bluuebunny/crossref_metadata_2025 huggingface dataset:
SUMO-1 Modification Alters ADAR1 Editing Activity
Authors: Desterro Joana M.P. , Keegan Liam P. , Jaffray Ellis , Hay Ron T. , O'Connell Mary A. , Carmo-Fonseca Maria
Published: August 2005

We identify ADAR1, an RNA-editing enzyme with transient nucleolar localization, as a novel substrate for sumoylation. We show that ADAR1 colocalizes with SUMO-1 in a subnucleolar region that is distinct from the fibrillar center, the dense fibrillar component, and the granular component. Our results further show that human ADAR1 is modified by SUMO-1 on lysine residue 418. An arginine substitution of K418 abolishes SUMO-1 conjugation and although it does not interfere with ADAR1 proper localization, it stimulates the ability of the enzyme to edit RNA both in vivo and in vitro. Moreover, modification of wild-type recombinant ADAR1 by SUMO-1 reduces the editing activity of the enzyme in vitro. Taken together these data suggest a novel role for sumoylation in regulating RNA-editing activity.
PUBLIC R&D AND INDUSTRIAL INNOVATIONS AT THE PROJECT LEVELS: AN EXPLORATION OF TAIWAN'S PUBLIC RESEARCH PROJECTS
Authors: JANG SHOW‐LING , HUANG GUO‐GANG
Published: August 2005

This study investigates the role of the ITRI in Taiwan's technological catch‐up. The authors examine the relationship between public R&D and industrial innovations in Taiwan using data encompassing 252 ITRI annual research projects and the survey on the characteristics of 5902 cases of transferred technologies within these projects. The authors develop a new index of innovative output to measure the monetary value of patents for research projects. They find that the influences of accumulated R&D stock, high‐level R&D personnel, and the intensity of process innovations on project‐level R&D productivity to be more pronounced when the monetary value of patents, instead of simple patent counts, is used as the proxy for innovation outputs. (JEL O12, L63)
DEFECT IN THE DEVELOPMENT OF THERMOTOLERANCE IN THE MOUSE TEMPERATURE‐SENSITIVE MUTANT ts85 LACKING UBIQUITIN‐ACTIVATING ENZYME
Authors: Mizuno Satoshi , Ohkawara Akiko , Suzuki Kazuo
Published: August 2005

We investigated the effect of heat shock on the development of thermotolerance using mouse FM3A cells and the temperature‐sensitive mutant ts85. The shift‐up incubation of FM3A from 33 to 39.5° induced thermotolerance to subsequent heating at 44°. In contrast, the similar treatment of ts85 at the nonpermissive temperature of 39.5° could not induce thermotolerance. Furthermore, when ts85 cells were treated at 33° after being heated at 44°, they developed a reduced level of thermotolerance as compared with that developed in FM3A cells. Since ts85 cells are defective in ubiquitin‐activating enzyme, these results suggest a role of the ubiquitin‐protein conjugation system in the development of thermotolerance.
Estrogen Inhibits the Growth of MCF‐7 Cell Variants Resistant to Transforming Growth Factor‐beta
Authors: Hagino Yoshiaki , Mawatari Masasumi , Yoshimura Akihiko , Kohno Kimitoshi , Kobayashi Michio , Kuwano Michihiko
Published: August 2005

Human breast cancer MCF‐7 cells containing estrogen receptor are killed by transforming growth factor‐beta (TGF‐β). We isolated variants of MCF‐7 highly resistant to TGF‐β. Variants ES‐1 and ES‐4 were cloned, and the growth of ES‐1 and ES‐4 was found to be inhibited by estradiol, whereas estradiol stimulated the growth of the parental MCF‐7 cells. ES‐1 cells contained about 2‐fold higher level of estradiol receptor than MCF‐7 cells. Addition of estradiol to the culture medium for MCF‐7 and the variant changed the expression of several secreted proteins. The repertoire of secreted proteins was markedly altered in the variant. Polypeptides of molecular weight 52,000 (52 K), 65 K and 160 K were increased about 10‐ to 50‐fold in both estradiol‐treated MCF‐7 and ES‐1 cells. Polypeptide of 130 K was decreased in estradiol‐treated ES‐1 cells while this polypeptide was increased about 4‐fold in estradiol‐treated MCF‐7, as compared with untreated MCF‐7. Polypeptide of 100 K was specifically secreted in ES‐1 whether or not estradiol was present, but there appeared to be no significant amount of the 100 K protein in MCF‐7. The estradiol‐hypersensitive phenotype is discussed in relation to its aberrant expression of secreting proteins.
Effects of PSK on Interleukin‐2 Production by Peripheral Lymphocytes of Patients with Advanced Ovarian Carcinoma during Chemotherapy
Authors: Kikuchi Yoshihiro , Kizawa Isao , Oomori Keibun , Iwano Ichiro , Kita Tsunekazu , Kato Koichi
Published: August 2005

The effects of PSK on OKT 4/OKT 8 cell ratio, interleukin‐2 (IL‐2) production and expression of IL‐2 receptor were examined in peripheral blood lymphocytes (PBL) from patients with advanced ovarian cancer during the course of chemotherapy. Preoperative levels of OKT 4/OKT 8 cell ratio and IL‐2 production in PBL from patients with advanced ovarian cancer were significantly lower than those in cases of benign ovarian tumor. However, the expression of IL‐2 receptor did not show any significant difference between ovarian cancer and benign ovarian tumor patients. When a combination chemotherapy of cisplatin, adriamycin and cyclophosphamide was given, the OKT 4/OKT 8 cell ratio was significantly increased with a significant decrease of the absolute number of the OKT 8 cell subset, while the expression of IL‐2 receptor and the absolute number of the OKT 4 cell subset remained unchanged. In contrast, the IL‐2 production was markedly depressed after the first course of chemotherapy. When PSK was combined with combination chemotherapy, the degree of inhibition of IL‐2 production was reduced (though the effect was not statistically significant). If treatment with PSK was initiated after completion of combination chemotherapy, in addition to a significant elevation of OKT 4/OKT 8 cell ratio the depressed IL‐2 production was restored to benign control levels. On the other hand, the expression of IL‐2 receptor remained unchanged even if PSK was given after completion of chemotherapy.
A NEW MEDIUM‐TERM BIOASSAY SYSTEM FOR DETECTION OF ENVIRONMENTAL CARCINOGENS USING DIETHYLNITROSAMINE‐INITIATED RAT LIVER FOLLOWED BY D‐GALACTOSAMINE TREATMENT AND PARTIAL HEPATECTOMY
Authors: Ito Nobuyuki , Imaida Katsumi , de Camargo Joao Lauro V. , Takahashi Satoru , Asamoto Makoto , Tsuda Hiroyuki
Published: August 2005

