has the anti-tumor effect. In this study, we synthesized sulfolipids each containing only one of these six fatty acids and tested their cytotoxicity against tumor cells and in vivo anti-tumor effects on nude-mice bearing solid tumors of human lung adenocarcinoma cell line A-549. The IC(50) values of all products against tumor cells were more than 10(-5) M, suggesting weak cytotoxic activity compared with other chemotherapeutic compounds for cancer. On the other hand, in vivo anti-tumor assay showed that sulfoquinovosylmonoacylglycerols (SQMG) composed of 14:1 and 18:1 (designated SQMG(14:1) and SQMG(18:1), respectively) were significantly effective in suppressing the growth of solid tumors. Our data suggested that these two SQMGs had a substantial anti-tumor effect in vivo, and they are of interest as candidate drugs for anti-cancer treatment.
Jpn J Cancer Res
· 2002 Jan · PMID 11802811
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One concept for immune therapy of cancer involves induction of antigen mimic antibodies to trigger the immune system into a response against the tumor cells. Anti-idiotypic antibodies (Ab2) directed against the antigen-c...One concept for immune therapy of cancer involves induction of antigen mimic antibodies to trigger the immune system into a response against the tumor cells. Anti-idiotypic antibodies (Ab2) directed against the antigen-combining site of other antibodies (Ab1) may functionally and even structurally mimic antigen and induce anti-anti-idiotypic immune response. We report here the generation of murine monoclonal antibody (mAb) WJ02 (Ab2) raised against the murine monoclonal immunoglobulin MJ01 (Ab1), which defines ovarian cancer antigen CA125. In enzyme immunoassays the binding of Ab2 to the variable region of Ab1 could be inhibited by CA125. In addition, the mimicry of mAb WJ02 to CA125 on cellular immune response was detected by human peripheral blood cells. The T cells primed by mAb WJ02 or CA125 proliferated in the presence of CA125 or mAb WJ02, respectively. Furthermore, T cells specific to mAb WJ02 could lyse ovarian cancer cells OVCAR-3 that express CA125. Finally, we proved that a patient immunized with mAb MJ01 could induce T cells that recognize mAb WJ02. In summary, we conclude that mAb WJ02 mimics CA125 on cellular response and such functional mimicry is one of the most important criteria to select Ab2 for cancer therapy.
Kanzaki A, Toi M, Neamati N
… +11 more, Miyashita H, Oubu M, Nakayama K, Bando H, Ogawa K, Mutoh M, Mori S, Terada K, Sugiyama T, Fukumoto M, Takebayashi Y
Jpn J Cancer Res
· 2002 Jan · PMID 11802810
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This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of thera...This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene / protein could be detected in 22.0% (9 / 41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well- / moderately differentiated carcinoma (P = 0.012). Furthermore, we found no association between the ATP7B gene / protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma.
Maekawa I, Satoh H, Aoki N
… +7 more, Morishita Y, Tsukamoto N, Karasawa M, Nonaka Y, Shiota M, Nojima Y, Mori S
Jpn J Cancer Res
· 2002 Jan · PMID 11802809
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T cell lymphoma carrying Epstein Barr virus (EBV(+) TL) is very rare among Western countries while it is much more common among Japanese. Here we report an EBV(+) TL which has been maintained for years by the use of mice...T cell lymphoma carrying Epstein Barr virus (EBV(+) TL) is very rare among Western countries while it is much more common among Japanese. Here we report an EBV(+) TL which has been maintained for years by the use of mice with severe combined immune deficiency (SCID) mice. Lymphoma was obtained from a 55-year-old male suffering from oculomotor nerve palsy and lymphadenopathy. A small piece of biopsied tumor was transplanted into SCID mice and the lymphoma has been maintained for over 3 years with passages every 2 - 3 weeks. The maintained lymphoma, termed as TMS24, and the original lymphoma cells showed identical phenotype and genotype, including diffuse medium-sized cell morphology lacking granules, suppressor / cytotoxic immunophenotype and identical T cell receptor beta-chain gene rearrangement mode. Further, both were shown to carry an identical EBV clone in terms of the number of terminal repeats and the latency II-type restricted gene expression profile. Cytogenetically, TMS24 retained two characteristic chromosomal translocations of t(1;18)(q32;q21) and t(6;12)(p21;q24). Since only one cell line with such characters has been reported previously, TMS24 should be useful for detailed analysis of EBV(+) TL.
