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Y Nishino

Publications and source records attributed to Y Nishino.

At least 19 recordsLinked to original sources
PubMed1992

The tumour-inhibiting potential of the progesterone antagonist Onapristone in the human mammary carcinoma T61 in nude mice.

The progesterone antagonist Onapristone proved to possess strong tumour-inhibiting activity in a panel of experimental mammary carcinomas. Its underlying mechanism of action is due to a progesterone-receptor-mediated induction of terminal differentiation and a specific blockade of the cell cycle and is also present in the absence of progesterone as was shown in the MXT mammary tumour. To prove this further, the tumour-inhibiting activity of Onapristone was investigated in the human postmenopausal T61 mammary tumour implanted in castrated male nude mice. Whereas Onapristone given alone had no effect on growth of established tumours, after stimulation of the relatively low progesterone receptor content of this tumour line with an oestrogen, Onapristone significantly inhibited tumour growth. Thus, we suggest that Onapristone exerts its antitumour action via progesterone receptors. As there is no endogenous progesterone in these mice, the tumour-inhibiting activity of Onapristone is not primarily due to a classical antihormonal effect.

Animals↗
PubMed1992

Major core proteins, p24s, of human, simian, and feline immunodeficiency viruses are partly expressed on the surface of the virus-infected cells.

We have previously shown the expression of human immunodeficiency virus type 1 (HIV-1) major gag protein, p24, on the surface of persistently HIV-1-infected cells by using murine monoclonal antibodies (mAb). We now report that the cell surface gag p24 antigen expression is a universal phenomenon among HIV-1, simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV). The mAbs prepared by immunization with purified HIV-1 particles were used as antibodies cross-reactive to HIV-1 and SIVagmp24 antigens. The mAbs to FIV p24 were raised against the gag precursor 50 kDa protein of FIV, which was expressed by Baculovirus vector. The p24 antigen expression on the cell surface was detectable in certain combinations of virus-host cell systems in all of these viruses. Since these p24 regions of the animal viruses seem to play as important a role in cell-mediated immunity as that of HIV-1, the p24 applicability as a candidate epitope for vaccine development could be evaluated in those animals.

Animals↗
PubMed1992

The antitumor potency of progesterone antagonists is due to their differentiation potential.

A new therapy for the progesterone receptor positive mammary carcinoma may be the treatment with progesterone antagonists. This new class of antihormones causes a strong inhibition of tumor growth comparable to the potency of ovariectomy in a panel of experimental mammary carcinomas. The mechanisms of the strong tumor-inhibiting action of progesterone antagonists on experimental mammary carcinomas mainly depends on a progesterone receptor mediated process leading to induction of terminal differentiation and a blockade of the cell cycle. To further characterize the antitumor mechanism of progesterone antagonists we analyzed the effects of Onapristone and ZK 112.993 on DMBA- and MNU-mammary tumors of the rat and MXT-tumors of the mouse after different therapy intervals. These hormone-dependent mammary tumors normally display intraductal growth in papillary, cribiform or solid formation, whereas after treatment periods of 2-6 weeks with progesterone antagonists they displayed dysplastic ductal and acinous formations, usually filled with secretory material. Whereas tumor size, mitotic index, and the grade of tumor malignancy decreased distinctly, the volume fraction of glandular structures in the tumors as well as the appearance of apoptosis increased 3-fold compared to the controls. In addition, the mammary glands of progesterone antagonist treated animals showed the morphological features of differentiation with the appearance of secretory activity. Interestingly, the staining pattern of some of the lectins used, especially UEA 1 binding pattern, fits to the concept of differentiation since recent studies revealed a higher degree of fucosylation only in benign lesions of human breast cancers. Therefore, these data underline the concept of a differentiation potential of progesterone antagonists on progesterone receptor positive mammary carcinomas.

Animals↗
PubMed1992

Progesterone antagonists: tumor-inhibiting potential and mechanism of action.

