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Biomedical subjects

Y Ueyama

Publications and source records attributed to Y Ueyama.

At least 163 records · Page 9Linked to original sources
PubMed1988

Responsiveness of human gastric tumors implanted in nude mice to clinically equivalent doses of various antitumor agents.

To reproduce clinical effects of various antitumor agents in the human tumor/nude mouse model, we investigated the responsiveness of 11 lines of human gastric tumor xenografts to doses of the agents pharmacokinetically equivalent to the respective clinical doses, which we designated the "rational dose" (RD). We found that the response rates to mitomycin C, 3-[(4-amino-2-methyl-5-pyrimidinyl]methyl-1-[2-chloroethyl]-1- nitrosourea (ACNU), adriamycin, 5-fluorouracil were 18%, and that to vinblastine was 30%; on the other hand, those to vincristine, methotrexate, and cyclophosphamide were poor. In contrast, in our previous study using the maximum tolerated doses, response rates to mitomycin C, ACNU, and vinblastine were as high as 64-82%, and those to adriamycin and 5-fluorouracil were 18%. When these results were compared with the clinical response rates of gastric tumors, as a whole, the results with RD's exhibited much better coincidence with the clinical data in terms of relative therapeutic potency, indicating the validity of the use of clinically equivalent doses instead of maximum tolerated doses in the human tumor model.

Animals↗
PubMed1988

Amplification of the structurally and functionally altered epidermal growth factor receptor gene (c-erbB) in human brain tumors.

By using Southern blot analysis, we found that in two cases of human glioblastoma multiforme, cells carried amplified c-erbB genes which bore short deletion mutations within the ligand-binding domain of the epidermal growth factor (EGF) receptor. The products of these mutated c-erbB genes were about 30 kilodalton (kDa) smaller than the normal 170-kDa EGF receptor, and the tumor cell membrane fractions containing the 140-kDa abnormal EGF receptor showed a significant elevation of tyrosine kinase activity without its ligand. In view of the similarity to the activated viral and cellular erbB genes in the avian system, these mutated and overexpressed EGF receptors might play a role in the onset or development of human glioblastoma cells.

Animals↗
PubMed1988

B-raf, a new member of the raf family, is activated by DNA rearrangement.

Complementary DNA clones of a putative transforming gene were isolated from NIH 3T3 cells transformed with human Ewing sarcoma DNA. The gene was termed B-raf because it is related to but distinct from c-raf and A-raf. It appears that substitution in the amino-terminal portion of the normal B-raf protein confers transforming activity to the gene.

Base Sequence↗
PubMed1988

[Antineoplastic effect of prostaglandins on human glioma in athymic nude mice].

The prostaglandins (PG) are known to have various physiological effects. Some series of prostaglandins such as PG D2 have been reported to inhibit growth of tumor cells. In this study, the growth-inhibitory effects of PG A2, PG D2, PG J2 and 6-keto PGE1 were investigated in nude mice receiving subcutaneous transplant of human brain tumor. One to two milligram of prostaglandins was given intraperitoneally every day for three weeks. Tumor volumes were measured twice weekly and the tumor reduction rates (treated/control) were evaluated. T/C rate treated with PG D2 or PG A2 was 50-60% respectively. The effectiveness of PG J2 or 6-keto PGE1 was inferior to that of PG A2 or PG D2. But in the evaluation of antitumor effects of PG J2, we must consider the fact that the activity of PG J2, is liable to be lost. The effect of PG D2 on proliferation of cultured glioma cells was also studied. At concentrations of 10 micrograms/ml, PG D2 strongly inhibited the proliferation of glioma cells. However, precise mechanism of prostaglandin action is presently unknown. Further studies are required to clarify the mechanism of antitumor effects of prostaglandins.

Alprostadil↗
PubMed1987

Induction of neutrophilic granulocytosis in mice by administration of purified human native granulocyte colony-stimulating factor (G-CSF).

Mice were subcutaneously (sc) injected once a day for up to 15 days with a purified human native G-CSF sample at a dose of 2.5 micrograms/injection or with control samples with or without added endotoxin. In the G-CSF-treated mice, blood neutrophil counts began to rise as early as 2 hours after the first injection, reached a level 8 times above the preinjection level after 15 days of injections with marked elevation of all progenitor cell levels in spleen, and returned to normal within 48 hours after cessation of the injections. Such neutrophilia was observed even when endotoxin-resistant C3H/HeJ mice were used, but not in control mice. It is possible that repeated G-CSF injections after administration of cyclophosphamide (CY) in mice could accelerate recovery of granulopoiesis with a rather transient rise in blood neutrophil counts.

