bluuebunny/crossref_metadata_2025 huggingface dataset:
Possible Mechanisms of Resistance to cis‐Diamminedichloroplatinum (II) of Human Ovarian Cancer Cells
Authors: Kikuchi Yoshihiro , Iwano Ichiro , Miyauchi Munenori , Kita Tsunekazu , Sugita Michio , Tenjin Yoshio , Nagata Ichiro
Published: August 2005

The mechanism of cis‐diamminedichloroplatinum (II) (CDDP) resistance was examined by using a CDDP‐resistant (KFr) cell line established by continuous exposure of KF cells (derived from serous cystadenocarcinoma of the ovary) to escalating doses of CDDP. When KFr cells were incubated with 66.7 μM CDDP, the uptake of CDDP was significantly inhibited and the cellular content in the KFr cells was about a half of that in KF cells after incubation for 4 h. When the KF or KFr cells were incubated for 4 h with 100 μM CDDP, the release pattern of CDDP from KFr cells was similar to that from KF cells. In addition, the DNA histogram of both KF and KFr cells revealed that KF cells seemed to contain two clones of cell population and the KFr cells may have been selected by exposure to CDDP. At 3 h after intraperitoneal administration of 0.5 mg of CDDP per mouse to nude mice with KF or KFr tumor, the CDDP content in the KFr tumor was significantly lower than that in the KF tumor. In contrast, at 6 or 9 h after CDDP administration the CDDP content in the KFr tumor was significantly higher than that in the KF tumor. Furthermore, the KFr cells had cross‐resistance to various CDDP analogues including carboplatin. It was shown that cellular uptakes of two CDDP analogues into KFr cells were significantly lower than those into KF cells.
Isolation of an Amplified DNA Sequence in Stomach Cancer
Authors: Nakatani Hiroshi , Sakamoto Hiromi , Yoshida Teruhiko , Yokota Jun , Tahara Eiichi , Sugimura Takashi , Terada Masaaki
Published: August 2005

By use of the in‐gel DNA renaturation method, the presence of amplified DNA sequences was demonstrated in KATO‐III, a cell line established from a signet ring cell carcinoma of the stomach. A DNA fragment from one of these amplified regions in KATO‐III cells was cloned and designated SAM0.2; the locus containing the SAM0.2 fragment was referred to as SAM. The SAM locus was shown to be amplified not only in KATO‐III cells, but also in three of 24 surgical specimens of stomach cancers and in two of 13 xenografts of human stomach cancers, all of these specimens being poorly differentiated adenocarcinoma or mucinous adenocarcinoma of the stomach. The SAM locus was not amplified in 14 cell lines of cancers of other organs or in 42 surgical specimens of lung cancers.
Antibody to HTLV‐I in Indigenous Inhabitants of the Andes and Amazon Regions in Colombia
Authors: Zamora Tomas , Zaninovic Vladimir , Kajiwara Masaharu , Komoda Haruko , Hayami Masanori , Tajima Kazuo
Published: August 2005

To explore the HTLV‐I‐carrying groups among the indigenous inhabitants in South America, a sero‐epidemiological study on HTLV‐I focusing on hinterland villages isolated from others in the Andes and Amazon regions was conducted. Five (2.9%) out of 171 subjects showed positive for HTLV‐I antibody in the gelatin particle agglutination (PA) test. Two out of 5 positives with high antibody titer (≫× 1024) in the PA test also showed a positive immunofluorescence (IF) test and anti‐HTLV‐I‐specific protein products, p19, p24, p28, gp46, and p53 in sera by the Western blotting (WB) test. One of three negatives in the IF test showed positive antibodies to p19 and p24 by the WB test. Finally, two were confirmed as HTLV‐I carriers and one was suspected of being a carrier. All three are Paez Indians from the central Andes; 53‐ and 34‐year‐old women and a 35‐year‐old man. The results show that HTLV‐1 carriers exist among isolated indigenous people in South America.
Induction of Hepatic Tumors with Butylated Hydroxyanisole in the Self‐fertilizing Hermaphroditic Fish Rivulus ocellatus marmoratus
Authors: Park Eun‐Ho , Chang Hwa‐Hyoung , Cha Young‐Nam
Published: August 2005

The three‐day‐old larvae of self‐fertilizing hermaphroditic fish Rivulus ocellatus marmoratus were fed a diet containing the antioxidant butylated hydroxyanisole (BHA) at levels of 0.01–0.8% for 12 days. Six months after BHA administration, hepatic tumors were found in all groups of BHA‐treated fish. The BHA‐induced tumor incidences were clearly dose‐dependent. These results show that dietary BHA is hepatocarcinogenic in Rivulus even at 0.01% dose.
Selection of Radioresistant Cells by Vitamin A Deficiency in a Small Cell Lung Cancer Cell Line
Authors: Terasaki Takeo , Shimosato Yukio , Wada Makio , Yokota Jun , Terada Masaaki
Published: August 2005

Radiation sensitivity of a human small cell lung cancer cell line, Lu‐134‐B cells, cultured in serum‐supplemented medium and of cells transferred to and cultured in delipidized serum‐supplemented (vitamin A‐deficient) medium was studied. The cells cultured in serum‐supplemented medium showed the phenotype of classic small cell lung cancer sensitive to radiation, while cells transferred to delipidized serum‐supplemented medium showed partial squamous cell differentiation and became resistant to radiation. These results suggest that some small cell lung cancer cells in vitro change their morphology and radiosensitivity depending on the culture conditions. The change in radiosensitivity was reproducible, and was not reversible by culture of the radioresistant cells in delipidized serum‐supplemented medium with addition of retinoic acid (vitamin A‐sufficient medium) for two months, although squamous cells disappeared. Acquisition of radioresistancy was considered to occur as the result of clonal selective growth in delipidized medium of a minor cell population in the original cell culture, based on a study of chromosome number. It was also found that there was no association of myc‐family oncogenes with the changes of radiosensitivity in this cell line.
Variant Cathepsin L Activity from Gastric Cancer Tissue
Authors: Chung Sung min
Published: August 2005

