bluuebunny/crossref_metadata_2025 huggingface dataset:
Chick Embryo Assay as Chemosensitivity Test for Malignant Glioma
Authors: Shoin Katsuo , Yamashita Junkoh , Enkaku Fumihide , Sasaki Takuma , Tanaka Motohiro , Yoshio Yoshio
Published: August 2005

To predict the efficacy of anticancer drugs such as ACNU [l‐(4‐amino‐2‐methyl‐5‐pyrimidinyl)‐methyl‐3‐(2‐chloroethyl)‐3‐nitrosourea hydrochloride] and MCNU [l‐(2‐chloroethyl)‐3‐(methyl‐α‐D‐glucopyranos‐6‐yl)‐l‐nitrosourea] in the treatment of malignant gliomas, the usefulness of the chick embryo assay as a Chemosensitivity test was studied. Fifty‐seven surgical specimens including benign tumors were examined by this method. All tumor specimens tested could be grafted on the chorioallantoic membrane of chick embryo; the evaluable ratio was 100%. Twenty‐one patients with previously untreated malignant glioma could be evaluated to test the predictability of the clinical effects, judged by computed tomography. There were 7 (78%) instances in which the assay response corresponded to a clinical partial response (true‐positive). There were 2 (22%) false‐positives for the assay, 0 (0%) false‐negative and 12 (100%) true‐negatives. The over‐all predictive accuracy was 90% (19/21). Thus, a high‐degree of positive association exists between the chick embryo assay and the clinical outcome. This in vivo assay system for malignant glioma is advantageous for Chemosensitivity tests because of its convenience, rapidity, and inexpensiveness.
Effects of Tumor Necrosis Factor and Hyperthermia on Meth‐A Tumors
Authors: Hiraoka Masahiro , Li Yu Ping , Tsutsui Kazushige , Abe Mitsuyuki , Yoshiki Yoshiki
Published: August 2005

The combined effects of purified human natural tumor necrosis factor (TNF) and hyperthermia were investigated in a transplanted TNF‐sensitive Meth‐A tumor model. We assessed the sequence and interval for the two treatments, the temperature that caused maximal heat sensitization, and the effects of pH modification on this combination therapy. Tumor response was evaluated by means of a tumor growth delay assay. TNF at a dose of 50 JRU/g caused significant tumor growth delay. A synergistic effect of TNF and hyperthermia was observed when TNF was administered 10 min before heating. This thermal enhancement of the action of TNF became more prominent with an increase in the heating temperature. Tumor growth delay was maximal when TNF was given immediately before or after hyperthermia. However, after an increase in the time interval to more than 2 h, there was no enhancement of growth delay. Injection of glucose (5 g/kg) caused a significant fall in pH at 10 and 30 min after administration. Further enhancement in tumor growth delay was seen with the tri‐modality of glucose, TNF, and heat compared to combined treatment with heat and either TNF or glucose at a hyperthermia of 42°C. This effect was not obtained with heating to 40°C. TNF appears to be a potent heat sensitizer when an appropriate temperature and time interval between hyperthermia and TNF administration are used. Trimodality treatment with hyperthermia, TNF, and glucose may be a new method of anticancer therapy.
Detection of Human Papillomavirus Type 16 in Sexual Partners of Patients Having Cervical Cancer by Polymerase Chain Reaction
Authors: Nakazawa Aiko , Inoue Masaki , Fujita Masami , Tanizawa Osamu , Akira Akira
Published: August 2005

The polymerase chain reaction (PCR) was employed to detect human papillomavirus (HPV) 16 and 18 in cytological samples from the uterine cervix and in urine samples from the male consorts. HPV 16 was detected in 2 (25%)of 8 males whose wives were positive for HPV 16, while it was detected in only one (7%) of 14 consorts whose wives were negative for HPV 16 and 18. This is the first report of the detection of HPV 16 in urine. Viral detection in urine samples by the PCR method is a non‐invasive, convenient and useful tool for large‐scale epidemiologic studies and investigations of the mechanism of virus transmission.
Human Tumor–infiltrating Lymphocytes Transfected with Tumor Necrosis Factor Gene Could Augment Cytotoxicity to Autologous Tumor Cells
Authors: Itoh Yoshinori , Kohgo Yutaka , Watanabe Naoki , Kanisawa Yuji , Sakamaki Sumio , Takahashi Minoru , Hirayama Yasuo , Ono Hiroyuki , Himeno Takeshi , Niitsu Yoshiro
Published: August 2005

Human tumor–infiltrating lymphocytes (TILs) derived from pleural or ascitic fluid were incubated with recombinant interleukin 2 and transfected with human tumor necrosis factor (TNF) a gene by the lipofection procedure. The resulting TILs secreted significant amounts of TNF in the culture supernatant and exhibited cytotoxicity against established cell lines, such as K562 and Daudi, and autologous tumor cells. The TNF gene–transfected TILs exhibited an augmented killing of autologous tumor cells.
Hepatocarcinogenesis in Transgenic Mice Carrying Albumin‐promoted SV40 T Antigen Gene
Authors: Hino Okio , Kitagawa Tomoyuki , Nomura Kimie , Ohtake Keiko , Cui Lixin , Furuta Yasuhide , Shinichi Shinichi
Published: August 2005