A new approach for the treatment of breast cancer could be the use of progesterone antagonists. These compounds were originally developed for the inhibition of progesterone-dependent processes and have been shown to be effective in inhibition of nidation and interruption of pregnancy. Although the roles of progesterone and the progesterone receptor in control of cell growth remain unclear, it was found in progesterone receptor positive mammary carcinoma cell lines that the antiprogestin, Mifepristone, had an inhibitory effect on cell growth and a growth-inhibiting action on the DMBA-induced mammary carcinoma of the rat. We have shown that the progesterone antagonists, Onapristone and ZK 112993, which possess a reduced antiglucocorticoid activity compared to Mifepristone, exert a strong tumor-inhibiting effect in a panel of hormone-dependent mammary tumor models. The effects of these compounds were in some systems superior to those of tamoxifen or high dose progestins and comparable to ovariectomy. Although prerequisites for their antiproliferative potency are an affinity to the progesterone receptor as well as a sufficient number of available receptors in the tumors, the strong tumor inhibiting potential of the antiprogestins cannot be explained by a classical anti-hormonal mechanism. Surprisingly, the antitumor activity is evident in spite of elevated serum levels of ovarian and pituitary hormones. It was established by morphometric procedures that treatment with Onapristone triggers differentiation of the mitotically active polygonal tumor epithelial cell towards secretory active glandular structures and acini. All our quantitative light and electron microscopic data indicate that the antitumor action of antiprogestins is accompanied by the initiation of terminal differentiation leading to (apoptotic) cell death. Finally, our flow cytometry studies revealed an accumulation of the tumor cells in the G0G1 phase of the cell cycle, which may result from induction of differentiation since a differentiation-specific G1 arrest has already been proposed for other stem cell systems. It can be concluded from these data that the progesterone receptor antagonists differ in their mode of action from compounds used in established endocrine treatment strategies for mammary carcinoma. The ability of progesterone antagonists like Onapristone to reduce the number of cells in S-phase may offer a significant clinical advantage, since it is established that the S-phase fraction is a highly significant predictor of disease-free survival among axillary node-negative patients with diploid mammary tumors.

Animals↗
PubMed1992

Involvement of the adrenal glands in the prolactin rise induced in the female rat by an antiprogestin, onapristone.

The present study was undertaken to investigate our recent finding that the peripheral levels of prolactin are elevated after the treatment of intact tumor-bearing rats with antiprogestins, like ONAPRISTONE (ON) and MIFEPRISTONE (MI). In ovariectomized rats, s.c. administration of ON (10 mg/kg/day for 5 days) induced a significant increase in the peripheral levels of prolactin without stimulating uterine growth or suppressing LH secretion. Additionally, treatment with ON enhanced the estradiol-induced increase in the serum prolactin levels, suggesting different mechanism(s) for the effects of ON and estradiol on prolactin secretion. In the castrated animals treated with ON we also found a significant increase in the serum levels of aldosterone and corticosterone, but no measurable amount of estradiol and no significant change in the levels of serum androstenedione. Accordingly, we supposed that the effect of ON on prolactin secretion may be induced by suppression of the known activity of adrenal corticosteroids in inhibiting the prolactin secretion. In a further study using ovariectomized and adrenalectomized rats we, in fact, found no appreciable effect of ON on the serum prolactin levels at all. By contrast, dexamethasone (DEX) (0.15 mg/kg for 5 days, s.c.) significantly decreased the prolactin levels which were elevated after adrenalectomy. This effect of DEX was partially reversed by a simultaneous application of ON. From the present observations, it is anticipated that the increase in the peripheral prolactin levels found after treatment with ON is partly due to the antiglucocorticoid effect of the compound.

Adrenal Glands↗
PubMed1992

Cells surviving infection by human immunodeficiency virus type 1: vif or vpu mutants produce non-infectious or markedly less cytopathic viruses.