Cathepsin L activity was partially purified by S‐Sepharose FF chromatography, concanavalin‐A Sepharose chromatography, phenyl‐Superose column chromatography, Mono S column chromatography, and TSK G3000SWXL column chromatography from gastric cancer tissue. The optimal pH of cathepsin L from gastric cancer tissue was 7.4, and the activity was retained even at alkaline pH. Heat stability tests showed that cathepsin L from gastric cancer tissue was heat stable; that is, 65% activity was retained after incubation at 56°C for 60 min. The molecular weight of cathepsin L from gastric cancer tissue was estimated as 115 kD by gel filtration or 110 kD by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis. The enzyme showed a different affinity for wheat germ agglutinin‐Sepharose than cathepsin L from gastric normal mucosa. These results suggest that cathepsin L from gastric cancer tissue may play an important role in gastric cancer invasion through the destruction of the surrounding extracellular matrix by its proteolytic activity.
Characteristics of Granulocyte‐Macrophage Colony Formation in Chronic Myelomonocytic Leukemia: A Comparative Study with Other Myelodysplastic and Myeloproliferative Disorders
Authors: Yuo Akira , Miyazono Kohei , Urabe Akio , Takaku Fumimaro
Published: August 2005

We studied granulocyte‐macrophage (GM) colony formation in chronic myelomonocytic leukemia (CMML, 6 cases), as compared with that in myelodysplastic syndromes (MDS, 6 cases) and myeloproliferative disorders (MPD, 12 cases). GM colony formation of bone marrow cells by colony‐stimulating factor (CSF) was normal in CMML and MPD patients, but was decreased in MDS patients. Circulating granulocyte‐macrophage progenitors (CFU‐GM) were detected in CMML and MPD patients, but not in MDS patients. GM colony formation without CSF was observed in CMML patients, but not in MDS or MPD patients. These endogenous colonies decreased markedly after adherent cell (AdC) depletion, but AdC did not form endogenous colonies in sufficient numbers to explain their marked decrease after AdC depletion. In CMML patients, the numbers of circulating CFU‐GM and endogenous colonies correlated with leukocyte and monocyte counts, respectively. The cellular composition of GM colonies was normal in MDS and MPD patients, whereas granulocytic colonies predominated in all CMML patients but one. The CSF‐producing capacity of peripheral blood cells was also studied and was found to be increased in CMML patients. This capacity was markedly decreased by AdC depletion; and AdC could produce CSF only in CMML patients. CSF produced by CMML patients supported granulocytic colonies to a greater extent than CSF produced by MDS or MPD patients. These results suggest that enhanced granulopoiesis in CMML patients is closely associated with the possible hyperproduction of granulocytic CSF by their adherent monocytes.
Detection of Hepatitis C Virus RNA in Sera and Liver Tissues of Non‐A, Non‐B Hepatitis Patients Using the Polymerase Chain Reaction
Authors: Ohkoshi Showgo , Kato Nobuyuki , Kinoshita Tomohiro , Hijikata Makoto , Ohtsuyama Yuko , Okazaki Nobuo , Ohkura Hisanao , Hirohashi Setsuo , Honma Akira , Ozaki Toshihiko , Yoshikawa Akira , Kojima Hideo , Asakura Hitoshi , Shimotohno Kunitada
Published: August 2005

Sera obtained from patients with non‐A, non‐B hepatitis were examined for the presence of hepatitis C virus (HCV) genome by using the reverse transcription‐polymerase chain reaction assay, as well as for antibody to HCV (anti‐HCV) by using an enzyme‐linked immunosorbent assay (ELISA). We also examined the presence of HCV RNA in liver tissue obtained by surgical resection of hepatocellular carcinoma. Among 33 patients, HCV RNA was detectable in 21 (64%), and the antibody was also positive in 21 (64%). Eighteen (55%) patients were positive for both assays. The two assays gave inconsistent results in 3 patients who were positive for HCV RNA but negative for anti‐HCV, and in 3 other patients who were negative for HCV RNA and positive for anti‐HCV. HCV RNA was also detected in 6 out of 10 non‐cancerous liver tissue specimens and in 3 out of 7 tumor tissue specimens. Using the polymerase chain reaction, the HCV genome was detected directly in many specimens obtained from patients with non‐A, non‐B hepatitis, suggesting the presence of replicating virus in patients positive for anti‐HCV. In addition, the differing results of the two assay systems suggest that the application of both is important for evaluation of the status of HCV infection.
Growth‐promoting Effect of Retinoic Acid in Transplantable Pituitary Tumor of Rat
Authors: Roy Bidyut , Fujimoto Nariaki , Ito Akihiro
Published: August 2005

MtT/F84 grew well in Fischer rats (F344), but tumor growth was promoted in hyperestrogenized rats. Effects of dietary retinoic acid (RA) on tumor growth, estrogen receptor (ER) and serum growth hormone (GH) level were examined. Tumor latency became shortened, and tumor take and weight were promoted by all‐trans RA at dosages of 50 and 200 mg/kg basal diet, but not dose‐dependently. ER level was elevated in tumor of RA‐treated rats, whereas the retinoic acid‐binding protein level remained unchanged. RA also elevated incorporation of 5‐bromo‐2′‐deoxyuridine, a thymidine analogue, into DNA of tumor cells. Average serum GH level was increased in tumor‐bearing rats treated with RA and was well correlated with tumor weight. RA may directly affect ER level and enhance estrogenic action, resulting in promotion of tumor growth, or it may act independently for tumor growth and elevation of serum GH level.
Survey of Anti‐human T‐Cell Leukemia Virus Type I Antibody in Family Members of Patients with Adult T‐Cell Leukemia
Authors: Momita Saburo , Ikeda Shuichi , Amagasaki Tatsuhiko , Soda Hisashi , Yamada Yasuaki , Kamihira Shimeru , Tomonaga Masao , Kinoshita Kenichiro , Ichimaru Michito
Published: August 2005