We have developed transgenic mice that inherit albumin promoter‐regulated simian virus 40 (SV40) large T antigen gene, expressed specifically in hepatocytes. These mice all develop multifocal hepatocellular carcinomas at around 5 months and die of liver insufficiency by 7 months. Sequential morphological observation of hepatocarcinogenesis revealed 5 distinct stages: (I) newborn to 2 weeks of age, neither recognizable histological changes nor cellular replication in spite of T antigen expression; (II) between 3 and 7 weeks, diffuse cytomegalic change of hepatocytes with numerous abnormal mitoses, usually resulting in cell death; (III) from 7 weeks onwards, quasi‐regenerative small hepatocyte foci with a decreased tendency for cytomegaly in spite of T antigen expression, rapidly replacing the hepatic tissue; (IV) 11 weeks of age and thereafter, neoplastic foci and nodules with enzymatic alteration; (V) 20 weeks of age and thereafter, gross hepatocellular carcinomas with occasional pulmonary metastases. Considerable variation existed both in morphological and enzymatic features and T antigen expression among neoplastic lesions, including carcinomas. Thus, these transgenic mice clearly show a multistep process in hepatocarcinogenesis with remarkable synchrony and provide a promising model for analyzing the essential events of carcinogenesis at different stages.
Newly Established Uterine Cervical Carcinoma Cell Line with Co‐amplification of Human Papillomavirus DNA and c‐myc Gene
Authors: Gotoh Masahiro , Nakajima Takashi , Yokota Jun , Tsunokawa Youko , Terada Masaaki , Shimoyama Yutaka , Teshima Shin‐ichi , Hirohashi Setsuo , Shimosato Yukio
Published: August 2005

A new human tumor cell line, NCC‐c‐CX‐1 (CX‐1), was established from a uterine cervical cancer xenografted in nude mice. This cell line harbored approximately 50 to 100 copies of human papillomavirus (HPV) type 18 DNA per haploid genome, and contained about 16‐fold‐amplified c‐myc gene with rearrangement. These genomic alterations found in CX‐1 cells were also present in both primary tumor and xenografted tumor. Histopathologically, original and xenografted tumors were poorly differentiated cancer and were characterized by neuroendocrine features such as positive neuron‐specific enolase and chromogranin A by immunohistochemistry and abundant neurosecretory‐type granules in the cytoplasm by electron microscopy. However, the established cell line had lost the neuroendocrine features. This cervical cancer cell line may be a useful model for studying cervical carcinogenesis, especially the interaction between HPV and c‐myc oncogene.
Prognostic Significance of Circulating Immune Complexes in Cancer Patients
Authors: Dass Tushar Kanti , Aziz Mehar , Ashok Ashok
Published: August 2005

Circulating immune complexes (CIC) were estimated in 100 cancer patients and 25 healthy control volunteers by means of the polyethylene glycol (PEG) precipitation test and latex agglutination inhibition (LAI) test. Pathological levels of CIC were found in 47% of the patients by PEG precipitation test and in 59% of the patients by LAI test; both tests were positive in 33% of the patients. Consequently, the use of the two assays resulted in 73% seropositivity for CIC. The PEG precipitation test detects antigen‐antibody complexes formed in the ratio of 2:1 (Ag2Ab), while the LAI test could detect immune complexes formed over an extended range of antigen‐antibody ratio including complexes as small as SS. CIC values were significantly higher by combined assays (P < 0.001) as compared to individual assays (P < 0.01) when compared with the control group. It was found that 75% of post‐operative follow‐up patients became seronegative for CIC in the combined assays, whereas the 25% of post‐operative patients who remained seropositive for CIC showed recurrence within three months after surgery. Immune‐complex deposition was demonstrated on malignant cells in vitro by direct immunofluorescence studies in 73.3% of patients, while 60% of patients revealed complement‐fixing antigen‐antibody complexes. It was found that 20% of patients showing positive immunofluorescence with anti‐C3‐antisera had decreased levels of CIC. Complement‐mediated cytotoxic injury results in reduction of tumor cell mass and subsequent decrease in CIC. Necrotizing and leucocytoclastic vasculitis in the tumor mass was initiated by raised CIC levels in vivo in 71% of patients. Necrosis of malignant tumors was seen in 58% of patients, and hemorrhage in 36% of patients. These changes were considered to be an aftermath of immuno‐complex vasculitis initiated by CIC.
P450 and Human Cancer
Authors: Kawajiri Kaname , Fujii‐Kuriyama Yoshiaki
Published: August 2005

Most of the chemical carcinogens in our environment are activated mainly by a restricted number of cytochrome P450 species, P450 1A1,1A2, 2E1, and 3A. This metabolic activation of procarcinogens is a crucial part of the initial host response to the environmental exposure, since most chemical carcinogens do not show any carcinogenicity by themselves. Inter‐individual variability in the metabolic activity may thus be a key host factor to explain the differences in susceptibility to chemical carcinogenesis among individuals. Recent studies on P450s in cancer etiology have provided some valuable insights into this problem.
Estrogen Receptor Levels and Tumor Growth in a Series of Pituitary Clonal Cell Lines in Rats
Authors: Fujimoto Nariaki , Watanabe Hiromitsu , Ito Akihiro , Inoue Kinji
Published: August 2005

Four kinds of in vitro clonal pituitary tumor cell lines named MtT/Se, MtT/SM, MtT/S and MtT/ E, each of which shows different sensitivity to estrogen on proliferation, were inoculated into fat pad of ovariectomized rats and estrogen‐loaded ovariectomized rats at 105 and 106 cells/site. They formed tumor with average latency ranging from 30 to 71 in ovariectomized rats and 13 to 63 days in estrogenized rats inoculated with 106 cells. MtT/Se was highly sensitive to estrogen for growth, and MtT/SM also grew well in estrogenized rats. With MtT/S and MtT/E, there was no significant shortening of average tumor latency in estrogenized rats. In vivo, the cytosolic estrogen receptor (ER) levels of MtT/Se, SM, S and E were measured to be 452 ±66, 370 ±115, 260 ±16 and 83 ±8 fmol/ mg protein, respectively. In vitro, however, the lowest ER level was noted in MtT/Se. Histologically, all four tumors grown in rats were composed of homogeneous round cells, and MtT/Se contained particularly large nucleated cells. In MtT/E, the cells appeared to be changing into ftbromatous cells. Three cell lines except MtT/E maintained the function of hormonal secretion in vivo as well as in vitro. Serum GH level was increased in rats with MtT/Se and MtT/S. Increased levels of both prolactin and growth hormone were measured in sera of rats with MtT/SM. Increases of hormones as well as tumor sizes were promoted by the estrogen.
Induction of Aberrant Crypt Foci in the Large Intestine of F344 Rats by Oral Administration of 2‐Amino‐l‐methyl‐6‐phenylimidazo[4,5‐b]pyridine
Authors: Takahashi Satoru , Ogawa Kumiko , Ohshima Hiroshi , Esumi Hiroyasu , Ito Nobuyuki , Sugimura Takashi
Published: August 2005