The effects of D‐galactosamine on induction of preneoplastic glutathione S‐transferase placental form positive liver foci were investigated in F344 rats pretreated with diethylnitrosamine (DEN) in an attempt to improve the predictive value of the medium‐term bioassay system developed in our laboratory. Two weeks after the initial single ip dose (200 mg/kg) of DEN, administration of test compounds was commenced simultaneously with an ip injection of D‐galactosamine at a dose of 300 mg/kg body wt. All rats were then subjected to two‐thirds partial hepatectomy (PH) at week 5 and sacrificed for assessment of lesion yield at week 8. Measurement and comparison of the numbers and areas of glutathione S‐transferase placental form positive (GST‐P+) foci per cm2 revealed a positive response to more carcinogens, including non‐hepatocarcinogens, than did the same bioassay system without injection of D‐galactosamine. Thus the results suggest that inclusion of this extra proliferative stimulus may improve the medium‐term detection of carcinogens and modifiers.
GENERATION OF INTRACELLULAR ACTIVE OXYGENS IN MOUSE FM3A CELLS BY 3‐HYDROXYAMINO‐1‐METHYL‐5H‐PYRIDO[4,3‐b]INDOLE, THE ACTIVATED TRP‐P‐2
Authors: Wataya Yusuke , Yamane Kazuko , Hiramoto Kazuyuki , Ohtsuka Yasuharu , Okubata Yuko , Negishi Kazuo , Hayatsu Hikoya
Published: August 2005

Mouse FM3A cells in culture were treated with a reactive metabolite of 3‐amino‐1‐methyl‐5H‐pyrido[4,3‐b]indole (Trp‐P‐2), 3‐hydroxyamino‐1‐methyl ‐ 5H ‐ pyrido[4,3 ‐b]indole (Trp ‐ P ‐ 2‐ (NHOH)). When the treated cells, which were judged as viable on the basis of trypan‐blue exclusion, were subjected to nitroblue tetrazolium staining, formazan was formed inside the cells, a fact suggesting the intracellular presence of superoxide. No formazan formation was detected on treatment of the cells with Trp‐P‐2. Single‐strand breaks in the cellular DNA took place during this treatment with Trp‐P‐2(NHOH). Since Trp‐P‐2(NHOH) in solution generates superoxide anion accompanying its oxidative degradation, we conclude that the Trp‐P‐2(NHOH) treatment produces intracellular active oxygens that can damage DNA.
Effect of a Rice‐rich Diet on the Therapeutic Efficacy of Cyclophosphamide with Special Reference to the Enhancement of Transplantation Immunity
Authors: Kodama Mitsuo , Kodama Toshiko
Published: August 2005

The present study investigated the problem of whether the therapeutic efficacy of cyclophosphamide in the in vivo Ehrlich ascites tumor system can be improved by adjuvant use of hydrocortisone or of dietary hydrocortisone mobilizers. In the chemotherapy experiment, female ICR mice each received an inoculum of 1 × 106 cells of Ehrlich ascites tumor ip followed by 2 ip injections of cyclophosphamide 36 and 37 hr later (2.4 mg/mouse for the 1st injection, and 1.0 mg/mouse for the 2nd injection). The effects of both cyclophosphamide and adjuvant treatments were assessed in terms of either survival rate or cure rate in the 1‐month experiment. The results obtained were as follows. 1) Prolonged use of hydrocortisone as an adjuvant can improve the survival of cyclophosphamide‐treated mice. 2) Adjuvant use of a rice‐rich diet for maintenance increased the rates of both survival and cure in the cyclophosphamide‐treated mice. 3) The same maintenance of mice on a rice‐rich diet increased transplantation immunity on the one hand, and induced a set of steroidal changes including hydrocortisone excess on the other hand. 4) Evidence is presented to indicate that the beneficial influence of a rice‐rich diet on the drug effect is related to an increase of transplantation immunity in the host, and that there could be a causal relationship between hormonal and immunological changes in rice‐saturated mice.
CELL‐LINE SPECIFIC ACTIVATION OF SV40 TRANSCRIPTIONAL ENHANCER BY p40tax OF HTLV‐1
Authors: Fujisawa Jun‐ichi , Seiki Motoharu , Toita Masami , Miyatake Shoichiro , Arai Ken‐ichi , Yoshida Mitsuaki
Published: August 2005

A transcriptional trans‐activator P40tax of HTLV‐1 was reported to activate HTLV‐1 enhancer, but not SV40 or Rous sarcoma virus enhancer. However, in certain cell lines, we found that SV40 enhancer was activated by p40tax. These cell lines were mostly T cells, where the SV40 enhancer showed only low activity without p40tax. Since p40tax‐mediated activation of the LTR is not cell line‐specific, the activation of enhancers by p40tax depends on the combination of enhancer and cell type used for the test. Thus, apparent activation by p40tax depends on variable cellular components involved in transcriptional regulation.
EXPRESSION OF CR2 (C3d RECEPTOR) ON THE CELL MEMBRANES OF ADULT T CELL LEUKEMIA
Authors: Kai Chieko , Okada Noriko , Okada Hidechika
Published: August 2005

MT ‐ 2 cells, which produce human T‐cell lymphotropic virus type I (HTLV‐I), are known to have a complement receptor. We have established that the complement receptor is CR2 which binds C3d on immune complexes but not CR1. CR2 was also detected on ATL‐3I cells but no complement receptor was detected on ATL‐1K cells which lack ATL antigen (ATLA). Since CR2 is not detectable on normal T lymphocytes, the presence of CR2 on some ATL cells might suggest that ATL cells were derived from a particular minor lineage of T cells, or HTLV‐I has a capacity to induce CR2, which has been demonstrated to be an α‐type growth factor for B lymphocytes and to be a receptor for Epstein‐Barr virus.
A MONOCLONAL ANTIBODY THAT RECOGNIZES A COMMON ANTIGEN IN MYELOID AND HUMAN T‐CELL LEUKEMIA VIRUS TYPE I‐CARRYING CELLS
Authors: Takeuchi Tamotsu , Kubonishi Ichiro , Takahashi Kiyoshi , Ohtsuki Yuji , Taguchi Hirokuni , Miyoshi Isao
Published: August 2005