Under conditions in which a clonal cell line (M10) isolated from a human T cell lymphotrophic virus type I-transformed MT-4 cell line was completely killed by infection with wild-type human immunodeficiency virus type 1 (HIV-1), equivalent M10 cells survived infection with HIV-1 vif, vpr or vpu mutant virus after transient cytopathic effects. Several cell clones, which were isolated from the proliferating M10 cells after infection with vif and vpu mutant viruses (M10/vif- and M10/vpu-), had heterogeneous HIV-1 phenotypes in terms of HIV-1 antigen expression, their syncytium forming capacity, reverse transcriptase activity and the infectivity of HIV-1 particles produced. When the replication kinetics of the HIV-1 particles produced were assayed in M10 cells, the clones could be classified into three types, i.e. type I producing non-infectious HIV-1, type II producing infectious HIV-1 with low replicative ability and type III producing infectious HIV-1 with a replicative ability similar to that of wild-type HIV-1. HIV-1 major viral cell proteins and virus particle fractions were almost typical in types II and III but not in type I. Electron microscopic examination of particles released by I, II and III clones revealed rare defective, predominantly defective and essentially normal virions, respectively. Northern and Southern blot analyses revealed no apparent deletion in the proviral DNA and mRNA prepared from these clones, except in the case of type I and II clones isolated from M10/vpu- which contained large deletions in the mRNAs for gag and gag-pol proteins. Thus, M10 cells surviving infection with HIV-1 vif or vpu mutants are heterogeneous, persistently expressing HIV-1 antigens and producing non-infectious or less cytopathic virus.

Blotting, Northern↗
PubMed1992

Highly conserved epitope domain in major core protein p24 is structurally similar among human, simian and feline immunodeficiency viruses.

Linear B cell epitopes were mapped on the major core protein p24 of human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus (SIVAGM) and feline immunodeficiency virus (FIV) using a fusion protein-based method and murine monoclonal antibodies reactive against the p24 antigens expressed on the surface of HIV-1- and FIV-infected cells. The results suggest that the sites identified here are encoded at similar positions in the three virus genomes and consist of highly conserved epitopes, which could exhibit immunodominance.

Amino Acid Sequence↗
PubMed1992

Altered cell tropism and cytopathicity of feline immunodeficiency viruses in two different feline CD4-positive, CD8-negative cell lines.

Two interleukin-2-dependent feline CD4-positive and CD8-negative cell lines, MYA-1 and the newly established FeL-039, were used as host cells for infection with feline immunodeficiency virus (FIV). All FIV strains used, the Petaluma strain and several new isolates, were highly cytopathic to MYA-1. In contrast, the kinetics of FIV replication in FeL-039 differed greatly depending on the strain tested, i.e., noninfectious strain, highly cytopathic strain, and less cytopathic strain producing a persistent state for a long period. It appears, therefore, that cell tropism for FIV differed with each FIV strain tested even in T-cell lines showing similar cell surface phenotypes. Cytopathicity of FIV is evidently due to both the FIV strain and the host T cell.

Animals↗
PubMed1992

[Solitary infected renal cyst: a case report].

A 48-year-old man was admitted to our hospital because of high fever and left flank pain. Laboratory findings revealed a high white blood cell count, high C-reactive protein level, and severe pyuria. Sonographic examination revealed an enlargement of the cyst at the upper pole of the left kidney that had already been detected. Percutaneous drainage was performed for the cyst and 60 ml of purulent fluid was obtained. Bacterial culture of the fluid was positive for Propionibacterium acnes and gamma-Streptococcus. The drainage and administration of povidone-iodine was continued for 7 days. The size of the cyst was reduced with disappearance of symptoms.

C-Reactive Protein↗
PubMed1991

Human immunodeficiency virus type 1 vif, vpr, and vpu mutants can produce persistently infected cells.