Carcinogenicity of 2‐amino‐l‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) to rat colon was investigated using the appearance of colonic aberrant crypt (AC), a preneoplastic lesion, as a marker. The number of AC foci per colon at experimental week 4 was 1.3 ± 0.8; almost half the level of AC foci induced by 2‐amino‐6‐methyIdipyrido[l,2‐a:3′,2′‐d]imidazole (Glu‐P‐1), which is a known colon carcinogen. No ACs were observed in rats of the control group. A repeat experiment showed that induction of AC foci by PhIP administration was reproducible and a significant increase in the number of AC foci, 3.0 ±0.0, was observed after 12 weeks of PhIP administration. The majority of ACs induced by PhIP were localized in the distal part of the colon. The distribution was similar to those induced by Glu‐P‐1 and 1,2‐dimethylhydrazine. Those data suggested that PhIP is possibly carcinogenic to rat colon.
Establishment and Characterization of an Epithelial Cell Line with Quasi‐normal Chromosomes from a Tubular Adenoma of a Familial Polyposis Coli Patient
Authors: Kawaguchi Tokuichi , Miyaki Michiko , Masui Tohru , Watanabe Motoko , Ohta Hirotoshi , Maruyama Masakazu , Utakoji Tadashi , Kitagawa Tomoyuki
Published: August 2005

An epithelial cell line designated FPCK‐1 has been established from a tubular adenoma developing in a male familial polyposis coli (FPC) patient. The FPCK‐1 cells grow very slowly with adundant mucus production and have been maintained stably for 3 years in culture. No growth was evident either in soft agar or nude mice, FPCK‐1 cells present a normal male karyotype and do not show loss of specific loci on chromosomes 5,17,18, and 22 which have been reported to be lost frequently in human colon carcinomas. The cells have neither a point mutation on codon 12 of K‐ras gene nor gene amplification of myc, c‐H‐ras, and/or c‐K‐ras genes. These results thus suggest the existence of hitherto unknown causative event(s) underlying adenoma development in FPC patients. The FPCK‐1 cell line should prove useful for further analytical investigation of the multiple steps involved in human colon carcinogenesis.
A Smoking Survey of College Students in India: Implications for Designing an Antismoking Policy
Authors: Gavarasana Satyanarayana , Doddi Vijaya Prasad , Prasad Gorty V. S N. R. , Allam Apparao , Murthy Bellana S. R.
Published: August 2005

A survey of 599 college students was conducted in Andhra Pradesh, India, to formulate an anti‐smoking policy for youth. There were 64.6% boys and 35.4% girls between 15 and 22 years, and 8.2% of students (n = 49, 48M + 1F) were smokers. It is a taboo for girls to smoke. There is no current anti‐smoking policy and one is proposed based on the smoking survey results. The policy includes parental pressure to curb smoking, and a ban on (1) advertising of tobacco products, (2) smoking in public places and (3) teachers smoking in school. An increase in the price of cigarettes was approved by a majority of the students. The survey revealed a gap in the knowledge of students about the ill effects of smoking, which can be rectified by health education programs.
Provirus Integration at the 3 Region of N‐myc in Cell Lines Established from Thymic Lymphomas Spontaneously Formed in AKR Mice and a [(BALB/c × B6)F1AKR] Bone Marrow Chimera
Authors: Yano Yoko , Kobayashi Seiichi , Yasumizu Ryoji , Tamaki Junko , Kubo Mitsumasa , Sasaki Akio , Hasan Shahid , Okuyama Harue , Inaba Muneo , Ikehara Susumu , Hiai Hiroshi , Kakinuma Mitsuaki
Published: August 2005

Among 18 thymic leukemia cell lines which have been established from spontaneous thymic lym‐phomas in AKR mice as well as in bone marrow chimeras which were constructed by transplanting allogeneic bone marrow cells into irradiated AKR mice, three proviral integration sites were identified; near c‐myc, N‐myc and pim‐l loci. No integration site specific for chimeric leukemia cell lines was found. In three thymic leukemia cell lines which contained rearranged N‐myc, genes, insertions of long terminal repeats (LTRs) of murine leukemia viruses were detected at 18 or 20 bp downstream of the translational termination codon. These results demonstrate that the 3’region of the N‐myc gene is one of the integration targets for murine leukemia viruses in spontaneous thymic lymphomas. In these three cell lines, N‐myc mRNA was stably transcribed and transcription of c‐myc mRNA was down‐regulated. The integrated murine leukemia viruses in AKR thymic leukemia were most likely AKV, though the DNA sequence of the LTR inserted in the genome of a leukemic cell line from [(BALB/c × B6)F1‐AKR], CAK20, was different from LTRs of murine leukemia viruses so far reported.
Preparation of Recombinant Protein A‐Lymphotoxin Chimeric Protein and Its Antitumor Effects in Mice
Authors: Miki Tetsuzou , Wada Masakatsu , Kasumimoto Takanori , Moriyama Ryoichi , Iwasaki Yuzo
Published: August 2005