A novel monoclonal antibody, designated D‐213, was generated to human myeloid cell line PL‐21. D‐213 defined a 47‐kD antigen which was specifically expressed in normal and leukemic cells of the myeloid lineage and in T‐cell lines carrying human T‐cell leukemia virus type I. This antibody was also reactive with adult T‐cell leukemia/lymphoma (ATLL) cells in formalin‐fixed, paraffin‐embedded tissues. D‐213 would be useful for making an immunohistochemical diagnosis of ATLL in cases where serological or virological information is not available.
MORPHOLOGIC CHANGES OF NEUTROPHILS IN MYELODYSPLASTIC SYNDROME TREATED WITH RECOMBINANT HUMAN GRANULOCYTE COLONY‐STIMULATING FACTOR
Authors: Toyama Keisuke , Ohyashiki Kazuma , Ohyashiki Junko H. , Takaku Fumimaro
Published: August 2005

Two cases of myelodysplastic syndrome (MDS) were treated with recombinant human granulocyte colony‐stimulating factor (rhG‐CSF). In both cases, an increase of peripheral neutrophil counts was noted with a peak within 12 hr after the rhG‐CSF administration. Neutrophils with ring shaped or hypersegmented nuclei were noted in the peripheral blood during the treatment, and they disappeared promptly after discontinuation of the therapy. The results indicate that the rhG‐CSF might have mobilizing and differentiating effects on neutrophils derived from the MDS clone.
A SYNTHETIC ADJUVANT EFFECTIVE IN INDUCING ANTITUMOR IMMUNITY
Authors: Kataoka Tetsuro , Tokunaga Tohru
Published: August 2005

Guinea pigs which were injected repeatedly with a mixture of a 3MKC1 extract of line 10 tumor and 6‐O‐(2‐tetradecyl‐hexadecanoyl)‐muramyl‐dipeptide (B30‐MDP) rejected a tumor graft of line 10. Such an adjuvant effect of B30‐MDP was also demonstrated when X‐ray‐treated line 10 cells were mixed with B30‐MDP dissolved in phosphatebuffered saline and inoculated into the animals.
Elevation of Serum Alpha‐fetoprotein and Proliferation of Oval Cells in the Livers of LEC Rats
Authors: Takahashi Hidetoshi , Oyamada Masahito , Fujimoto Yoshinori , Satoh Mutsumi I. , Hattori Atsuo , Dempo Kimimaro , Mori Michio , Tanaka Toshiyuki , Watabe Hiroyuki , Masuda Ryuichi , Yoshida Michihiro C.
Published: August 2005

Alpha‐fetoprotein (AFP) in the sera of 35 LEC (Long‐Evans with a cinnamon‐like coat color) rats between 7 and 25 weeks of age was evaluated by enzyme‐linked immunosorbent assay (ELISA). Elevation of serum AFP and proliferation of oval cells in the liver were observed in most LEC rats, which suffered from acute hepatitis. On the other hand, the serum AFP level was within the normal range before the onset of hepatitis. Immunohistochemical staining for AFP revealed that some of the proliferating oval cells produced AFP, Morphotnetric analysis of AFP‐positive cells and ELISA for serum AFP demonstrated that there was a statistically significant correlation between the number of AFP‐positive cells in the liver and the concentration of AFP in the serum. Histological examination revealed the transition and differentiation of the oval cells to small hepatocytes. These results suggested that the phenomena which occurred in LEC rats suffering from acute hepatitis were similar to those that occurred during the early stage of azo dye hepatocarcinogenesis, although the extent of the oval cell proliferation and the elevation of serum AFP in LEC rats were not as great as those in rats treated with azo dye. This is the first report on a rat strain with proliferation of AFP‐producing oval cells during its natural history.
High Susceptibility to Hepatocellular Carcinoma Development in LEC Rats with Hereditary Hepatitis
Authors: Masuda Ryuichi , Yoshida Michihiro C. , Sasaki Motomichi , Dempo Kimimaro , Mori Michio
Published: August 2005

A remarkably high incidence of hepatocellular carcinomas was observed in long‐surviving LEC rats with hereditary hepatitis. Among the 60 LEC rats examined between 12 and 28 months of age from F29, and F30, 55 (92%) developed putative preneoplastic and neoplastic lesions such as hyperplastic foci and nodules, and hepatocellular carcinomas. Of these, hepatocellular carcinomas were observed with a high frequency (46/55; 84%). All rats of advanced age that survived more than 18 months developed hepatocellular carcinomas. These results suggest that the development of liver tumors in LEC rats is an age‐associated phenomenon with serial hepatic alterations after the subsidence of acute hepatitis. The long‐surviving rats had no normal tissue and showed chronic hepatitis in nontumorous tissues of the liver. Cholangiofibrosis was also found in most rats with hepatic lesions. Metastasis of hepatocellular carcinomas was found in four rats. Histologically, the hepatocellular carcinomas were of a well‐differentiated type with a typical trabecular structure. Thus, LEC rats seem to be a promising animal model for studying the pathogenesis of hepatitis and hepatocellular carcinoma.
Proliferative Effect of Human Granulocyte Colony‐stimulating Factor on Blast Cells of Acute Promyelocytic Leukemia
Authors: Kitano Kiyoshi , Suda Toshio , Sato Yuko , Miura Yasusada
Published: August 2005