Animals↗
PubMed1987

Differentiation antigens defined by mouse monoclonal antibodies against human germ cell tumors.

We have developed two mouse monoclonal antibodies, M912-2A2 and M912-2G10, against cell surface antigens of a human infantile embryonal carcinoma cell line, MTE. The distribution of these antigens (designated as 2A2 and 2G10) was almost identical in human germ cell tumors in which they hallmarked yolk sac components and some tubular endodermal structures. Immunoelectron-microscopically, the antigens were located on the microvilli of MTE tumor cells. These antigens were not found on other common childhood tumors. In normal and fetal tissues they exhibited quite different distributions. In the kidney, 2A2 and 2G10 were present on the collecting tubules and proximal/distal tubules, respectively. Expression of both antigens was already observed in fetal kidneys of 10 weeks gestational age. In hematopoietic cells 2G10 was present only on granulocytes and on erythrocytes regardless of ABO blood group, whereas 2A2 was not present on any peripheral blood cells. Both antigens were equally expressed in testis and epididymis. Biochemically, reactivity of both antibodies was abolished with periodate treatment, suggesting their carbohydrate nature. Further biochemical characterization revealed that antibody to 2G10 reacts with the nonreducing terminal structure of type 2 carbohydrate chain, Ga1 beta 1-4G1cNAc, common to nLc4 (paragloboside), nLc6 (neolactohexaose), and Y4 neutral glycolipids of O-type erythrocytes. These data illustrate the complexity of carbohydrate antigens on yolk sac components of human germ cell tumors and provide a basis for the study of primitive endodermal and yolk sac differentiation in these tumors.

Animals↗
PubMed1987

[Antineoplastic effect of beta-IFN and gamma-IFN on malignant gliomas].

We have compared the anti-tumor effects of beta- and gamma-interferons (IFN) against human glioma cells using in vitro model, flow cytometry and xenograft in nude mouse. Contrary to gamma-IFN which had a negligible effect on the growth of glioma cells, beta-IFN showed a dose dependent growth-inhibitory effect on glioma cells in vitro. Our flow cytometry studies revealed that proportion of DNA contents which represent the S and/or G2M phase of cell cycle was markedly increased in cells treated with beta-IFN. However, in cells treated with gamma-IFN, no perturbations in cell cycle distribution were observed. Regarding the anti-tumor effect examined using xenograft of human glioma cells in nude mouse, the tumor reduction rate which was calculated from the ratio of tumor volume between treated (T) and control (C) groups and expressed as T/C value, was 0.44 in animals treated with beta-IFN. However, T/C value in animals treated with gamma-IFN was 0.80 which was derived from the weaker anti-tumor effect of gamma-IFN as compared with that of beta-IFN. Beta-IFN was found to cause a partial suppression of the growth of glioma strain used in this study which confirms our previous report that beta-IFN is effective in reducing tumor size in 2 of 6 glioma strains tested. On the other hand the anti-tumor effect of gamma-IFN, at least in terms of direct effect, against glioma cells used in this study was minimum. However, the mechanism of gamma-IFN's anti-tumor effect may exert mainly through the potentiation of immuno-defence mechanism and the further studies on its pharmacodynamics will be necessary to evaluate the anti-tumor effect of gamma-IFN.

Animals↗
PubMed1987

Relationship between LDL receptor activity and development of coronary heart disease in Japanese cases with heterozygous familial hypercholesterolemia.

To assess the clinical significance of low density lipoprotein (LDL) receptor activity on the development of coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH), we determined the binding, internalization and degradation of 125I-LDL using skin fibroblasts from 66 Japanese cases with heterozygous FH over 30 years old. Although the LDL receptor activity showed a wide variation in the subjects with heterozygous FH, it negatively correlated with the serum LDL-cholesterol levels (r = -0.407, p less than 0.01 for internalization; r = -0.384, p less than 0.01 for degradation). There was no difference in the levels of serum total- and LDL-cholesterol between the CHD (+) (positive) and the CHD (-) (negative) groups, while the serum high density lipoprotein (HDL)-cholesterol level was lower in the CHD (+) group than in the CHD (-) group (p less than 0.01). The mean receptor activity (degradation) of the CHD (+) group was significantly lower than that of the CHD (-) group (p less than 0.05). Stepwise linear discriminant analysis disclosed that not the level of LDL-cholesterol but the LDL receptor activity could also be a discriminator of CHD in patients with heterozygous FH as well as age, serum HDL-cholesterol level and a smoking habit. In conclusion, LDL receptor activity of cultured fibroblasts may also be one of the factors involved in the development of CHD in patients with heterozygous FH.