To evaluate the intrafamilial clustering of HTLV‐I, we examined the sera or plasma of 296 healthy family members of patients with adult T‐cell leukemia (ATL) for anti‐HTLV‐I antibodies. Of 296 subjects, 132 (44.6%) had anti‐HTLV‐I antibodies. Fifty‐nine (41.0%) out of 144 males and 73 (48.0%) out of 152 females were seropositive. The positive rates of antibody to HTLV‐I increased with age, especially between the 30–39 and the 40–49 age groups. Five out of 6 fathers, 3 out of 4 mothers, 31 (60.8%) out of 51 spouses, 40 (63.5%) out of 63 siblings and 46 (33.8%) out of 136 children of patients with ATL had anti‐HTLV‐I antibodies. Of 74 children with an ATL father, 14 (18.9%) were seropositive, while 32 (51.6%) out ot 63 children with an ATL mother were seropositive. This difference was statistically significant (P<0.001). Of those children with an ATL father, 12 (26.1%) out of 46 whose mothers were HTLV‐I carriers had antibodies to HTLV‐I. In contrast, none of the 13 children whose mothers were not carriers were seropositive. These results supported the hypothesis that the mother‐to‐child transmission is one of the most important modes of HTLV‐I transmission. In wives of male patients with ATL, the positive rate of antibody to HTLV‐I was 65.6% (21/32), and in husbands of female patients, it was 52.6% (10/19). The high positive rate of antibody to HTLV‐I not only in wives of male patients but also in husbands of female patients suggests that either HTLV‐I is more frequently transmitted from wives to their husbands than we had originally expected, or that ATL may develop even in wives who acquire HTLV‐I from their husbands after marriage.
Detection of Human Papillomavirus Types 6/11, 16 and 18 in Exfoliated Cells from the Uterine Cervices of Japanese Women with and without Lesions
Authors: Yokota Harushige , Yoshikawa Hiroyuki , Shiromizu Kenji , Kawana Takashi , Mizuno Masahiko
Published: August 2005

Human papillomavirus (HPV) infection of the uterine cervices of Japanese women with and without lesions was identified by the filter in situ hybridization method. Exfoliated cervical cells from 23 cervical papillary condylomas, 70 cervical intraepithelial neoplasia (CIN) grade I/II, 26 CIN III, 31 invasive cervical cancers and 666 cervices without evidence of disease (including 53 pregnant women) were tested for the presence of HPV types 6/11, 16 and 18. The positive rates for the detection of HPV types 6/11, 16 and 18 DNA were 47.8%, 26.1% and 8.7% in cervical condylomas, 5.7%, 15.7% and 8.6% in CIN I/II, 0, 34.6% and 0 in CIN III, 3.2%, 38.7% and 9.7% in invasive cervical cancers and 0.9%, 1.8% and 0.6% in the control cervices. These data suggest that, in Japan, HPV6/11, HPV16 and HPV18 infections are also prevalent in cervical cells with normal phenotype, and the type of HPV infection of the uterine cervix is related to the histological diagnosis.
X Protein of Hepatitis B Virus Resembles a Serine Protease Inhibitor
Authors: Takada Shinako , Koike Katsuro
Published: August 2005

The × protein of hepatitis B virus (HBV) has been shown to be a trans‐activator for viral and cellular genes. Amino acid sequences in × protein were found to be highly homologous to functionally essential sequences in the “Kunitz domain,’characteristic of Kunitz‐type serine protease inhibitors. Mutations at these sequences completely abolished trans‐activation. Consequently, HBV × protein resembles a serine protease inhibitor or its analogue, and may bring about trans‐activation by activating certain transcriptional factors through proteolytic cleavage alteration.
Detection of the c‐myc Gene Product in Urinary Bladder Cancer
Authors: Kotake Toshihiko , Saiki Shigeru , Kinouchi Toshiaki , Shiku Hiroshi , Nakayama Eiichi
Published: August 2005

Expression of the c‐myc gene product in urinary bladder cancer was investigated by immunohistochemical staining with anti‐c‐myc monoclonal antibody (mAb) MYC‐1. Positive staining was observed in the cytoplasm, but not in the nucleus in tissues fixed with 10% formalin. On the other hand, positive staining was localized in the nucleus in cryopreserved tissues. Of 34 cryopreserved specimens examined, positive staining with MYC‐1 mAb was observed in 1 of 12 (8.3%) of grade 1 (G1), 12 of 15 (80%) of G2 and 6 of 7 (86%) of G3. Positive staining with Ki‐67 mAb was observed in 2 of 12 (17%) of G1, 12 of 15 (80%) of G2, and 6 of 7 (86%) of G3. These results suggest that tumors with higher nuclear pleomorphism contain more proliferating cells.
Expression of Transforming Growth Factor‐β1 mRNA in Human Hepatocellular Carcinoma
Authors: Ito Nobuyuki , Kawata Sumio , Tamura Shinji , Takaishi Kenji , Yabuuchi Iwao , Matsuda Yasuo , Nishioka Minoru , Tarui Seiichiro
Published: August 2005

We investigated the expression of transforming growth factor β1 (TGF‐β1) mRNA in tumor tissues surgically removed from ten patients with hepatocellular carcinoma (HCC). All HCC tissues expressed TGF‐β1 mRNA at different levels, indicating the presence of activated transcription of TGF‐β1 gene in human HCC tissues in vivo. The level of TGF‐β1 mRNA expression showed no relationship to main tumor size or plasma α‐fetoprotein level. Some HCC tissues presenting a relatively low grade of histological differentiation showed the highest levels of TGF‐β1 mRNA expression.
Recognition of the Polypeptide Core of Mucin by Monoclonal Antibody MUSE11 against an Adenocarcinoma‐associated Antigen
Authors: Hinoda Yuji , Nakagawa Naoaki , Ohe Yasuo , Kakiuchi Hideki , Tsujisaki Masayuki , Imai Kohzoh , Yachi Akira
Published: August 2005