The effect of human granulocyte colony‐stimulating factor (G‐CSF) on leukemic cells of acute promyelocytic leukemia (APL) was examined. Mononuclear cells obtained from bone marrow cells containing more than 90% blasts from seven APL patients were incubated in the presence of G‐CSF using semisolid and liquid culture systems. On day 7, the cells from all the patients produced many clusters consisting of 8–40 cells. These cells appeared to be promyelocyte‐like blast cells in four patients and had differentiated to more mature neutrophils in three patients. On day 14, the number of clusters decreased except for two patiens. Blast cells from the two patients showing the increase of blast clusters could proliferate in a liquid culture containing G‐CSF. Blast cells cultured for 14 days formed many secondary cultures after replating on a methylcellulose medium. Moreover, chromosomal analyses of blasts cultivated in the presence of G‐CSF for 7 days showed t(15;17) in all metaphases in one patient. It appears that the leukemic cells from APL patients could proliferate in the presence of G‐CSF.
The Expression of Tumor Rejection Antigen on Rat Fetus Fibroblasts Transformed by the ras Oncogene
Authors: Okubo Mamoru , Yagihashi Atsuhito , Torigoe Toshihiko , Konno Arimitsu , Sato Noriyuki , Kikuchi Kokichi
Published: August 2005

The expression of tumor rejection antigens (TRA) was analyzed on clones of rat fetus‐derived fibroblasts, WFB, transformed or transfected by oncogenes. It was shown that a tumorigenic W14 clone, which is an activated H‐ras transformant of parental WFB, expressed TRA in transplantation experiments using syngeneic WKA rats. The data also showed that W14 TRA was acquired in the event of cell transformation, since it was not detected on parental non‐transformed WFB cells or Wmyc‐4 clone which is a transfectant of WFB by mouse plasmacytoma‐derived c‐myc DNA. However, TRA was not expressed or at least was not detected on highly tumorigenic W31, another clone of H‐ras transformants of parental WFB, in the transplantation experiments. We also assessed the level of expression of major histocompatibility antigens (MHC) class I molecules on these cells by using R4‐8B1 Mab that reacts specifically with rat class I antigen. The data indicated that it was decreased on W14, W31, and Wmyc‐4, but not on parental WFB. Although this molecule was weakly positive on W14 cells, W31 and Wmyc‐4 showed even greater decreases. These data may indicate that the TRA expression and its recognition by syngeneic hosts are dependent upon the transformed clones, although their parental cell is the same. We discuss in detail this difference of expression and recognition of TRA in the context of the cell transforming process.
Inductions of Ornithine Decarboxylase and DNA Synthesis in Rat Stomach Mucosa by Formaldehyde
Authors: Furihata Chie , Yamakoshi Akira , Matsushima Taijiro
Published: August 2005

Administration of formaldehyde at doses of 11 to 110 rag/kg body weight by gastric intubation to male F344 rats induced up to 100‐fold increase in ornithine decarboxylase activity with a maximum after 16 hr and up to 49‐fold increase in DNA synthesis with a maximum after 16 hr in the pyloric mucosa of the stomach. These results suggest that formaldehyde has tumor‐promoting activity in carcinogenesis in the glandular stomach.
Antitumor Effector Mechanism at a Distant Site in the Double Grafted Tumor System of PSK, a Protein‐bound Polysaccharide Preparation
Authors: Ebina Takusaburo , Kohya Hidehiko
Published: August 2005

The antitumor effect at a distant site of PSK, a Coriolus preparation, was analyzed with the double grafted tumor system in which BALB/c mice received simultaneous intradermal inoculations of Meth‐A tumor in the right (106 cells) and left (2 × 105 cells) flanks and were then injected with PSK in the right‐flank tumor on day 3. PSK inhibited the growth of not only the right but also the left (non‐treated) tumor. Immunized spleen cells were taken from mice which had been cured by the intratumoral administration of 5 mg of PSK and were injected into the Meth‐A tumor on day 3. Adoptive transfer of PSK immunized spleen cells caused the complete regression of Meth‐A tumors. The effector cell activity was lost only after treatment with anti‐Lyt‐1 monoclonal antibody plus complement. Spleen cells and right and left regional lymph node cells prepared from PSK immunized mice were examined for Thy‐1, Lyt‐1, Lyt‐2 and asialo GM1 phenotypes. The number of Lyt‐1‐positive lymphocytes increased in the right regional lymph nodes after intratumoral administration of PSK. A massive accumulation of macrophages and polymorphonuclear leukocytes was found in the right tumor and an infiltration of macrophages and Lyt‐2‐positive lymphocytes was found in the left (non‐treated) tumor by immunohistochemical analyses. These results suggest that intratumoral administration of PSK induces Lyt‐1‐positive cells first in regional lymph nodes, then in the spleen, and subsequently induces macrophages and Lyt‐2‐positive cells in the left (non‐treated) tumor, thus bringing about the regression of metastatic tumors.
Effect of Recombinant Human Interleukin 2 on the Growth of a BALB/c Sarcoma Induced by Moloney Murine Sarcoma Virus
Authors: Mitsunaga Shin‐ichirou , Kimura Hideki , Yamaguchi Yutaka , Mikata Atsuo
Published: August 2005

The effect of in vivo administration of recombinant interleukin 2 (rIL2) on the growth of a primary female BALB/c sarcoma induced by Moloney marine sarcoma virus (M‐MSV) was studied. Although low‐dose administration of (6,000 JU/mouse × 14 days) rIL2 had no effect on the growth of the tumors, high‐dose (15,000–80,000 JU/mouse × 14 days) intraperitoneal inoculation of rIL2 induced tumor regression, dose‐dependently. Tumors in mice which received 80,000 JU/mouse/day of rIL2 regressed completely 2 weeks after the initiation of treatment. The survival rates of the treated groups were significantly higher than those of the control group. A time course experiment disclosed that the effect of rIL2 was restricted only to the group in which rIL2 treatment started 8 days after the inoculation of M‐MSV. The cytotoxic activity of regional lymph node lymphocytes from rIL2‐treated mice was demonstrated against primary culture of M‐MSV‐induced sarcoma but not against syngeneic tumor induced by methylcholanthrene (Meth A). The effect of rIL2 was partially blocked by the administration of anti‐IL2 receptor antibody. Immunohistochemical examination revealed that infiltration of Thy1.2+Lyt1+2‐ (helper/inducer subset) lymphocytes into the tumor tissue was prominent in mice which received high‐dose rIL2. The results indicated that IL2 induced regression of M‐MSV‐induced sarcoma mainly through activation of IL2‐receptor‐positive helper T cells in the tumor tissues and of killer cells in the draining lymph nodes.
Dietary and Other Risk Factors of Ovarian Cancer among Elderly Women
Authors: Mori Mitsuru , Miyake Hirotsugu
Published: August 2005