We have investigated the in vivo function of a chimeric protein constructed by recombinant DNA techniques. The behavior and antitumor activity of a protein A‐lymphotoxin chimera (ALT) was examined on a murine tumor in mice in comparison with ammo‐terminal 19 amino acid‐deleted lymphotoxin (dLT), Seven‐week‐old male BALB/c mice were implanted intradermally with Meth‐A fibrosarcoma on day 0. ALT and dLT caused tumor regression, hemorrhagic necrosis and complete regression in a dose‐related way when each agent was given intratumorally 5 times (days 5–9). The ratio of the median effective doses for complete tumor regression was 1.6 between ALT and dLT on a molar basis. ALT caused tumor regression and body weight loss when given intravenously on the same schedule. Biodistribution studies with 125I‐labeled ALT and dLT demonstrated that, after intratumoral administration, ALT was retained longer in the administered site and was cleared more slowly from the mouse body than dLT. These findings suggest that a protein A‐lymphotoxin chimeric protein expresses both antitumor activity similar to that of lymphotoxin and characteristic in vivo behavior of the fused protein A portion.
Quantitative Risk Assessment of Carcinogenicity of Urethane (Ethyl Carbamatc) on the Basis of Long‐term Oral Administration to B6C3F1 Mice
Authors: Inai Kouki , Arihiro Koji , Takeshima Yukio , Yonehara Shuji , Tachiyama Yoshiro , Khatun Nasima , Nishisaka Takashi
Published: August 2005

A carcinogenicity study of urethane was performed for quantitative assessment of Its risk in humans. Three hundred 6‐week‐old male B6C3F1 mice were divided into 6 groups, each consisting of 50 mice, and urethane was given ad libitum in drinking water at levels of 0 (control), 0.6, 3, 6, 60 and 600 ppm for 70 weeks. The tumors with a clear dose‐response relationship were lung tumor (alveolar/ bronchiolar adenoma or carcinoma) and liver tumor (hemangioma or angiosarcoma). The incidences of these two types of tumor were applied to estimation of the virtually safe dose (VSD) at the level of 10 6 by using four mathematical models (Logit, Probit, Weihull and Multistage models). The VSD based on the incidences of lung tumor by using the Logit model was estimated to be 1.8 × 10 4 mg/kg body weight/day. On the other hand the VSD based on those of liver tumor by using the Weibull model was 7.2 × 10−5 mg/kg body weight/day. Thus, the VSDs based on the incidences of the two different types of tumor using the most compatible mathematical model in each case, as judged from the P‐values, were similar.
Abnormal Copper Accumulation in Non‐cancerous and Cancerous Liver Tissues of LEC Rats Developing Hereditary Hepatitis and Spontaneous Hepatoma
Authors: Li Yu , Togashi Yuji , Sato Shin , Emoto Tadasu , Kang Jong‐Hon , Takeichi Noritoshi , Kobayashi Hiroshi , Kojima Yutaka , Une Yoshie , Uchino Junichi
Published: August 2005

We studied the copper concentrations in the non‐cancerous and cancerous liver tissues of LEC rats with hereditary hepatitis and spontaneous hepatoma by atomic absorption spectrophotometry. Copper concentration in the non‐cancerous livers of 29‐month‐old male LEC rats was comparable to that in the livers of LEC rats aged 2, 3 and 8 months whose hepatic copper concentrations were more than 40 times those of normal LEA rats. Copper concentration in spontaneously developed hepatocellular carcinomas of the 29‐month‐old male LEC rats was lower than that in the surrounding non‐cancerous liver tissues, but was still more than 39 times that of 8‐month‐old male LEA rats. These findings suggest that in LEC rats an abnormal copper metabolism may be maintained during the process of hepatic carcinogenesis.
Relatively Low Prevalence of Human Papillomavirus 16, 18 and 33 DNA in the Normal Cervices of Japanese Women Shown by Polymerase Chain Reaction
Authors: Nishikawa Akira , Fukushima Michio , Shimada Masamitsu , Yamakawa Yasushi , Shimano Satoshi , Kato Ikunoshin , Fujinaga Kei
Published: August 2005

Ninety‐two cervical scrapes and tissues, obtained from cytologically or histologically normal cervices of Japanese women, were examined for the presence of human papillomavirus (HPV) 16, 18 and 33 DNA by the polymerase chain reaction (PCR) method. Five out of 92 cases were HPV 16 DNA‐positive, but neither HPV 18 nor 33 DNA was detected. The HPV (type 16, 18 and 33) prevalence rate in pregnant women, including postpartum, was 10% (3/31), which was higher than that in non‐pregnant women. In two HPV 16‐positive cases, we detected HPV 16 DNA again 2 months later. HPV (type 16, 18 and 33) prevalence in normal cervices was shown to be relatively low. However, it is very important to follow up the HPV‐positive cases in cytologically normal cervices in order to elucidate the relation between HPV infection and the progression of cervical cancer.
Potential Value of Cetylmannoside‐modified Liposomes as Carriers of Macrophage Activators to Human Blood Monocytes
Authors: Yamashita Chikamasa , Sone Saburo , Ogura Takeshi , Kiwada Hiroshi
Published: August 2005

The present study was undertaken to examine the potential value of cetylmannoside‐modified multilamellar liposomes (Man‐MLV) as carriers for transfer of macrophage activators to blood monocytes. Highly purified blood monocytes were isolated by centrifugal elutriation from healthy donors under cndotox in‐free conditions. Freshly prepared monocytes phagocytosed Man‐MLV to a lesser extent than monocyte‐derived macrophages, but they took up Man‐MLV much more effectively than control liposomes without cetylmannoside (control MLV). Phagocytosis of Man‐MLV, but not control MLV by monocytes was inhibited by addition of D‐mannose, but not of D‐galactose. Desmethyl‐muramyl dipeptide (norMDP) entrapped in Man‐MLV was far more effective than norMDP entrapped in MLV in activating monocytes to the tumoricidal state. The effect of encapsulation of recombinant human macrophage colony‐stimulating factor (M‐CSF) in Man‐MLV on prolongation of survival of monocytes was examined. Blood monocytes that had been incubated for up to 21 days with Man‐MLV containing 5–20 U of M‐CSF per ml were effective in prolonging monocyte survival, but monocytes that had been incubated in medium with less than 50 If/ml of M‐CSF or with control MLV containing 5–10 U of M‐CSF showed no increase of monocyte survival over that in medium alone. Addition of rabbit anti‐M‐CSF antiserum did not affect survival prolongation of monocytes by M‐CSF encapsulated in Man‐MLV. We conclude that liposomes modified with cetylmannoside are far more effective than unmodified liposomes as a carrier to deliver biological response modifiers to human blood monocytes.
Expression of a Rat Ovary‐independent Mammary Tumor‐associated Antigen Defined by a Monoclonal Antibody, TAK‐B1
Authors: Takahashi Kazuo , Yoshida Hiroki , Sonoda Shunrou , Yoshida Aichi , Umekita Yoshihisa , Ohi Yasuyo , Oneda Satoru
Published: August 2005