Monoclonal antibody (MAb) MUSE11 detects an adenocarcinoma‐associated antigen and is useful for the serodiagnosis of pancreas cancer. We established a sandwich enzyme immunoassay using MAb MUSE11 and MAb DP3 against a breast cancer‐associated mucin core protein as a catcher and a tracer, respectively. With this assay system, the binding of the tracer MAb DF3 to an antigen in the human kidney tissue lysate was clearly inhibited by MAb MUSE11. In addition, MAb MUSE11 showed a significant binding activity to the synthetic peptide corresponding to the tandem repeat of a human epithelial mucin core protein. These data suggest that MAb MUSE11 could detect the polypeptide core of a mucin, and may be of use for studying mucin as a gene product.
Increase in the Level of P‐Glycoprotein mRNA Expression in Multidrug‐resistant K562 Cell Lines Treated with Sodium Butyrate Is Not Accompanied with Erythroid Differentiation
Authors: Shibata Hiroyuki , Kanamaru Ryunosuke , Sato Toshiaki , Ishioka Chikashi , Konishi Yukari , Ishikawa Akira , Wakui Akira , Tsuruo Takashi
Published: August 2005

We examined the effects of hemin, sodium butyrate and mitomycin C on levels of P‐glycoprotein mRNA in human myelogenous K562 cells by northern blot analysis. After treatment with sodium butyrate a dose‐dependent increase of P‐glycoprotein mRNA expression was observed in the adriamycin‐resistant K562 and vincristine‐resistant K562 lines. With 10 mM sodium butyrate, the level of P‐glycoprotein mRNA reached 20 times that of control adriamycin‐resistant K562 and with 30 mM sodium butyrate, it exceeded 5 times that of control vincristine‐resistant K562. In contrast, hemin and mitomycin C had almost no effect on P‐glycoprotein mRNA. In this experiment, since expression of P‐glycoprotein mRNA was not necessarily accompanied with induction of erythroid differentiation, the increased amount of P‐glycoprotein mRNA is unlikely to be a result of differentiation.
Chemoprevention of 7,12‐Dimethylbenz[a]anthracene‐induced Mammary Carcinogenesis in Rat by the Combined Actions of Selenium, Magnesium, Ascorbic Acid and Retinyl Acetate
Authors: Nitin Rao Araga Ramesha , Rao Araga Ramesha , Jannu Laxmi Narayna , Hussain Syed Perwez
Published: August 2005

The chemopreventive actions of sodium selenite (SS), magnesium chloride (MC), ascorbic acid (AA) and retinyl acetate (RA), given singly or in combinations, on mammary carcinogenesis induced by 30 mg of 7,12‐dimethylbenz[a]anthracene (DMBA) in female adult rats were evaluated. Administration of modulators was carried out from the age of 40±3 days to 240±3 days. When DMBA alone was given 100% of the rats developed mammary tumors. When modulators were given singly the tumor incidences were reduced to 51.77% (SS), 46.4% (MC), 57.1% (AA) and 48.1% (RA). When the modulators were given in combination of twos, the tumor incidences were further reduced to 29.5% (SS + MC), 31% (SS + AA), 29.6% (SS + RA), 25.9% (MC + AA), 31.8% (MC + RA) and 34.6% (AA + RA). Administration of modulators in combinations of threes resulted in still further reduction of tumor incidences to 22.2% (SS + MC + AA), 19.2% (SS + MC + RA), 16% (MC + AA + RA) and 23.1% (AA + RA + SS). When all four modulators were given concurrently the tumor incidence was only 12%. Further, the number of tumors per tumor‐bearing animal declined with the increase in the number of agents used in combination for modulation.
The Role of Bone Fracture at the Site of Carcinogen Exposure on Nickel Carcinogenesis in the Soft Tissue
Authors: Ohmori Takaaki , Uraga Naomi , Komi Kiyoshi , Tabei Ryo , Shibata Taiho
Published: August 2005

The influence upon nickel subsulfide (α‐Ni3S2; Ni‐SS)‐induced carcinogenesis in the soft tissue of bone fracture at the site of Ni‐SS exposure was studied using female Fischer rats. During the one year of the experiment, the group subjected to bone fracture exhibited the shortest tumor induction time and survival time, and a significantly higher metastatic rate. The present study may suggest a model for the metastasis of human soft tissue tumors.
Tumor‐promoting Phorbol Ester Induces Alterations of Sialidase and Sialyltransferase Activities of JB6 Cells
Authors: Miyagi Taeko , Sagawa Junji , Kuroki Toshio , Matsuya Yutaka , Tsuiki Shigeru
Published: August 2005

Sialidase and sialyltransferase activities were studied in JB6 mouse epidermal cells before and after exposure to phorbol ester, 12‐O‐tetradecanoyl phorbol‐13‐acetate (TPA), which irreversibly induces anchorage‐independent growth and tumorigenicity. JB6 cells exhibited sialidase activities toward 4‐methylumbelliferyl‐α‐d‐N‐acetylneuraminic acid (4MU‐NeuAc) and gangliosides at pH 4.5 in the particulate fraction but apparently not in the cytosol at pH 4.5 or 6.0. In JB6 cells exposed to TPA and in the anchorage‐independent transformants, the sialidase activity toward 4MU‐NeuAc was decreased and the activity toward gangliosides was increased compared with those in untreated JB6 cells. Immunological analysis with antisera against membrane‐associated sialidases I and II revealed that plasma membrane‐associated sialidase I was increased and lysosomal membrane‐associated sialidase II was decreased under these conditions. TPA treatment also affected the sialyltransferase activities of JB6 cells: an elevation of the transfer activities toward asialo‐orosomucoid and asialo‐porcine submaxillary mucin but a reduction of GM3 and GD3 synthase activities were observed on exposure to TPA and in cells transformed by TPA to retain anchorage‐independency. These results suggest that an increase in sialic acid bound to glycoproteins and a decrease in that bound to glycolipids may occur in JB6 cells exposed to TPA and in the anchorage‐independent transformants.
Antitumor Activities of IKP‐104, a 4(1H)‐Pyrizinone Derivative, on Cultured and Implanted Tumors
Authors: Mizuhashi Fukutaro , Murata Kyoji , Kitagaki Tadaharu , Nezu Masao , Sano Mituaki , Tomita Isao
Published: August 2005