A series of human immunodeficiency virus type 1 (HIV-1) mutants in vif, vpr, vpu, and nef were constructed from an infectious plasmid (pNL 432) containing the full-length HIV-1 DNA by frameshift mutations. The capacities for replication and cell killing of these mutant viruses were examined in a clonal cell line (M 10) isolated from HTLV-I-transformed MT-4 cells. In all cases, the mutant viruses replicated, expressed HIV-1 antigens, and induced drastic cytopathic effects. However, some M 10 cells survived infection with vif, vpr, and vpu mutant viruses and became persistently HIV-1-infected, whereas no cells survived infection with the nef mutant as well as the wild-type virus. The HIV-1 particles produced from the surviving cells after infection with the vif, vpr, or vpu mutant viruses were fully replicative in M 10 cells without apparent cytopathic effects.

Cell Death↗
PubMed1991

A bioassay for the evaluation of antiproliferative potencies of progesterone antagonists.

A bioassay which allows quantification of the antiproliferative potency of progesterone antagonists on the mammary gland was developed. For this purpose, ovariectomized rats were substituted with oestrone and progesterone and a further group simultaneously treated with the progesterone antagonists Mifepristone (= RU 38.468), Onapristone (= ZK 98.299), or ZK 112.993 (Schering AG, Berlin). A morphometric analysis of the tubulo-alveolar buds in the inguinal mammary glands revealed a dramatic antiproliferative effect of the progesterone antagonists after as little as 3 days of treatment. Several less specific mammary gland growth parameters (weight, DNA- and RNA-content) proved to be less sensitive. This bioassay measures the potency of progesterone antagonists to competitively antagonize the specific effects of progesterone on the target organ mammary gland. Further advantages of this bioassay are the use of a hormonally standardized biological system, the quantitative results, the small amount of test compound necessary, as well as the substitution with progesterone and oestrone since the antiproliferative potency of progesterone antagonists on experimental hormone dependent mammary carcinomas is most potently displayed in ovariectomized animals substituted with both sex hormones.

Animals↗
PubMed1991

Aldosterone antagonists. 4. Synthesis and activities of steroidal 6,6-ethylene-15,16-methylene 17-spirolactones.

Several steroidal 6,6-ethylene-15,16-methylene 17-spirolactones were synthesized to find new progestogens that exhibit both progestational and antimineralocorticoidal activities. The influence of substituents in the 10- and 13-position of the steroidal framework on both properties was investigated. It was found that only compound 12, carrying methyl groups at the 10- and 13-positions, possesses high progestational and antimineralocorticoidal activity.

Adrenalectomy↗
PubMed1991

Analysis of the protective effect of the haemagglutinin-neuraminidase protein in Newcastle disease virus infection.

The role of immune responses to haemagglutinin-neuraminidase (HN) protein in protection against a Newcastle disease virus (NDV) infection was investigated using a recombinant vaccinia virus expressing HN (HN-RVV). Live HN-RVV replicated in chickens and completely protected them from lethal infection with virulent NDV. Inactivated HN-RVV also protected chickens when administered with adjuvant but not when administered without adjuvant. However, large amounts of the inactivated HN-RVV (100-fold excess) without adjuvant provided protection. Specific antibodies against the HN protein of NDV were detected in sera from survivors but not from dying birds. However, the kinetics of antibody responses in chickens inoculated with live HN-RVV and inactivated HN-RVV were considerably different. These results clearly confirm that immune response(s) solely to the HN protein of NDV can provide chickens with protection against NDV challenge, and show that the presence of antibodies to the HN protein correlates significantly with the protection from NDV infection at least in HN-immunized chickens.

Animals↗
PubMed1991

Pharmacological characterization of a novel oestrogen antagonist, ZK 119010, in rats and mice.