A monoclonal antibody, TAK‐B1, was produced by immunization of BALB/c mice with mammary carcinoma induced in inbred Sprague‐Dawley rats by treatment with 7,12‐dimethylbenz[a]anthra‐cene. TAK‐B1 reacted with ovary‐independent mammary carcinoma cells which had been transformed from ovary‐dependent mammary carcinoma cells, but did not react with original mammary carcinoma cells or with cells from mammary glands exhibiting fibrocystic changes or normal mammary glands. However, TAK‐B1 reacted not only with basal cells of the epidermis and epithelial cells of the bottom portion of crypts of the small intestine in adult rats, but also with basal cells of epidermis in skin and mesenchymal cells around developing hair follicles in fetuses. We therefore classify TAK‐B1 as an ovary‐independent rat mammary tumor‐associated antigen. Immunoelectron microscopic examinations revealed that the antigen recognized by TAK‐B1 was localized in the cell surface membrane of ovary‐independent mammary carcinoma cells. Immunoprecipitation assay revealed that the antigen recognized by TAK‐B1 was composed of M 220,000 protein and four other minor proteins.
A Cooperative Randomized Study on Tegafur plus Mitomycin C versus Combined Tegafur and Uracil plus Mitomycin C in the Treatment of Advanced Gastric Cancer
Authors: Kurihara Minoru , Izumi Tuguhiko , Yoshida Shigeaki , Ohkubo Toshiharu , Suga Shoji , Kiyohashi Atsushi , Yaosaka Tohru , Takahashi Hiromu , Ito Tetsuo , Sasai Tadashi , Akiya Toshikazu , Akazawa Shugo , Betsuyaku Takashi , Taguchi Susumu
Published: August 2005

A randomized controlled trial involving 13 institutions in Japan was conducted in order to compare the efficacy of tegafur plus mitomycin C (MMC) (Regimen A) and UFT (a combination of uracil and tegafur at a molar ratio of 4 to 1) plus MMC (Regimen B) for patients with advanced gastric cancer, who had not received any prior cancer chemotherapy. Regimen A (tegafur+MMC) consisted of 5 mg of MMC/m2/week given intravenously, and 500 mg of tegafur/m2/day given orally. Regimen B consisted of the same schedule of MMC and 375 mg of UFT/m2/day given orally. One hundred and eighty‐six patients with primary gastric cancer were entered; 183 were eligible and 3 were ineligible for the study. A total of 169 were evaluable for efficacy of the treatment, including 90 patients with Regimen A and 79 with Regimen B. A response rate of 7.8% (7/90 cases) for Regimen A and one of 25.3% (20/79 cases) for Regimen B were obtained, indicating a significantly higher response rate for Regimen B according to the Criteria for Evaluating Efficacy of Chemotherapy /Radiation Therapy in the Treatment of Gastric Cancer (P= 0.004), Regarding side effects, no marked differences in either severity or incidence were observed between the two groups. The group assigned to Regimen B showed a significant survival advantage after adjustment for major prognostic factors using a proportional hazards model (P=0.0398). Moreover, a close correlation of antitumor effect and survival duration was found when the above criteria were used.
A Case of Cervical Carcinoma of the Uterus Presenting with Hyperosmolar Non‐ketotic Coma as a Manifestation of Ectopic Adrenocorticotropic Hormone Syndrome
Authors: Shirahige Yutaka , Watanabe Toru , Oki Yutaka , Sonoda Takahiko , Adachi Isamu
Published: August 2005

A case of advanced cervical carcinoma of the uterus with ectopic adrenocorticotrophic hormone (ACTH) syndrome is described. The patient was seen for general malaise 21 months after surgical treatment of the primary lesion whose histology was undifferentiated small cell carcinoma of the uterine cervix. She had extensive metastases in the liver and the abdominal wall. In addition to the typical clinical manifestations of Cushing's syndrome such as moon face, central obesity and acne vulgaris, hyperglycemia was so severe that she was in a hyperosmolar non‐ketotic coma. Endocrino‐logical examinations revealed elevated plasma ACTH and cortisol, and urinary excretion of 17‐hydroxycorticosteroids and 17‐ketosteroids, which were not suppressed by high‐dose dexamethasone administration. Based on these clinical and laboratory findings, a diagnosis of ectopic ACTH syndrome was made. Among the results of other endocrinological examinations conducted to find the etiological cause of the hyperglycemic coma, which seemed to be unusual for ectopic ACTH syndrome, the plasma somatostatin level was abnormally high. Metastatic tumors in the liver obtained at the time of autopsy contained large amounts of both ACTH and somatostatin, and gel filtration studies revealed that the peptides produced by the tumor had the molecular sizes of the biologically active forms of the respective peptides. These observations suggest possible involvement of the somatostatin in deteriorating glucose intolerance to develop hyperglycemic hyperosmolar non‐ketotic coma as a drastic disturbance of metabolism
Toxicological and Tumoricidal Evaluations of a New Platinum Complex, (–)‐(R)‐2‐Aminomethy lpyrrolidine (1,1‐cyclobutanedicarboxylato) platinum (II) Monohydrate, in Rats
Authors: Akamatsu Ken‐ichi , Endo Koichi , Matsumoto Tomoko , Morikawa Kazumi , Koizumi Masuo , Koizumi Kinya , Mitsui Hiroki
Published: August 2005