Antitumor activities of IKP‐104, a 4(1H)‐pyrizinone derivative, were investigated with cultured tumor cell lines and implanted tumors in mice. IKP‐104 inhibited the growth of cultured murine tumor cell lines (L1210 leukemia, Lewis lung carcinoma and B16 melanoma) and human tumor cell lines (K562 leukemia and HeLa cervical carcinoma). It also had antitumor effects on implanted murine ascitic tumors (L1210 leukemia and sarcoma 180) and a murine solid tumor (Lewis lung carcinoma). IKP‐104 could be classified as a phase‐dependent cytostatic drug based on the mode of growth inhibition of cultured B16 melanoma cells compared with those of several other antitumor agents. The effect of IKP‐104 on the cell cycle traverse of cultured B16 melanoma cells was estimated by morphological and flow cytometric analyses. Cells accumulated in the mitotic phase, and abortive mitosis or polyploidy or multinucleation was induced from 6 h after exposure to IKP‐104. Based on these results, IKP‐104 is expected to be useful for the treatment of tumors, and its mode of action seemed to be similar to that of metaphase arrestants such as colchicine or vinca alkaloids.
Multi‐drug Combination Therapy with Vincristine‐Melphalan‐Cyclophosphamide‐Prednisolone Was More Effective than Cyclophosphamide‐Prednisolone in Stage III Myeloma
Authors: Shimizu Kazuyuki , Kamiya Osamu , Hamajima Nobuyuki , Mizuno Harumitsu , Kobayashi Masahide , Hirabayashi Noriyuki , Takeyama Hideo , Kato Ryoichi , Kawashima Kohei , Nitta Masakazu , Hotta Tomomitsu , Utsumi Makoto , Nagura Eiichi
Published: August 2005

A cooperative randomized clinical trial to compare the effectiveness of multi‐drug combination chemotherapy (VMCP, vincristine‐melphalan‐cyclophosphamide‐prednisolone) with CP (cyclophosphamide‐prednisolone) for the treatment of multiple myeloma was performed. When the whole group of patients was evaluated, the choice of chemotherapy (VMCP or CP) was not a significant prognostic factor associated with response or survival by uni‐ or multivariate analysis, and the difference between the survival curves of the treatment groups was only marginally significant. However, when the analysis was confined to stage III patients, the choice of chemotherapy became a significant prognostic factor associated with both response rate and survival, and the statistical difference between survival curves was significant. Taking the disease characteristics of multiple myeloma into consideration, the better result obtained with multi‐drug combination chemotherapy in the treatment of stage III patients is consistent with other studies supporting the superiority of multi‐drug combination chemotherapy for patients with overt systemic disease.
Expression of Membrane‐associated Lymphotoxin/Tumor Necrosis Factor‐β on Human Lymphokine‐activated Killer Cells
Authors: Abe Yasuhito , Miyake Masazumi , Horiuchi Atsushi , Kimura Shigeru , Yasuo Yasuo
Published: August 2005

A membrane‐associated lymphotoxin (LT)‐related molecule was detected on human lymphokine‐activated killer (LAK) cells by flow cytometric analysis. Kinetic analysis revealed that the LT antigenicity on LAK cells appeared at 9 h after the beginning of culture and was maintained thereafter. By autoradiography, the molecular weight of membrane LT was estimated to be 31 kD and/or 62 kD.
Multiple Primary Cancers in Patients with Squamous Cell Carcinoma of the Oral Cavity
Authors: Saikawa Masahisa , Ebihara Satoshi , Yoshizumi Takashi , Ohyama Waichiroh
Published: August 2005

During the 27 years between 1962 and 1988,984 patients visited the National Cancer Center Hospital for previously untreated squamous cell carcinoma of the oral cavity and lip. The records of all these 984 patients were reviewed to determine the incidence of additional primary carcinoma. 1) One hundred and thirty‐five additional carcinomas developed in 111 patients (11.2%) during 5,689.2 person‐years of observation. The incidence of additional primary carcinoma was 23.7 per 1,000 person‐years. 2) The cumulative rate of additional primary carcinoma during the first five years of observation showed a tendency to increase in the most recently treated patients (from 1980 to 1988). 3) The observed‐to‐expected ratio (O/E ratio) for all sites was 2.77 and this is significantly high (P < 0.01). The calculation of the O/E ratio for each site revealed significantly high risks in the oral cavity and pharynx, esophagus and skin. The O/E ratio for the oral cavity and pharynx was extremely high (79.45). 4) The O/E ratio for all sites in each year of follow‐up was the highest in the first year, stayed nearly constant from the second to 14th years, and decreased gradually afterwards. Significantly high risk was observed until the 13th year of follow‐up. Patients with oral squamous cell carcinoma must be under frequent and regular examination for almost 15 years.
Increased N‐Acetylglucosamine‐l‐phosphotransferase Activity in Sera from Patients with Leukemia
Authors: Uehara Yoshio , Gasa Shinsei , Makita Akira , Sakurada Keisuke , Tamotsu Tamotsu
Published: August 2005

In human cancer, lysosomal hydrolases contain increased amounts of phosphorylated sugar chains. Sugar chains of the hydrolases undergo post‐translational processing which is catalyzed by N‐acetyl‐glucosamine‐1‐phosphotransferase (GIcNAc‐phosphotransferase) at the first step. In the present study we estimated serum GlcNAc‐phosphotransferase in 50 adults suffering from leukemia and myelo‐dysplastic syndrome. The serum GlcNAc‐phosphotransferase was increased to moderate or high levels in patients with acute nonlymphocytic leukemia (ANLL), acute lymphoblastic leukemia and chronic myelogenous leukemia, suggesting that the serum transferase is released from leukemic cells. In many cases of ANLL examined,activity of the transferase was decreased concomitantly with reduction of peripheral blastic cells by effective chemotherapy.
Ciliated Gastric Cells among Japanese Living in Hawaii
Authors: Rubio Carlos A. , Stemmermann Grant N. , Takuji Takuji
Published: August 2005