The oestrogenic and antioestrogenic effects of a new nonsteroidal compound ZK 119010 (2-(4-hydroxyphenyl)-3-methyl-1-[6-(1-pyrrolidinyl)-hexyl]-indol-5-ol) were evaluated and compared with those of tamoxifen and ICI 164384. In immature mice, ZK 119010 administered once daily for 3 days (s.c.) inhibited the uterotrophic and vaginotrophic effect of oestradiol in a dose-dependent manner and was distinctly more potent than tamoxifen or ICI 164384 in exerting antioestrogenic effects. When antioestrogens in combination with oestradiol were administered once daily for 5 days to ovariectomized adult rats, ZK 119010 at lower doses (less than or equal to 1 mg/kg) was slightly less effective than tamoxifen in inhibiting the uterotrophic effect of oestradiol. At the higher doses, however, ZK 119010 was strongly antioestrogenic, and ICI 164384 was less effective than ZK 119010 or tamoxifen. ZK 119010 at 10 mg/kg, like ICI 164384 at 30 mg/kg, caused an almost complete inhibition of the oestradiol-induced uterine growth in rats. The antioestrogenic effect of tamoxifen in rats was also limited by its inherent oestrogenic property. The oestrogenic activity of ZK 119010 was much below that of tamoxifen, whereas ICI 164384 did not show oestrogenicity. The present results indicate that ZK 119010 is a novel type of non-steroidal antioestrogen which has only a marginal oestrogenic effect in rats and mice. Such an antioestrogen may be useful for the treatment of oestrogen-sensitive diseases in man.

Animals↗
PubMed1991

Noninfectious doughnut-shaped human immunodeficiency virus type 1 can induce syncytia mediated by fusion of the particles with CD4-positive cells.

A defective doughnut-shaped human immunodeficiency virus type 1 (HIV-1)-producing cell clone (designated as L-2) was isolated from persistently HIV-1-infected MT-4 cells. The syncytium-forming capacity of the cell and virus particle fractions was examined in human CD4-positive T cells. Several cell lines producing infectious HIV-1 particles, such as persistently HIV-1-infected MOLT-4 (MOLT-4/HIV-1) cells, were used as controls. Syncytia were formed within 20 h by the cell fraction of both L-2 and MOLT-4/HIV-1 and the virus particle fraction of L-2, but not MOLT-4/HIV-1. These formations were not affected by 3'-azido-3'-deoxythymidine (ZDV). In contrast, similar syncytium formation was first observed 2 days after the incubation of the virus particle fraction of MOLT-4/LAV-1 and this syncytium formation mediated by the cell fractions of MOLT-4/HIV-1 and L-2 or the virus particle fraction of L-2 differently.

Antibodies, Monoclonal↗
PubMed1990

Antitumor activity and mechanism of action of different antiprogestins in experimental breast cancer models.

Onapristone and other antiprogestins proved to possess a potent antitumor activity in several hormone-dependent experimental breast cancer models. This activity is as strong or even better than that of tamoxifen or ovariectomy in the MXT-mammary tumor of the mouse and the DMBA-and MNU-induced mammary tumor of the rat. The antitumor activity is evident in these models in spite of elevated serum levels of ovarian and pituitary hormones. The detailed analysis of all our data including the morphological (ultrastructure) studies of the mammary tumors of treated animals and the effects on growth and cell cycle kinetics using DNA flow cytometry indicates that the antitumor action of antiprogestins is mediated via the progesterone receptor and related to the induction of terminal cell differentiation leading to increased cell death. The strong antitumor activity of antiprogestins in our experimental breast cancer models does not primarily depend on a classical antihormonal mechanism. The antiprogestin-related reduction of the number of mammary tumor cells in the S-phase in our experimental tumor models (G0G1 arrest) emphasizes the unique innovative mechanism of action of these new agents in the treatment of human breast cancer.

Animals↗
PubMed1990

Aldosterone antagonists. 3. Synthesis and activities of steroidal 7 alpha-(alkoxycarbonyl)-15,16-methylene spirolactones.

Several A- and D-ring substituted steroidal 7 alpha-alkoxycarbonyl spirolactones were synthesized with the purpose of increasing the aldosterone antagonistic potency and reducing the endocrinological side effects relative to the standard drug spironolactone. It was found that the 15 beta,16 beta-methylene derivative 17 exhibited a 2-fold higher aldosterone antagonistic activity compared to either spironolactone or the 15,16-unsubstituted derivative 29 while showing remarkably reduced antiandrogenicity.

Animals↗