The toxicities and antitumor activity of a new anticancer platinum compound, (‐)‐(R)‐2‐amino‐methylpyrrolidine(l,l‐cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis‐diammine(1,1‐cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight <10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub‐LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35–43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.
Kinin‐generating Cascade in Advanced Cancer Patients and in vitro Study
Authors: Matsumura Yasuhiro , Maruo Keishi , Kimura Masami , Yamamoto Tetsuro , Konno Toshimitsu , Maeda Hiroshi
Published: August 2005

The role of the bradykinin‐generating system in the pathogenesis of cancer was explored by simultaneously measuring plasma prekallikrein (PK), the precursor of kallikrein, which is the major enzyme responsible for kinin generation, and plasma kininogens (KNG), which are precursors of kinin, in patients with various cancers. The mean value of plasma PK in healthy volunteers was 2.5 ± 0.5 (mean ± SD) units/mg plasma protein and that in cancer patients (all stage IV) was 1.7 ± 0.7 units/ mg plasma protein. The mean value of plasma KNG in healthy volunteers was 12.5 ± 2.0 ng kinin equivalents/mg plasma protein and that in cancer patients was 10.9 ± 2,8 ng. These data showed that plasma PK and plasma KNG values were significantly lower in cancer patients compared with healthy volunteers (P < 0.0005 for PK; 0.0005 < P < 0.005 for KNG; n = 28 for healthy subjects; n = 29 for cancer patients). These data appear to indicate that conversion of PK to kallikrein would probably occur with concomitant consumption of KNG by newly generated kallikrein for kinin generation in cancer patients. Early stage cancer patients showed little difference from healthy volunteers. For the in vitro study, activation of purified Hageman factor (HP) and PK was examined by using cancer cell lines and virus‐transformed cells that produced plasminogen activator (PA) at a high rate. Both HF and PK were activated in the presence of plasminogen. Diploid cell lines and primary fibroblasts, which did not produce PA, activated neither HF nor PK. Taking all these data together, we conclude that kinin generation does occur in the plasma of patients with advanced cancer, and that one of the initiation mechanisms of the kinin‐generating cascade appears to be mediated by plasmin and to depend on cancer cell‐derived PA activity.
Detection of Hepatitis C Virus Infection by Enzyme‐linked Immunosorbent Assay System Using Core Protein Expressed in Escherichia coli
Authors: Muraiso Kanae , Hijikata Makoto , Kato Nobuyuki , Shimotohno Kunitada , Okazaki Nobuo , Ohkoshi Showgo , Uura Masashi , Kaneko Shuichi , Kobayashi Kenichi , Omata Masao , Ohnishi Hiroo , Mutou Yasutoshi , Hattori Nobu
Published: August 2005

Enzyme‐linked immunosorbent assay of the core protein of hepatitis C virus (HCV) expressed in E. coli led to detection of the antibody against this virus in patients with chronic hepatitis. Some of the negative results obtained using a different viral protein became positive with this E. coli‐expressed viral protein, and were also positive for the viral RNA. Thus, use of the core protein of HCV facilitates accurate detection of HCV infection.
Familial Aggregation of Cancer from Proband Cases with Childhood Adrenal Cortical Carcinoma1
Authors: Tsunematsu Yukiko , Watanabe Shaw , Oka Toshiaki , Tsukamoto Taiji , Kawa‐Ha Keisei , Hirata Yoshiaki , Yamanaka Hiromichi , Ohira Mutsuro , Ono Michiko
Published: August 2005

Family pedigree of Li‐Fraumeni syndrome was investigated from probands with childhood adrenocortical carcinoma in Japan. From 47 probands, 7 families had 3 or more cancer cases at ages less than 45 years within the first generation; one satisfied Li's original criteria, two were acceptable because of multiple primary cancer in the probands, and others showed an aggregation of cancers with onsets at early ages, though no sarcoma of mesenchymal origin was found. A significantly higher occurrence of cancer in the mothers of the probands, especially of the breast, was consistent with reports from the USA, and liver cancer, osteosarcoma and lung cancer among family members under the age of 45 also showed a higher frequency than in the general population. Similarities and differences between Japanese and Caucasian cases are discussed.
Proline Is Required for Transcriptional Control of the Aromatic Hydrocarbon‐inducible P1450 Gene in C57BL/6 Mouse Monolayer‐cultured Hepatocytes
Authors: Nemoto Nobuo , Sakurai Junko
Published: August 2005

Expression of aryl hydrocarbon hydroxylase (AHH) and the corresponding gene, CyplA1 or P1450 in mice, in C57BL/6 mouse hepatocytes in primary culture was investigated after exposure to benz[a]‐anthracene with respect to proline‐related metabolic regulation. When the cells were cultivated in complete Waymouth MB752/1 (Way), prominent induction of AHH by benz[a]anthracene was observed, whereas the induction was inefficient in the same but proline‐deflcient medium [Way‐(‐pro)]. Constitutive AHH activities decreased with increasing culture period. P1450 gene transcripts were slightly expressed when the medium was changed, independently of whether the cells were cultivated in either Way or Way(‐pro), followed by decrease within 24 h and no apparent induction of AHH. However, treatment with Δ1‐pyrroline‐S‐carboxylic acid (P5C), a biosynthetic precursor for proline, dose‐dependently increased basal AHH activities in the cells cultivated in Way‐(‐pro). Benz[a]anthracene induction of AHH in cells cultivated in Way(‐pro) was additively increased in the presence of P5C as much as with proline. Treatment with o‐aminobenzaldehyde, which inactivates P5C, drastically reduced the induced AHH activities in hepatocytes cultivated in either P5C‐added Way (‐pro) or Way medium. Benz[a]anthracene induced both P1450 and P3450 mRNAs. Neither proline nor P5C increased the induced transcripts within 12 h after the start of benz[a]‐anthracene treatment, but the two compounds increased the amounts of P1450 mRNA found at later time points. After treatment with actinomycin D, the half‐life of the induced P1450 mRNA was approximately 12 h, being independent of the presence of either proline or P5C. Our observations suggest that induction of AHH after treatment with polycyclic aromatic hydrocarbon is dependent on proline‐related metabolism which influences the transcriptional process of P1450 gene expression.
Chromosome Changes in Desmoid Tumors Developed in Patients with Familial Adenomatous Polyposis
Authors: Yoshida Mitsuaki A. , Ikeuchi Tatsuro , Iwama Takeo , Miyaki Michiko , Mori Takeo , Ushijima Yasuhiko , Kara Akio , Miyakita Makoto , Tonomura Akira
Published: August 2005