A total of 129 consecutive gastrectomy specimens from Japanese (99), Philippinos (11), Hawaiians (8), Koreans (5), Chinese (4) and Caucasians born in Hawaii (2) were examined under high‐power light microscopy (1000X) for the presence of ciliated gastric cells. Fifty‐two of the 129 gastrectomy specimens (40.3%) contained ciliated cells. Ciliated cells were found in the hasal segments of antral glands (usually cystically dilated) whose superficial segments had undergone intestinal metaplasia. The presence of ciliated cells in the gastric mucosa was influenced by the age of the patient and by the degree of intestinal metaplasia: the older the patient, the greater the degree of intestinal metaplasia and the greater the frequency of specimens with ciliated cells. The presence of ciliated cells was also influenced by the type of lesion in the specimen. Although the highest frequency (47.2%) was found in stomachs removed for adenocarcinoma, a substantial number of stomachs removed for gastric ulcer also showed that change (36%). The data suggest that increasing age and advanced atrophic gastritis, especially of the antrum, provide the necessary conditions that lead to the development of cilia, not only in Japanese subjects, but in other Hawaiian ethnic groups as well.
A New Rat Colon Cancer Cell Line Metastasizes Spontaneously: Biologic Characteristics and Chemotherapeutic Response
Authors: Inoue Yuichiro , Kashima Yuji , Aizawa Kikuo , Katsuyoshi Katsuyoshi
Published: August 2005

A new cell line (RCN‐9) was established in culture from a transplantable rat colon adenocarcinoma, which was induced in the colon of a male Fischer F344 rat by subcutaneous administration of 1,2‐dimethylhydrazine. When RCN‐9 cells were injected subcutaneously or into the cecal subserosa of syngeneic rats, carcinomas with progressive growth were obtained and the development of lung (63.6%) and liver (40.0%) metastases, respectively, ensued. Antitumor effects of 5‐fluorouracil (5‐FU), adriamycin (ADM) and mitomycin C (MMC) against RCN‐9 were examined in vivo and in vitro. 5‐FU and ADM had antitumor effects both in vivo and in vitro; MMC had antitumor effects in vitro. These results show that the RCN‐9 cell line can be used both as a model to study mechanisms of metastasis from colon carcinoma and as a model in chemotherapeutic studies of metastatic disease from colon carcinoma.
Mechanism of the Combined Antitumor Effect of Natural Human Tumor Necrosis Factor‐α and Natural Human Interferon‐α on Cell Cycle Progression
Authors: Muro Masahiko , Naomoto Yoshio , Orita Kunzo
Published: August 2005

We have studied the mechanism of the synergistic effect of the combination of tumor necrosis factor‐α (TNF‐α) and interferon‐a (IFN‐α) on cell cycle progression using two‐parameter flow cytometry in vitro and an immunohistochemical staining method in vivo. The cells used were human colon cancer cell line RPMI 4788 in vitro and in vivo, and human breast cancer cell line MX‐1 and human renal cancer cell line NAMKO‐1 in vivo. In the in vitro experiment, the cell cycle progressed normally as time elapsed in the control group. However, in the group treated with TNF‐α and IFN‐α in combination (combination group), it appeared that the transition from the S phase to the G2/M phase was blocked, and the cells that accumulated in the S phase died. In the in vivo experiment with male nude mice of a CD‐1 genetic background, the antitumor effect on all three kinds of cancer cells was significantly greater in the combination group than in the control group. The cell labeling index on staining with bromodeoxyuridine in the combination group became markedly larger and the mitotic index smaller than in the other groups. From these results, it was concluded that in the combination group, both in vitro and in vivo, tumor cells markedly accumulated in the S phase and their progression from the S phase to the G2/M phase in the cell cycle was inhibited.
Cytostatic Effect of Deoxyspergualin on a Murine Leukemia Cell Line L1210
Authors: Hiratsuka Masaharu , Kuramochi Hiroshi , Takahashi Katsutoshi , Takeuchi Tomio , Mitsuo Mitsuo
Published: August 2005

The mode of antiproliferative action of deoxyspergualin (NKT‐01) was examined. The growth‐inhibitory effect on a murine leukemia cell line L1210 following treatment with NKT‐01 was time‐dependent, and there was little or no effect on the syntheses of DNA and RNA. Thus, the inhibitory activity of NKT‐01 was not attributable to the inhibition of DNA and RNA syntheses. The influence of NKT‐01 on cell cycle progression was studied by flow cytometric analysis. Bromodeoxyuridine/DNA distribution patterns in cells that were treated for 72 h, showed that the growth inhibition is due to the delay of cell cycle progression but not to cytotoxicity. This finding was also supported by evidence that the treated cells were re‐proliferative in fresh medium. In addition, a majority of drug‐treated cells was prevented from traversing from the G0/G1 phase to the S phase by 144 h or longer exposure to NKT‐01. The results suggest that NKT‐01 is cytostatic, preventing G0/G1‐S progression.
Timing Effects of Uracil‐induced Urolithiasis on Amplification of Second‐stage Promotion in Rat Bladder Carcinogenesis
Authors: Shibata Masa‐Aki , Hasegawa Ryohei , Sano Masashi , Shirai Tomoyuki , Shoji Shoji
Published: August 2005

The post‐initiation enhancing activities of the non‐genotoxic agent NaHCO3 and the genotoxic agent N‐ethyl‐]N‐(4‐hydroxybuty])nitrosainine (EHBN) in combination with uracil‐induced urolithiasis were investigated in a rat bladder carcinogenesis model. Animals were treated with 0.05%N‐butyl‐N‐(4‐hydroxybutyl)nitrosamine (BBN) for 4 weeks, and then 3% uracil was given for 3 weeks in the early (weeks 4‐7), middle (weeks 8 11) or late (weeks 12–15) post‐initiation phase. In addition, administration of 3% NaHCO3, 20 ppm EHBN or no chemical supplement was performed for the 13 weeks when the rats were not receiving BBN or uracil. NaHCO3 in sequential combination with early and middle stages uracil treatment strongly enhanced tumorigenesis in the urinary bladder, while EHBN treatment amplified lesion development at the middle stage only of uracil treatment. DNA synthesis and associated epithelial surface alterations observed by scanning electron microscopy tended to be increased in the NaHCO3 and EHBN groups without BBN initiation, independently of uracil treatment timing. The present results demonstrated that uracil‐induced urolithiasis during the middle post‐initiation phase is highly active in enhancing bladder tumor development under the influence of a promoter or carcinogen.
Effects of Hormones on Tumor Growth and Immunoreactive Insulin–like Growth Factor–1 of Estrogen Receptor–positive Human Breast Cancer (MCF‐7) Transplanted in Nude Mice
Authors: Noguchi Masakuni , Koyasaki Naohiro , Miyazaki Itsuo , Yuji Yuji
Published: August 2005