The age‐specific mortality rate of ovarian cancer is increasing among women over 50 years of age, but remaining at a stable level among women under 50. This case‐control study of ovarian cancer was undertaken to assess the environmental factors which may increase the mortality of the disease in the elderly. Fifty‐six women with primary epithelial ovarian cancer whose ages were 50 years old or over were compared with two age‐matched control groups. The results of the Mantel‐Haenszel analysis were as follows. More cases were found to have never married than controls (P<0.05), a larger proportion of cases were nulliparous (P<0.05), a smaller proportion of cases had experienced an induced abortion (P< 0.05) or had undergone permanent sterilization by tubal ligation (P<0.05), the occurrence of breast or uterine cancer was more common in the mother or sisters of cases (P<0.01), a larger percentage of cases used to eat meat daily (P< 0.01) or used to eat fish daily (P< 0.05), and a larger proportion of cases weighed under 40 kg (P<0.05). Daily meat consumption was significantly associated with the occurrence of ovarian cancer even after adjusting for reproductive and other risk factors by conditional logistic regression analysis. The attributable risk for ovarian cancer in the elderly was 19.2% for daily meat consumption. The recent change in dietary habits might in part explain the rise of the mortality rate among the Japanese elderly.
Antitumor Activity and Neutrophil‐selective Hematopoietic Toxicity of Busulfan Analogs in Mice
Authors: Kato Taketoshi , Ohta Yuko , Suzumura Yasuko , Kohda Kohfuku , Kimoto Hiroshi , Kawazoe Yutaka
Published: August 2005

The antitumor activity and hematopoietic toxicity of two busulfan analogs were evaluated in comparison with those of busulfan. Although a program of five daily ip treatments with busulfan was not effective in treating sarcoma 180‐bearing mice, a fluorine‐containing busulfan analog, 1,4‐butanediol di‐2,2,2‐trifluoroethanesulfonate (BFS), and a water‐soluble analog, 1,4‐butanediol diisethionate (BIT), were significantly effective when given on the same schedule. Busulfan did not appreciably prolong the life span of either P388‐ or Meth A‐bearing mice, whereas BFS and BIT produced significant increases in the life span. It is worth noting that both the analogs were definitely less toxic to the host mice than busulfan. All the drugs examined exhibited suppressive effects on the counts of total WBCs, neutrophils, and lymphocytes. Relative toxicity toward neutrophils versus lymphocytes was increased significantly in the BFS and BIT treatments compared with busulfan treatment. It seems that the toxicity of busulfan in host mice might be due to unidentified side effects other than bone marrow suppression. These results suggest that BFS and BIT could be improved substitutes for busulfan.
Hyperthermic Enhancement of the Antitumor Effect of Natural Human Tumor Necrosis Factor‐α and ‐β: an in vitro and in vivo Study
Authors: Maeda Tetsuya , Fuchimoto Sadanori , Orita Kunzo
Published: August 2005

A synergistic antitumor effect of natural human tumor necrosis factor‐β (TNF‐β) in combination with hyperthermia was found, in comparison with that of TNF‐α, using an in vitro antiproliferative assay on a human colon cancer cell line (RPMI4788) and an in vivo tumor growth inhibition assay on Meth A sarcoma cells. In vitro combined treatment with TNF‐β (10,000 U/ml) and hyperthermia (at 43° for 60 min) synergistically inhibited the proliferation of the cells. Combined effects of TNF‐α or natural human interferon‐α or ‐γ (IFN‐α, ‐γ) and hyperthermia were also examined, and furthermore, the combinations of TNFs and IFNs were examined in combination with hyperthermia at 42°; their antiproliferative effects were further augmented by hyperthermia. In vivo growth of Meth A sarcoma cells (5 × 105), transplanted subcutaneously into BALB/c mice, was inhibited significantly (P<0.05) with the combination of TNF‐α or ‐β (2 × 105 U/mouse) and hyperthermia (at 43° for 60 min) as compared to either a single intravenous injection of TNF‐α or ‐β alone or the hyperthermia alone. The influence of TNF‐β and hyperthermia on the cell cycle was examined. Flow cytometric analysis showed that RPMI4788 cells treated with TNF‐α or ‐β accumulated in the S phase of the cell cycle, and that hyperthermia (at 42° for 60 min) alone had no influence on the cell cycle and did not augment the S phase accumulation of the cells treated with TNF‐α or ‐β.
Preventive Effect of 3‐Aminobenzamide on the Reduction of NAD Levels in Rat Liver Following Administration of Diethylnitrosamine
Authors: Uchida Kazuhiko , Takahashi Seiichi , Fujiwara Kunio , Ueda Kunihiro , Nakae Dai , Emi Yohko , Tsutsumi Masahiro , Shiraiwa Kazumi , Ohnishi Takeo , Konishi Yoichi
Published: August 2005

Nicotinamide adenine dinucleotide is utilized as the substrate of a chromatin‐bound enzyme, poly(ADP‐ribose) polymerase. The effects of diethylnitrosamine and/or 3‐aminobenzamide, a potent inhibitor of poly(ADP‐ribose) polymerase, on the cellular NAD levels in rat liver were investigated. 3‐Aminobenzamide (600 mg/kg) administered intraperitoneally was not detectable in the liver within 12 hr after administration; the inhibitor had a calculated half life of 90 min. Diethylnitrosamine reduced the NAD levels in rat liver in a dose‐dependent way. The NAD content reached a minimum level at 8 hr, returning to 78% of the control value after 48 hr. The reduction of the NAD levels caused by diethylnitrosamine was completely prevented when 3‐aminobenzamide was administered either simultaneously with diethylnitrosamine or 4 hr after diethylnitrosamine treatment. Furthermore, an immunohistochemical study showed that nuclear poly(ADP‐ribose) decreased 1 hr after the administration of 3‐aminobenzamide. These results suggest that inhibition of poly(ADF‐ribosyl)ation is involved in the initiation of liver carcinogenesis by diethylnitrosamine and 3‐aminobenzamide.
Two Distinct Mechanisms Involved in the Infiltration of Lymphocytes into Tumors
Authors: Shijubo Noriharu , Uede Toshimitsu , Takami Tsuyoshi , Torimoto Yoshihiro , Lupin Daniel , Min Shen , Kikuchi Kokichi
Published: August 2005