Chromosome analyses were performed on benign desmoid tumors obtained from two female patients with familial adenomatous polyposis (FAP), one of whom was diagnosed as having Gardner syndrome (GS). The modal chromosome number was 46 in both specimens, and detailed Q‐banding analysis in Case 1 (GS) revealed a clonal abnormality of an interstitial deletion of the long arm of chromosome 5, del(5)(q2lq31). The deleted region included an assigned locus for an FAP major gene (5q21‐q22). All of the metaphases analyzed in this case showed an extra segment of bright fluorescence on the short arm of chromosome 15, but this unusual chromosome (15p +) was observed in both peripheral lymphocyte and skin fibroblast cultures from the patient, indicating that the 15p+ was constitutional in nature. In Case 2, no clonal rearrangements were Identified and most cells had a normal karyotype. However, two cells showed rearrangements involving a 17q with non‐identical breakpoints, one of which was observed as a solitary chromosome change. Based on the present findings in Case 1 and those reported so far, the chromosomal defect on 5q might be one of the causal genetic events primarily associated with the development of both benign desmoid tumors and colorectal adenomas and carcinomas in FAP patients.
Antitumor Effect of Recombinant Human Interleukin‐2 on the Growth of Murine Hemangioendothelioma D14 in Nude Mice: Occurrence of Large Granular Cells in the Tumor
Authors: Sakura Yasufumi , Houkan Takashi , Ootsu Koichiro , Shino Akio
Published: August 2005

The antitumor effect of recombinant human interleukin‐2 (rIL‐2) on murine hemangioendothelioma D14 (D14) in female BALB/c‐nu/nu mice was examined histologically. D14 cells which had been maintained in vitro were transplanted subcutaneously into nude mice on day 0 (1 × 107 cells/mouse). The mice with established tumor on day 28 received rIL‐2 subcutaneously at a dose of 20 μg/mouse/ day for 35 days. On day 63, the mice were killed, and the tumor, spleen and bone marrow were examined histologically. In the mice that had received rIL‐2, tumor growth was significantly suppressed. Histologically, there was marked infiltration of large granular cells (about 15‐30 μ in diameter) in the tumors. In the adjacent areas, there was a significant increase in the number of tumor cells showing karyorrhexis. The large granular cells (LGC) contained periodic acid Schiff‐positive round granules in the cytoplasm and were stained positively for Thy‐1.2 surface antigen. The LGC were also positive for asialo GM1 surface antigen but not for Lyt‐1, Lyt‐2 or IgG surface antigens. This evidence suggests that the LGC are lymphokine‐activated killer‐like cells which were derived from a natural killer cell lineage. The concomitant increases in the number of LGC and the number of cells showing karyorrhexis in the tumors of the mice treated with rIL‐2 suggest that LGC play an important role in the destruction of tumor cells.
Comparison of the Effects of Intravenously Bolus‐administered Endothelin‐1 and Infused Angiotensin II on the Subcutaneous Tumor Blood Flow in Anesthetized Rats
Authors: Tanda Shigeru , Hori Katsuyoshi , Saito Sachiko , Shinozaki Mika , Zhang Qiu‐Hang , Suzuki Maroh
Published: August 2005

To evaluate the effects of endothelin‐1 (ET‐1) on tumor blood flow, the authors measured the mean arterial blood pressure (MABP) of enflurane‐anesthetized male Donryu rats and the tissue blood flow of subcutaneously implanted tumor (Yoshida rat ascites hepatoma LY‐80) by using a hydrogen clearance method. The tumor blood flow was evaluated in terms of the ratio to the maximum blood flow, which was defined as the largest flow in the same position during successive measurements. After bolus intravenous administration of ET‐1 (1.0 nmol/kg), MABP reached approximately 140 mmHg (at 5 30 min), diminishing gradually to the baseline level over 2 h. The tumor blood flow increased from 36.7 ± 20.6 to 59.5 ± 30.2% (n = 32, P <0.001, at 2 min), returning to the baseline level at 10 min. On the other hand, at 2 min after the beginning of continuous intravenous infusion of [Asp1, Ile5]‐angiotensin II (AII; the dose was determined by a blood pressure control system for keeping MABP at approximately 150 mmHg, consequently 0.26 μg/kg/min on the average), the tumor blood flow increased from 42.3 ±21.6 to 76.4±22.6% (n = 32, P < 0.001), which was significantly larger than the flow after ET‐1. The results indicate that hypertension induced by systemic ET‐1 injection is less effective than hypertension induced by continuous systemic AII infusion in increasing tumor blood flow; AII is probably a suitable agent as a safe and effective enhancer of tumor blood flow. Moreover, ET‐1 appears to constrict arterial vessels in the microcirculation time‐dependently, while AII constricts probably only normal peripheral arterioles.
Transforming Activity of a Synthetic c‐Ha‐ras Gene Containing O6‐Methylguanine in Codon 12
Authors: Kamiya Hiroyuki , Miura Kazunobu , Ohtomo Noriko , Nishimura Susumu , Ohtsuka Eiko
Published: August 2005