The effects of estrogens and tamoxifen were analyzed on estrogen receptor–positive human breast cancer (MCF–7) transplanted into athymic nude mice. It was found that (1) the tumor growth and the proportion of 3H–thymidine –labeled cells were significantly increased in the 17β– estradiol dipropionate (E2) group, but significantly decreased In the tamoxifen (TAM) group with respect to the control group, and (2) the tumor content of insulin–like growth factor–1 (IGF–1) and the rate of IGF–1–positive cells were significantly lower in the E2 group, but significantly higher in the TAM group than in the control group. It was concluded that the tumor content of IGF–1 and the proportion of IGF–I–positive cells were inversely correlated to the tumor growth and the 3H–thymidine labeling index in vivo,
Bispecific Antibody‐directed Antitumor Activity of Human CD4+Helper/Killer T Cells Induced by Anti–CD3 Monoclonal Antibody plus Interleukin 2
Authors: Nishimura Takashi , Nakamura Yoshihiko , Takeuchi Yasuhiro , Gao Xiuhua , Tokuda Yutaka , Okumura Ko , Sonoko Sonoko
Published: August 2005

Freshly isolated human CD4+T cells can not respond to recombinant interlenkin 2 (rIL–2) because of their lack of p75 IL–2 receptor expression. However, we succeeded In inducing a marked proliferation of purified CD4+T cells by activation with rIL–2 plus anti–CD3 monoclonal antibody (mAb) cross–linked to a plastic plate. The proliferated CD4+T cells produced a significant amount of IL–2 upon stimulation with phorbol ester plus A23187. Interestingly, CD4+T cells activated with anti–CD3 mAb plus rIL–2 revealed a strong cytotoxic activity against Fc receptor (FcR)–positive tumor cells in the presence of anti–CD3 mAb. Moreover, the CD4+T cells could lyse FcR–negative glioma cells by targeting with bispecific mAb containing anti–CD3 mAb and anti–glioma mAb. Thus, we demonstrated that rIL–2 and immobilized anti–CD3 mAb allowed the rapid generation of human CD4+helper/killer T cells, which may be useful for the development of a new adoptive tumor immunotherapy.
Summation Effects of Uracil and Other Promoters on Epithelial Lesion Development in the F344 Rat Urinary Bladder Initiated by N‐Butyl‐N‐(4‐hydroxybutyl)nitrosamine
Authors: de Camargo João Lauro Viana , Shirai Tomoyuki , Kato Toshio , Asamoto Makoto , Shoji Shoji
Published: August 2005

Five non‐genotoxic chemicals previously demonstrated to be bladder cancer promoters in 36‐week in vivo assays for carcinogenesis were reevaluated in a 20‐week experiment in order to assess the summation influence of dietary nracil, a component of RNA, on the development of (pre)neoplastic lesions. The test chemicals, sodium bicarbonate, sodium L‐ascorbate, sodium citrate, butylated hydroxytoluene and ethoxyquin, were mixed into the diet at concentrations of 3%, 5%, 5%, 1% and 0.8%, respectively, and administered to male F344 rats after initiation with 0,05% N‐butyl‐N‐(4‐hydroxybutyDnitrosamine (BBN) in their drinking water for 4 weeks. The test chemicals were given from the 4th to the 8th and the llth to 20th experimental weeks, uracil being administered at the level of 3% in the diet during the intervening period. Rats in the control group received only BBN and uracil. All animals were killed at week 20 and the bladders were evaluated for the occurrence of putative preneoplastic papillary or nodular (PN) hyperplasia and tumors. Significant increase in the occurrence of FN hyperplasia was observed in all groups initiated with BBN and fed uracil and test chemicals. Quantitative values for papillomas were also significantly increased except in the ethoxyquin‐treated group. The results confirm that uracil given in the middle of the post‐initiation stage enhances the promoting activity of chemicals and suggest that the use of this chemical might be useful to reduce the duration of current bioassays for bladder chemical carcinogens.
Activation and Suppression of a Cryptic Promoter in the Intron of the Human Melanoma‐associated ME491 Antigen Gene
Authors: Takahashi Nobuo , Hotta Hak , Morio Morio
Published: August 2005

A deletion mutant of the human melanoma‐associated ME491 antigen gene starting at the first intron (λR31) differentially mediates the antigen expression depending on the cell type. Cryptic promoter activity residing in a 270‐base‐pair (bp) fragment of the first intron was examined by primer extension analysis and recombinant chloramphenicol acetyltransferase (CAT) assay. The cryptic promoter, further localized within a 153‐bp fragment (fr153BN), exerted its effect in Ltk‐ and H‐ras‐transformed NIH3T3 (3T3‐Hras) but not in parental NIH3T3 cells. The results suggested that the cryptic promoter was associated with a novel ras‐responsive positive regulatory element, since fr153BN did not contain an AP‐1‐binding sequence motif, known as the rew‐responsive enhancer element. The cryptic promoter activity of fr153BN was suppressed by an upstream 121‐bp fragment (fr121SB) which contained a consensus sequence motif for binding of a repressor protein, GC factor, and regions showing sequence similarity with putative cis‐acting repressor elements found in the vimentin gene. The degree of the suppression was greater in 3T3‐Hras than in Ltk‐ cells. These positive and negative regulatory elements may be differentially involved in the regulation of ME491 antigen expression depending on the cell type.
Characterization of High‐Molecular‐Mass Forms of Basic Fibroblast Growth Factor Produced by Hepatocellular Carcinoma Cells: Possible Involvement of Basic Fibroblast Growth Factor in Hepatocarcinogenesis
Authors: Shimoyama Yutaka , Gotoh Masahiro , Ino Yoshinori , Sakamoto Michiie , Kato Koichi , Setsuo Setsuo
Published: August 2005