Adult↗
PubMed1987

Utilization of nude mice in research on human cancer--screening system of anticancer agents using human tumor xenografts in nude mice.

Human cancers including eleven lines of stomach cancer, thirteen lines of lung cancer and six lines of glioma xenotransplated in nude mice were tested for experimental treatment by seven different anticancer agents in the present project. The doses used in this experiment were the maximum tolerated dose (MTD) and rational dose (RD) which was determined to maintain the blood level of drugs in nude mice the same as that in humans to obtain clinical effectiveness. In this experimental regimen, the response rate (number of effective lines/number of total lines tested) in the MTD treated group was much higher than the clinical response rate, but the response rate in the RD-administered group was almost the same as the clinical response rate.

Animals↗
PubMed1986

Purification and characterization of human granulocyte colony-stimulating factor (G-CSF).

A colony-stimulating factor (CSF) has been purified to homogeneity from the serum-free medium conditioned by one of the human CSF-producing tumor cell lines, CHU-2. The molecule was a hydrophobic glycoprotein (mol. wt 19,000, pI = 6.1 as asialo form) with possible O-linked glycosides. Amino acid sequence determination of the molecule gave a single NH2-terminal sequence which had no homology to the corresponding sequence of the other CSFs previously reported. The biological activity was apparently specific for a neutrophilic granulocyte-lineage of both human and mouse bone marrow cells with a specific activity of 2.7 X 10(8) colonies/10(5) non-adherent human bone marrow cells/mg protein. The purified CSF can be regarded as a G-CSF of human origin and will become a useful material for investigation of regulatory mechanisms of human granulopoiesis.

Amino Acids↗
PubMed1986

A 31-year-old woman with homozygous familial hypercholesterolemia without significant lesions in the coronary arteries.

Cardiovascular complications were examined in a 31-year-old woman with homozygous familial hypercholesterolemia (FH) (LDL receptor defective type), who had had no clinical symptoms of coronary artery disease. She had delivered 2 children without any cardiac complications, and her exercise electrocardiogram showed no positive findings for ischemic heart disease. Coronary angiography showed no significant arterial lesions, and left ventriculography revealed good contraction of the left ventricle (ejection fraction: 67%). This is considered to be a very rare case of homozygous FH without significant lesions in the coronary arteries. This might be attributed at least in part to her dietary regimen consisting of a very low fat and low calorie diet, to the residual LDL receptor activity or to the low value of prothrombin time.

Adult↗
PubMed1986

A new mouse model of genetically transmitted polycystic kidney disease.

The clinical and pathologic characteristics of the murine polycystic kidney were examined in a mutant cy/cy mouse found in the KK strain, which is known to be a diabetic strain. This cy/cy mutant appeared to resemble human adult polycystic kidney disease in clinical course and morphology although inheritance was an autosomal recessive trait. Histologic studies of early postnatal animals suggested that cystic alterations might occur in any part of a collecting tubule or nephron. The cy/cy mutant might be a useful model animal for further investigation of early morphologic alterations and progression of cystic disease.

Animals↗
PubMed1986

Interactions of human fibroblast interferon with chemotherapeutic agents and radiation against human gliomas in nude mice.

The growth inhibitory effects of the combination of beta-interferon (beta-IFN) and conventional anticancer drugs such as adriamycin (ADM) and ACNU were evaluated in nude mice receiving subcutaneous transplants of human glioblastoma. Next, the anticancer and radiation sensitizing effects of beta-IFN on human glioblastoma was also evaluated in nude mice model. After three weeks of combined treatment, tumour reduction rates (treated/control values) were evaluated by the Battelle's method. In conclusion, the growth inhibitory effect of IFN was most enhanced when IFN was administered following radiotherapy. Furthermore, the combined effect was enhanced in proportion to the dose of radiation.

Animals↗
PubMed1986

Production of bone-resorbing activity and colony-stimulating activity in vivo and in vitro by a human squamous cell carcinoma associated with hypercalcemia and leukocytosis.