A mutagenic DNA‐adduct, O6‐methylguanine, was introduced into codon 12 of the synthetic c‐Ha‐ras gene by cassette mutagenesis. Transfection of this modified ras gene into normal NIH3T3 cells by the calcium phosphate procedure resulted in significant induction of focus formation. The ras gene inserted into the transformed cells was found to have a G to A transition at the position of the modified base. These results indicate that an O6‐methylguanine residue in DNA may lead to a mutation and be one cause of activation of the ras gene.
Effects of Glucocorticoids and Calcitonin on Parathyroid Hormone‐related Protein (PTHrP) Gene Expression and PTHrP Release in Human Cancer Cells Causing Humoral Hypercalcemia1
Authors: Kasono Keizo , Isozaki Osamu , Sato Kanji , Sato Yasuko , Shizume Kazuo , Ohsumi Kazuaki , Demura Hiroshi
Published: August 2005

Glucocorticoids are widely used for the treatment of malignancy‐associated hypercalcemia to delay the occurrence of an escape phenomenon inherent in calcitonin therapy. Using parathyroid hormone‐related protein (PTHrP)‐producing squamous carcinoma cells (T3M‐1 and EC‐GI) established in our laboratory, we investigated the in vitro effects of glucocorticoids and calcitonin on PTHrP mRNA expression in the cells and release of PTHrP into the culture medium. The PTHrP gene was constitutively expressed in the logarithmic growth phase in both squamous carcinoma cell lines. When these cells became superconfluent, PTHrP mRNA expression was greatly diminished in T3M‐1 cells but was not distinctly diminished in EC‐GI cells. Hydrocortisone inhibited the PTHrP mRNA expression in T3M‐1 cells and EC‐GI cells in a dose‐dependent manner. In accordance with the decreased expression of PTHrP mRNA, the release of immunoreactive as well as bioactive PTHrP also decreased in the conditioned medium of glucocorticoid‐treated cells. The minimal effective concentration of prednisolone was about 10 ‐7 M, which is readily attainable in the serum of patients treated with the agent. Calcitonin and indotnethacin did not affect the PTHrP mRNA expression or PTHrP release into the medium. Calcitonin did not modulate the hydrocortisone‐induced inhibition of PTHrP production. These in vitro findings suggest that the combined use of glucocorticoids and calcitonin plays a beneficial role in the treatment of malignancy‐associated hypercalcemia, since the steroid hormone can suppress PTHrP mRNA expression and release of bioactive PTHrP in certain PTHrP‐producing tumors.
Cytotoxic Effects of Vitamin A in Combination with Vincristine, Daunorubicin and 6‐Thioguanine upon Cells from Lymphoblastic Leukemic Patients
Authors: Pieters Rob , Huismans Dieuwke R. , Loonen Anne H. , Hählen Karel , Veerman Anjo J. P.
Published: August 2005

We studied whether isotretinoin potentiated the effects of vincristine (VCR), daunorubicin (DNR), and 6‐thioguanine (6‐TG) against cells obtained from 24 patients with acute lymphoblastic leukemia (ALL). Treatment with 5 μg/ml isotretinoin alone resulted in a leukemic cell survival of 82%± 28.1%. So isotretinoin is toxic to ALL cells. Dose‐response curves were obtained for VCR, DNR and 6‐TG in the presence and absence of isotretinoin Isotretinoin showed additive leukemic cell kills in combination with VCR and DNR, When corrected for cell kill by isotretinoin alone, it appeared that isotretinoin did not significantly enhance leukemic cell kills by VCR, DNR and 6‐TG. No differences were found between samples from patients at initial diagnosis and at relapse with respect to cell kill by isotretinoin alone and with respect to a possible synergistic effect of isotretinoin and the cytostatic drugs. It is concluded that isotretinoin has additive antileukemic effects in combination with VCR or DNR. However, isotretinoin does not potentiate the antileukemic effects of VCR, DNR and 6‐TG against leukemic cells obtained from patients with ALL.
Organ‐specific Modification of Tumor Development by Low‐dose Combinations of Agents in a Rat Wide‐spectrum Carcinogenesis Model
Authors: Fukushima Shoji , Shibata Masa‐Aki , Hirose Masao , Kato Toshio , Tatematsu Masae , Ito Nobuyuki
Published: August 2005

The combined effects of low doses of various carcinogens and carcinogenesis modifiers on tumor development were investigated by using a wide‐spectrum organ carcinogenesis model in F344 rats. These agents were administered as three groups: (1) a group of known hepatocarcinogens; (2) a group of nitroso compounds having various target organ specificities; and (3) a group of antioxidants having various inhibiting or enhancing activities depending on the target organ. Doses were used which were generally below the known effective level for the individual chemical. These groups of chemicals were administered with or without prior administration of N‐diethylnitrosamine (100 mg/kg body wt., i.p.), N‐methylnitrosourea (4 × 20 mgAg body wt., i.p.) and dihydroxy‐di‐N‐propylnitrosamine (0.1% in drinking water for 2 weeks). The hepatocarcinogen group in combination with various nitroso compounds increased the incidences of liver hyperplastic nodules and hepatocellular carcinomas. In contrast, incidences were clearly reduced when the hepatocarcinogens and/or the nitroso compounds were administered in combination with the antioxidants. For the urinary bladder, the combination with nitroso compounds and antioxidants enhanced cancer development, and the addition of hepatocarcinogens further increased tumorigenesis. For the glandular stomach, additive effects on the numbers of pepsinogen isozyme 1‐altered pyloric glands, a putative preneoplastic lesion, were produced by the combination treatment of antioxidants and the nitroso compounds. No synergistic effects on tumor development were seen in other organs. The results of the present study demonstrated that combinations of various compounds at low doses can additively or synergistically exert either enhancing or inhibitory effects on the development of preneoplastic and neoplastic lesions in different organs in a single model having a wide spectrum of organ effects.