Growth factor(s) with a strong mitogenic effect on BALB/c3T3 cells was purified from an extract of C‐Li21 cells, a human hepatocellular carcinoma line, by a combination of heparin‐affinity chromatography and reversed‐phase high‐performance liquid chromatography (HPLC). Two major peaks of mitogenic activity were obtained by reversed‐phase HPLC. Sodium dodecyl sulfate‐polyacrylamide gel electrophoresis analysis of the two peaks revealed that one was composed of three proteins with relative molecular masses of 27, 24 and 23 kilodaltons (kD), whereas the other was a single 19‐kD protein. Immunoblot analysis showed that all four of these molecules were immunoreactive species of human basic fibroblast growth factor (bFGF). N‐Terminal sequence analysis of these molecules revealed that most of them were N‐terminally blocked. However, small proportions of the 23 and 19‐kD molecules were not blocked, and their respective N‐terminal sequences were found to correspond to Gly ‐40‐Gl‐27 and Pro29‐Phe40 of human bFGF deduced from the cDNA sequence of a human hepatoma cell line, SK‐HEP‐1. Expression of bFGF in hepatocellular carcinomas was then investigated by RNA blot analysis. All of the examined hepatocellular carcinoma cells expressed bFGF, and the degree of expression was higher in surgically resected hepatocellular carcinomas than in the corresponding adjacent non‐cancerous liver tissue. Transcripts of bFGF were not detected in normal liver. These results suggest that C‐Li21 cells produce four molecular forms of bFGF, and that bFGF may be involved in hepatocarcinogenesis. Moreover, it appears that bFGF is a potent mitogen toward primary‐cultured hepatocytes, and that high‐molecular‐mass forms of bFGF produced by C‐Li21 cells have stronger mitogenic effects on hepatocytes and are more stable under acidic conditions than the low‐molecular‐mass form, composed of 146 amino acids.
Antitumor Effector Mechanism of Interleukin‐lβ at a Distant Site in the Double Grafted Tumor System
Authors: Ebina Takusaburo , Kazuko Kazuko
Published: August 2005

Recombinant human interleukin‐lβ (IL‐lβ) Inhibited the growth of not only the right, but also the left non‐treated tumor in a double grafted tumor system. Since the antitumor activity of IL‐lβ against the right and left tumors was not seen in nude mice, lymphocytes have a key role in the antitumor effect of intratumoral administration of IL‐lβ. TIL (tumor‐infiltrating leukocytes) obtained from left and right side tumors treated with IL‐1β were examined by Winn assay for their antitumor activity against Meth‐A sarcoma in BALB/c mice. TIL from the right side clearly inhibited the growth of admixed Meth‐A cells, but control TIL did not. Spleen cells and right and left regional lymph node cells prepared from IL‐1‐treated mice were examined for Lyt‐1, Lyt‐2 and L3T4 phenotypes. The number of Lyt‐1‐positive lymphocytes increased in the spleen and in the right regional lymph nodes after intratumoral administration of IL‐1. Isolated tumor cells obtained from the right tumor treated with IL‐lβ and the left side tumor on day 6 were cultured in RPMI1640 with 10% fetal calf serum for 24 h. The culture supernatants were harvested and tested for the presence of chemotactic activity for neutrophils or macrophages. Significant neutrophil chemotactic factor and macrophage chemotactic factor activities were detected in the culture media from IL‐1‐treated tumor tissues cultured for 24 h. Neither significant neutrophil nor macrophage chemotactic activity was detected in the media from untreated tumor tissues. These results suggest that intratumoral administration of IL‐1 first induces neutrophils and macrophages in the right tumor, then Lyt‐1‐positive cells in the right regional lymph nodes and in the spleen, and subsequently induces macrophages in the left, non‐treated tumor.
Antitumor Activity and Metabolism of a New Anthracycline‐containing Fluorine (ME2303) in Lewis Lung Carcinoma‐bearing Mice
Authors: Tigo Masaaki , Hoshi Akio , Kadosawa Hiroyuki , Fujigaki Masao
Published: August 2005

(7‐O‐(2,6‐Dideoxy‐2‐fluoro‐α‐L‐talopyranosyl)adriamycmone‐14‐hemipimerate (ME2303) showed a more marked growth inhibition of Lewis lung carcinoma than adriamycin (ADM). When administered to s.c. Lewis lung carcinoma‐hearing mice, ME2303 in the plasma and liver was rapidly metabolized and disappeared. However, ME2303 was incorporated into the tumor at higher concentrations and remained in the tumor for a longer period than in the plasma and liver. ME2303 was metabolized to 7‐O‐(2,6‐dideoxy‐2‐fluoro‐α‐L‐talopyranosyl) adriamycinone (M1), the product of esterolysis, and its reduced derivative at the C‐13 position (M2), Larger amounts of these metabolites were found in the analyzed tissues than in plasma. The maximum concentration of Ml in the tumor was observed at 2 h posttreatment, while the maxima in the plasma and liver were observed at 15 min. On the other hand, i.v. injection of M1 into mice showed a weaker antitumor effect than ME2303 injection, though Ml levels in the plasma and tumor were almost the same as those after administration of ME2303 at the maximum tolerated doses. Some metabolites of ME2303 were found in the tumor after administration of ME2303, but not after administration of M1. ADM remained in the analyzed tissues for a long period and ADM concentrations in the tumor were much higher than in the plasma but less than in the liver. M1 reached a concentration higher than that of ADM in the tumor, opposite to the pattern observed in the liver. The conversion process from ME2303 to M1, the metabolites and their locations in the tumor may be important for the marked antitumor effect of ME2303 in vivo.
A Tubule Cell Line Established from Transgenic Mice Harboring Temperature‐sensitive Simian Virus 40 Large T‐Antigen Gene
Authors: Yanai Nobuaki , Satoh Takeshi , Kyo Shiro , Abe Keishi , Suzuki Misao , Masuo Masuo
Published: August 2005

Immortalization of cell lines with specific functions is important for examination of organ‐specific functions in vitro. We established a kidney tubule cell line (TKC2) exhibiting a specific physiological response to hormone from the primary culture of kidneys of adult transgenic mice harboring temperature‐sensitive SV40 large T‐antigen gene. TKC2 cells showed temperature‐sensitive growth in culture and exhibited characters of distal tubule cells such as dome formation at confluent culture and stimulation of cAMP synthesis by arginine vasopressin. These phenotypes are maintained after long passages in culture and may provide a new experimental system for studying renal physiology.