A squamous cell carcinoma of 33-yr-old patient who developed marked leukocytosis and hypercalcemia was transplanted into nude mice in which more marked leukocytosis and hypercalcemia also developed. This tumor (LJC-1-JCK) produced a colony-stimulating factor (CSF) and formed a cyst in the tumor from which a CSF-producing cell line (T3M-1) was established. The CSF causes predominantly formation of granulocytic colonies in addition to macrophage colonies. Bone-resorbing activity (BRA) was detected in the cystic fluid and was eluted as two separate peaks with proteins of an apparent molecular weight of 30,000-50,000 and 10,000-20,000. Colony-stimulating activity (CSA) was eluted at an apparent 30,000 mol wt. The conditioned medium of the T3M-1 cells also contained a BRA with an apparent 14,000 mol wt, whereas CSA eluted at an apparent 30,000 mol wt. PTH, epidermal growth factor, transforming growth factor-alpha, prostaglandin Es, and vitamin D could not account for the powerful BRA. In contrast to CSA, BRA was not inactivated by trypsin and more stable at 70 degrees C. When T3M-1 cells were transplanted into nude mice, marked hypercalcemia developed in addition to granulocytosis. Our findings suggest that the tumor produces and secretes a powerful BRA in vivo and in vitro, which is different from CSA in terms of molecular weight, heat stability, and trypsin treatment. We speculate that the synergistic action of CSF that stimulates macrophage colony formation and recruits osteoclast precursors, and BRA, which stimulates mononuclear phagocytes and/or osteoclasts were responsible for a marked increase in osteoclastic bone resorption and humoral hypercalcemia in the patient.

Animals↗
PubMed1986

Evaluation of response rates to various antitumor agents of human gastric tumors implanted in nude mouse.

To ascertain the clinical predictability and, in the long run, the usefulness of the human tumor/nude mouse model as a screening tool for antitumor agents, it seems particularly important to use as many tumor lines as possible and to evaluate the therapeutic effectiveness of antitumor agents in terms of the overall response rate of a range of tumors. In this study, using 11 strains of established human gastric tumor xenografts with various histological characteristics and proliferation behavior, the experimental response rates to 8 typical antitumor drugs (mitomycin C, cyclophosphamide, ACNU, cisplatin, adriamycin, vincristine, vinblastine and 5-fluorouracil) were determined and compared with the clinical values. The experimental response rates to adriamycin, vincristine and 5-fluorouracil were in good accordance with the clinical results. However, with the other drugs, significantly higher response rates were observed with the nude mouse model as compared to clinical therapy, indicating that this model tends to overestimate the responsiveness of human tumor to a number of antitumor agents. These results strongly suggest the importance of using appropriate dose levels in the nude mouse to reproduce clinically equivalent effects in this model.

Animals↗
PubMed1986

Analysis of structure and activation of some receptor-type tyrosine kinase oncogenes.

We first describe the characterization of proto-oncogene of v-ros in chicken and human genomes. v-ros sequence of UR2 avian sarcoma virus carries a hydrophobic short stretch upstream of the kinase domain, suggesting that its proto-oncogene encodes for a receptor molecule. Using v-ros DNA as a probe we isolated chicken and human c-ros proto-oncogenes. These c-ros DNAs contained a tyrosine kinase domain, transmembrane domain and a part of an extracellular domain carrying an N glycosylation site which was not acquired by UR2 sarcoma virus. These results strongly suggest that proto-oncogene c-ros encodes for a receptor of cell growth or differentiation factor(s) and that the v-ros sequence is a truncated form of this receptor molecule. Structural alteration and overexpression under the control of viral promoter may be crucial for transforming activity of v-ros gene. We then report another example where a receptor-type oncogene is qualitatively and quantitatively activated. By screening with various onc probes we detected two human glioblastomas which have amplification of structurally altered c-erbB1 (epidermal growth factor (EGF) receptor) gene. c-erbB1 gene in these tumors bears a small deletion within the extracellular domain, and the gene product 140 kd protein shorter than the normal 170 kd EGF receptor was heavily phosphorylated on tyrosine residue even without ligand in in vitro phosphorylation reaction. Thus, these mutated EGF receptors seem to be fixed as a "switch-on" form in signal transduction for cell growth and might be involved in the transformation of glial cells.

Amino Acid Sequence↗