We have analyzed the mechanism controlling the infiltration of lymphocytes into tumor tissues. W3/25 (+) (helper/inducer phenotype) T cells obtained from tumor tissues of T‐9 sensitized rats produced soluble factors. We demonstrated that the soluble factors were responsible for the infiltration of T lymphocytes into tumor tissues by using a modified Boyden chamber technique. We established a system in which we stained filters of the Boyden chamber by an immunoperoxidase technique, thus directly determining the phenotype of cells that had actually migrated into the filters in response to the soluble factors. Upon fractionation of soluble factors produced by W3/25 (+) T cells, four peaks of lymphocyte migration factor (LMF) activity were detected. Peaks B and C exhibited strong LMF activity and specifically attracted R1‐10B5 (+) (suppressor/killer phenotype) T cells. Thus, the infiltration of R1‐10B5 (+) T cells into tumor tissues was partly explained by LMF produced by tumor‐infiltrating W3/25 (+) T cells. The expression of a putative receptor for LMF by lymphocytes may also influence the degree of lymphocyte infiltration into tumors.
Establishment and Characterization of a Human Cell Strain, KT, with High Sensitivity to UV‐killing and to Cell Proliferation Inhibition by Interferon
Authors: Suzuki Nobuo , Inaba Noriyuki , Sgano Isamu , Umehara Seiichi , Murakami Takashi , Takakubo Yoshiaki
Published: August 2005

We have established a human cell line, designated KT, with high susceptibility to both cell proliferation inhibition by interferon and UV‐killing, from a metastatic breast carcinoma. A tumor marker, a pregnancy‐specific glycoprotein (Schwangerschaftsprotein 1; SP1), and carcinoma characteristics compatible with ductal carcinoma of the breast were seen in KT cells by electron microscopic observation. KT cells were slightly more resistant to X‐ray‐induced toxicity than fibroblastic cells, termed KS, from the scalp of the patient. But, KT cells had lower cloning efficiency after UV irradiation than did KS cells: D0 values of 1.5 J/m2 and 7.2 J/m2, respectively. KT cells also appeared more susceptible to human interferon (HuIFN) preparations (α, β, γ and natural or recombinant) than did KS cells, as measured by cell colony formation ability, proliferation rates, and [3H]deoxythymidine incorporation levels into acid‐insoluble cell materials. The sensitivity of KT cells to UV and HuIFN was greater than that of human RSa cells, a cell line with high sensitivity to both agents. KT cells had more capacity for UV‐induced DNA‐repair replication synthesis than did RSa cells, the capacity being much the same as that of KS cells. There was no significant difference in levels of antiviral activity induced by HuIFN and binding capacity for 125I‐labeled IFN‐αA between KT and KS cells. KT cells appeared refractory to cell proliferation inhibition by tumor necrosis factor (TNF) preparations.
The Induction of Enhanced Antitumor Effect against a Nonimmunogenic Tumor by Highly Immunogenic Variants Obtained by Mutagen Treatment
Authors: Sainouchi Ryouhei , Terata Nobukuni , Kodama Masashi
Published: August 2005

Nonimmunogenic 1767‐3 fibrosarcoma was treated with the mutagen N‐methyl‐N′‐nitro‐N‐nitrosoguanidine, and stable variant cell clones (M‐clones) were obtained that were able to elicit an immunological rejection response in syngenic C3H mice. Mice immunized with some M‐clones were protected against a challenge from the original nonimmunogenic fibrosarcoma. Furthermore, when spleen cells of immunized syngenic mice were restimulated in vitro with M‐clones, cytotoxic T lymphocytes (CTL) were obtained that were able to lyse not only M‐clones but also the original nonimmunogenic tumor. These in vivo and in vitro results demonstrate the immunogenicity of M‐clones and the existence of a singular antigenic specificity between the original nonimmunogenic tumor and M‐clones. For the purpose of application of this mutagen treatment to cancer therapy, we combined it with lymphokine‐activated killer (LAK) adoptive immunotherapy (AIT). With interleukin 2 and in vitro stimulation with highly immunogenic variant clones, we tried to induce transfer cells that had not only nonspecific LAK cells but also CTL with specific immunity against the original nonimmunogenic tumor. Successful results were obtained in the LAK AIT models. These findings indicate that an immunotherapy of human cancers that are thought to be weakly or nonimmunogenic may be possible by the application of this approach to LAK AIT.
XENOGENIZATION OF TUMOR CELLS BY TRANSFECTION WITH PLASMID CONTAINING env GENE OF FRIEND LEUKEMIA VIRUS
Authors: Sugiura Chihiro , Itaya Toshiyuki , Kondoh Nobuo , Oikawa Tsuneyuki , Kuzumaki Noboru , Takeichi Noritoshi , Hosokawa Masuo , Kobayashi Hiroshi
Published: August 2005

A rat hepatocellular carcinoma cell line (cKDH‐8 cl‐11) showed decreased tumorigenicity after transfection with an envelope gene derived from a Friend leukemia virus (FV‐env gene). FV‐env gene product was found by indirect immunofluorescence staining to be expressed on the cell surface of the FV‐env gene‐transfected cells. The FV‐env‐transfected cells (FV‐env cKDH‐8), however, grew well in X‐irradiated immunosuppressed rats, indicating that the reduction in tumorigenicity of the transfected cells is based on immunological reaction in the host. The rats which rejected FV‐env cKDH‐8 cells showed resistance to rechallenge with the parent cKDH‐8 cl‐11 tumor cells. These results suggest that the FV‐env gene product may elicit antitumor immunity against FV‐env cKDH‐8 cells in a host with a resultant reduction in the tumorigenicity of these cells.
PRODUCTION OF PARATHYROID HORMONE‐RELATED PROTEIN IN ADULT T‐CELL LEUKEMIA CELLS
Authors: Honda Satoshi , Yamaguchi Ken , Miyake Yoshio , Hayashi Nakanobu , Adachi Naoto , Kinoshita Ken‐ichiro , Ikehara Osamu , Kimura Satoshi , Kinoshita Tomohiro , Shimotohno Kunitada , Shimoyama Masanori , Abe Kaoru
Published: August 2005