Shindo-Okada N, Takeuchi K, Han BS
… +1 more, Nagamachi Y
Jpn J Cancer Res
· 2002 Jan · PMID 11802808
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This article reports the establishment of variant cell lines with high and low metastatic potential by the dilution plating technique. Two clones with high metastatic potential, 2S Lu-4 and 11S Lu-1 and two clones with l...This article reports the establishment of variant cell lines with high and low metastatic potential by the dilution plating technique. Two clones with high metastatic potential, 2S Lu-4 and 11S Lu-1 and two clones with low metastatic potential, 8S and 16S were established from A549 human lung adenocarcinoma. The high-metastatic cell lines produced enhanced lung metastases, but the low-metastatic cell lines did not produce lung metastasis after injection into the tail vein of 5-week-old BALB / c nude mice. The primary tumors produced by the two high-metastatic cells grew fast and showed enhanced angiogenesis. The high-metastatic cells were small and flat-shaped, while the low-metastatic cells were large and flat-shaped. When the four variant cell lines and original A549 cells were embedded in collagen gels, the colonies of 2S Lu-4, 11S Lu-1 and A549 grew actively, whereas almost of all the colonies of 8S and 16S did not survive after 35 days in culture. These four cloned cell lines originated from heterogeneous populations of the parental A549 cells should be an excellent tool for studying the process of metastasis of lung cancer.
Vinh PQ, Sugie S, Tanaka T
… +5 more, Hara A, Yamada Y, Katayama M, Deguchi T, Mori H
Jpn J Cancer Res
· 2002 Jan · PMID 11802807
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The modifying effects of dietary administration of a flavonoid antioxidant, silymarin, a mixture of three flavonoids isolated from milk thistle seeds, on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bla...The modifying effects of dietary administration of a flavonoid antioxidant, silymarin, a mixture of three flavonoids isolated from milk thistle seeds, on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis were examined in male ICR mice. Animals were divided into 5 groups, and groups 1 to 3 were given OH-BBN (500 ppm) in drinking water for 6 weeks. Mice in group 2 were fed a diet containing 1000 ppm silymarin for 8 weeks during the initiation phase starting 1 week before OH-BBN exposure, and mice in group 3 were fed the diet for 24 weeks during the postinitiation phase. Animals in group 4 were given only the test compound, and those in group 5 were given the basal diet alone throughout the experiment. Animals were sacrificed at the end of week 32. The frequency of bladder lesions, cell proliferation and cell cycle progression activity estimated in terms of the 5-bromodeoxyuridine (BrdU) labeling index or cyclin D1-positive cell ratio were compared among the groups. Administration of silymarin in the initiation or postinitiation phase significantly decreased the incidences of bladder neoplasms and preneoplastic lesions. Dietary exposure to this agent significantly reduced the labeling index for BrdU and the cyclin D1-positive cell ratio in various bladder lesions. These findings suggest that silymarin is effective in preventing OH-BBN-induced bladder carcinogenesis in mice.
Jpn J Cancer Res
· 2002 Jan · PMID 11802806
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Lactic acid bacteria are known to have beneficial effects on the host, such as preventing carcinogenesis. The present study was designed to evaluate the chemopreventive effects of Lactobacillus rhamnosus strain GG (LGG)...Lactic acid bacteria are known to have beneficial effects on the host, such as preventing carcinogenesis. The present study was designed to evaluate the chemopreventive effects of Lactobacillus rhamnosus strain GG (LGG) in suppressing bladder cancer formation in a murine subcutaneous model of bladder cancer involving the inoculation of MB49 cells in C57B / L6 mice. After tumor implantation, one group of mice (n = 8) was fed LGG immediately. The remaining mice that had tumors between 0.03 - 0.1 cm(3) were divided into two groups: those fed LGG after 7 days (n = 7) and those fed saline (n = 7). A second group of mice without any inoculation of MB49 cells was fed either LGG (n = 10) or saline (n = 10) and served as non-tumor-bearing controls. LGG was administered orally at 1.6 x 10(8) colony-forming units daily. Mice fed LGG immediately after tumor cell implantation formed smaller tumors and some did not develop tumors (2 out of 8 mice), when the tumor burden was small. The level of spleen CD3, CD4 and CD8a T lymphocytes, as well as natural killer cells in mice fed immediately with LGG was also higher than that in control tumor-bearing mice. There was an increase in lymphocytes and granulocytes in tumor sections, especially from the immediately fed group as compared to the controls. Our results suggest that oral consumption of LGG may prevent tumor growth via modulation of the immune system. The potential of LGG as an adjunct therapy in the treatment of bladder cancer could be further explored.