Human parathyroid hormone‐related protein (PTHrP) mRNA was detected in peripheral leukemic cells obtained from adult T‐cell leukemia (ATL) patients as well as in cultured human T‐cell leukemia virus type I (HTLV‐D‐infected T‐cell lines. In contrast, PTHrP mRNA was not detected in other types of leukemic cells. Using radioimmunoassay, immunoreactive PTHrP was also detected in the spent media of HTLV‐I‐infected T‐cell lines. These results suggest that PTHrP plays an important role in developing the hyperealcemia frequently observed in ATL patients.
Inhibitory Effect of Ellagic Acid on N‐2‐Fluorenylacetamide‐induced Liver Carcinogenesis in Male ACI/N Rats
Authors: Tanaka Takuji , Iwata Hitoshi , Niwa Kenji , Mori Yoshio , Mori Hideki
Published: August 2005

The effect of ellagic acid (EA) on the hepatocarcinogenesis induced by N‐2‐fluorenylacetamide (FAA) was investigated in male ACI/N rats. Rats were fed diet containing 200 ppm FAA and 400 ppm EA for 16 weeks, and diet containing 400 ppm EA alone was fed to the animals for one week before FAA exposure and one week after the carcinogen treatment. Animals were killed at intervals up to 20 weeks after cessation of the carcinogen. Liver altered foci and neoplasms were quantified using γ‐glutamyl transpeptidase reaction as well as conventional staining for identification. Exposure to FAA alone induced a substantial number of altered foci and at the end of experiment (week 36), the incidence of hepatocellular neoplasms was 100%. In the group receiving EA together with FAA, the number of altered foci was decreased at all time points and at termination, the final incidence of hepatocellular neoplasms (30%) was also reduced. Thus, EA inhibited the hepatocarcinogenesis induced by FAA when it was administered concurrently with the carcinogen.
Induction of Differentiation of Mouse Myeloid Leukemia M1 Cells by Serum of Patients with Chronic Myeloid Leukemia
Authors: Okabe‐Kado Junko , Honma Yoshio , Hayashi Moriaki , Hozumi Motoo , Sampi Kazumi , Sakurai Masaharu , Hino Ken‐ichiro , Tsuruoka Nobuyoshi
Published: August 2005

We examined the capacities of sera from patients with myeloid leukemia to induce differentiation in mouse myeloid leukemic M1 cells. Higher differentiation‐inducing activity (D‐activity) was detected in sera of patients with chronic myelomonocytic leukemia or chronic myeloid leukemia (CML) than in sera of patients with acute myeloid leukemia and normal volunteers. The D‐activity in the sera was lost on heating the sera at 56° for 30 min. The major peak of D‐activity on Sephadex G‐200 gel filtration had an apparent molecular weight of 160,000. The origin of the D‐activity in sera of patients with CML was studied by culturing fractions of peripheral blood cells of patients with D‐activity for 3 days and then measuring the ability of the conditioned medium (CM) to induce differentiation of M1 cells. The cells in the myeloblast and promyelocyte fraction differentiated spontaneously into macrophage‐like cells during culture for 3 days and the cells in the late granulopoietic cell fraction differentiated into neutrophil‐like cells. Higher D‐activity was present in CM of cells in the myeloblast and promyelocyte fraction than in CMs of late granulopoietic cell fractions. These results suggest that human leukemic cells produce D‐activity for M1 cells during their differentiation into macrophage‐like cells.
Inhibitory Effect of Tamoxifen on Diethylstilbestrol‐promoted Hepatic Tumorigenesis in Male Rats and Its Possible Mechanism of Action
Authors: Kohigashi Katsuji , Fukuda Yoshihiro , Imura Hiroo
Published: August 2005

Male Sprague‐Dawley rats were given a single intraperitoneal injection of diethylnitrosamine (DEN, 200 mg/kg body weight). Two weeks later the rats were divided into 4 groups; DEN‐C group rats were given no further treatment; DEN‐DES group rats were fed diethylstilbestrol (DES, 0.5 mg/day); DEN‐TMX group rats were given tamoxifen (TMX, 1.0 mg/ day) orally; DEN‐DES TMX group rats were fed both DES and TMX for 8 months. Rats of the DEN‐DES group developed grossly visible hepatic tumors. On the other hand, tumor development was significantly inhibited in rats of the DEN‐DES TMX group. Total area of γ‐glutamyl transpeptidase‐positive lesions and the mean area per lesion were significantly larger in rats of the DEN‐DES group than those of the DEN‐C, DEN‐TMX or DEN‐DES TMX group. Estrogen receptor (ER) content of liver cytosol assayed by enzyme immunoassay (EIA) was significantly greater in rats of the DEN‐DES group than in those of the DEN‐C group and smaller in rats of the DEN‐TMX and DEN‐DES TMX group than in the DEN‐C group. On the contrary, ER content of liver nuclei was significantly greater in rats of the DEN‐TMX and DEN‐DES TMX group than in those of the DEN‐C or DEN‐DES group. These results suggest that the promotive action of DES and the inhibitory action of TMX on DES‐promoted hepatic tumorigenesis are, at least in part, mediated by ER in the rat.
Establishment of a Human Monoclonal Antibody to Hanganutziu‐Deicher Antigen as a Tumor‐associated Carbohydrate Antigen
Authors: Usuba Osamu , Fujii Yoichi , Miyoshi Ichiro , Naiki Masaharu , Sendo Fujiro
Published: August 2005