Asamoto M, Ota T, Toriyama-Baba H
… +3 more, Hokaiwado N, Naito A, Tsuda H
Jpn J Cancer Res
· 2002 Jan · PMID 11802805
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We have previously shown that transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are highly susceptible to N-methyl-N-nitrosourea (MNU) mammary carcinogenesis. All transgenic rats treate...We have previously shown that transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are highly susceptible to N-methyl-N-nitrosourea (MNU) mammary carcinogenesis. All transgenic rats treated with 50 mg / kg MNU, i.v. at 50 days of age, were found to rapidly develop multiple, large mammary carcinomas within as short a period as 8 weeks. In the present study, the effects of ovariectomy and treatment with d-limonene, known to inhibit mammary carcinogenesis in non-transgenic female rats, were investigated in Hras128 animals treated with MNU to clarify the role of the human c-Ha-ras proto-oncogene and to characterize the induced mammary carcinomas. Although ovariectomy completely inhibited development of mammary carcinomas in their wild-type counterparts, it did not affect either the incidence or the multiplicity of the mammary carcinomas in the Hras128 rats. On the other hand, treatment with d-limonene, an inhibitor of ras protein isoprenylation, inhibited the breast tumor development. These results indicate that aberrant c-Ha-ras gene expression is involved in ovarian hormone-independent growth and c-Ha-ras protein isoprenylation plays an important role in mammary carcinogenesis.
Nishikawa A, Furukawa F, Miyauchi M
… +5 more, Son HY, Okazaki K, Koide A, Mori Y, Hirose M
Jpn J Cancer Res
· 2002 Jan · PMID 11802804
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The modifying effects of cigarette smoke (CS) exposure on a heterocyclic amine (HCA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced carcinogenesis were investigated in male F344 rats. Groups 1 and 2 were f...The modifying effects of cigarette smoke (CS) exposure on a heterocyclic amine (HCA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced carcinogenesis were investigated in male F344 rats. Groups 1 and 2 were fed MeIQx at a dose of 300 ppm, and simultaneously received CS and sham smoke (SS) for 16 weeks, respectively. Groups 3 - 5 were given the MeIQx diet for 4 weeks, and simultaneously exposed to CS for 4 weeks (group 3), exposed to CS for 12 weeks after the MeIQx treatment (group 4) or received SS for 16 weeks (group 5). Groups 6 and 7 were fed basal diet and respectively received CS and SS for 16 weeks. In terms of the mean number or area, the development of glutathione S-transferase placental form-positive (GST-P(+)) liver cell foci was significantly (P < 0.01) greater in group 1 than in group 2. The mean number of colonic aberrant crypt foci (ACFs) per animal was increased by continuous CS exposure regardless of MeIQx feeding, the differences between groups 4 and 5 (P < 0.05), and between groups 6 and 7 (P < 0.05) being significant. Immunoblot analysis confirmed that the hepatic CYP1A2 level in group 6 was remarkably increased as compared to that in group 7. In addition, liver S9 from rats in group 6 consistently increased the mutagenic activities of six HCAs including MeIQx as compared to those in group 7. Thus, our results clearly indicate that CS enhances hepatocarcinogenesis when given in the initiation phase via increasing intensity of metabolic activation for MeIQx and possibly colon carcinogenesis when given in the post-initiation phase in rats induced by MeIQx.