We have established a human‐human hybridoma producing a monoclonal antibody against a tumor‐associated carbohydrate‐specific antigen, Hanganutziu‐Deicher (HD) antigen. Human spleen lymphocytes from a patient with esophageal varices complicated with liver cirrhosis were cultured in serum‐free medium and co‐stimulated with both anti‐human μ‐chain antibodies and supernatants of concanavalin A‐stimulated human spleen cell culture (ConA sup). The activated lymphocytes were subsequently primed in vitro with particulate HD3 antigen and fused with a parent hybrid myeloma cell line, KR‐12. A hybridoma, 1F43E31G7 produced anti‐HD human monoclonal antibody (IgM λ). This monoclonal antibody reacted strongly with N‐glycolyl‐neuraminyl α2‐3 lactosylceramide (HD3) and slightly with N‐glycolylneuraminyl α2‐3 lactoneotetraosylceramide (HD3), but did not react with N‐glycolylneuraminyl α2‐3 lactoneohexaosylceramide (HD7), N‐acetylneuraminyl α2‐3 lactosylceramide (GM3) and other derivatives of HD3 prepared by chemical modification of the sialic acid residue of HD3, which indicates that the monoclonal antibody is directed precisely toward the terminal sialic acid and whole structure of HD3.
Radiation, Hyperthermia, and Their Combination in Treatment of Chemically Induced Autochthonous Tumors in Mice
Authors: Sato Setsu , Ootsuyama Akira , Tanooka Hiroshi
Published: August 2005

All autochthonous tumors induced chemically in the thighs of C3H/He mice showed recurrence after single X‐irradiation with 20–60 Gy when they were 10 mm in diameter, although this treatment caused temporary, dose‐dependent regression. Hyperthermia for 30 min at 43.0° alone had little effect. However, in 2 of 16 mice, hyperthermia after irradiation at 60 Gy resulted in complete cure, i.e., survival of mice without recurrence for more than 120 days after treatment. These results indicate that the combined treatment of radiation and hyperthermia is necessary to obtain the cure of mouse autochthonous tumors.
NEW HERITABLE FRAGILE SITE ON CHROMOSOME 8 INDUCED BY DISTAMYCIN A
Authors: Ochi Hisako , Watanabe Shaw , Yamamoto Hiroshi
Published: August 2005

A possible new heritable fragile site at band 8q24.1, which is known to be a breakpoint in various cancers and contains the c‐myc locus, was found in the lymphocytes from a woman with mastopathy. This fragile site was induced by distamycin A treatment, and expressed as gaps and breaks in 18% of the metaphases examined. The lymphocytes from one of her two sons examined also revealed gaps or breaks at the same site of chromosome 8 in 34% of the metaphases. This fragile 8q24.1 band is considered to be a new heritable fragile site induced by distamycin A.
H‐ras p21 AND PEANUT LECTIN IMMUNOREACTIVITY OF HYPERPLASTIC, PRENEOPLASTIC AND NEOPLASTIC URINARY BLADDER LESIONS IN RATS
Authors: Ward Jerrold M. , Hagiwara Akihiro , Tsuda Hiroyuki , Tatematsu Masae , Ito Nobuyuki
Published: August 2005

Hyperplastic, preneoplastic and neoplastic urinary bladder lesions induced by bladder carcinogens and toxins in the rat were evaluated for immunoreactivity with polyclonal or monoclonal antibodies to H‐ras p21 or binding to peanut lectin with avidin‐biotin immunocytochemistry. A low proportion (<20%) of hyperplastic and neoplastic bladder lesions induced by N‐butyl‐N‐(4‐hydroxybutyl)‐nitrosamine and fixed in Bouin's fixative only were immunoreactive on the cell membrane with the antibodies to H‐ras p21. Lectin binding was found for these lesions, as well, even in formalin‐fixed tissue and for lesions induced by other carcinogens, but not in regenerative bladder hyperplasias after cyclophosphamide exposure or in bladder exposed to bladder tumor promoters. The latter lesions were also not immunoreactive with antibodies to p21. Our results suggest that this relatively simple technique might be used for identification and screening of tumors for involvement of ras oncogenes and carcinogen initiation.
Factors Related to Late Menopause and Early Menarche as Risk Factors for Breast Cancer
Authors: Kato Ikuko , Tominaga Suketami , Suzuki Tsuguyoshi
Published: August 2005

To investigate underlying factors of late menopause and early menarche which are regarded as risk factors for breast cancer, we analyzed the relationships between ages at menarche and menopause, and other environmental and physical factors using the data of a population‐based survey conducted in Aichi Prefecture, Japan. The analysis on menopause was based on 3,148 women aged 55 or more and the analysis on menarche was based on 16,392 women aged 40 or more. These subjects were grouped into three groups (early, average and late groups) according to their ages at menopause and menarche. Women with late menopause had larger height, weight and body mass index and included more professional, administrative and office workers, more daily fish & shellfish consumers and more women with colorectal cancer history of the mother and less current smokers. Women with early menarche also had larger height, weight and body mass index and more residence in a metropolitan area and consumed more bread, meats, fish & shellfish, vegetables, fruits, milk and black tea and less rice, miso soup and pickles. In a multiple regression analysis, occupation, weight, daily or occasional drinking and daily intake of fish & shellfish were positively and smoking was inversely associated with late menopause, while residence in a metropolitan area, weight and daily intakes of bread, milk and green‐yellow vegetables were positively associated with early menarche. These results suggest the importance of underlying factors of early menarche and late menopause in the etiology and prevention of breast cancer.
Selection Pressure and Altered Hepatocellular Islands after a Single Injection of Aflatoxin B1
Authors: Moore Malcolm A. , Nakagawa Kazuhiko , Ishikawa Takatoshi
Published: August 2005

Development of glutathione S‐transferase placental form (GST‐P)‐positive focal populations was investigated subsequent to single injections of the hepatocarcinogens aflatoxin B1 (AfB1), dimethylnitrosamine (DMN) and diethylnitrosamine (DEN). While DEN proved far more potent at inducing putative initiated hepatocytes, the AfB1 treatment was associated with a very rapid (3 weeks) development of lesions approaching nodular proportions. Autoradiographic investigation revealed selective incorporation of label into GST‐P‐positive hepatocytes and oval cells at the day 7 time point following AfB1 treatment. Administration of butylated hydroxyanisole (BHA) subsequent to carcinogen injection was associated with a decrease in the final yield of lesions and increased tritiated thymidine incorporation in perivenular zone 3 background hepatocytes. The results suggest that ‘selection pressure’, resulting in rapid growth and development of putative preneoplastic lesions, is inherent in a single injection of the mycotoxin and indicate that variations of the present short‐term model may be useful for elucidating the mechanisms underlying AfB1‐induced hepatocarcinogenesis.