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Biomedical subjects

Y Koseki

Publications and source records attributed to Y Koseki.

At least 55 records · Page 3Linked to original sources
PubMed1987

Comparative effects of adriamycin and DNA-non-binding analogues on DNA, RNA, and protein synthesis in vitro.

Drug-DNA binding is claimed to be the basis by which the antitumor antibiotic adriamycin (doxorubicin) inhibits DNA and RNA synthesis in vitro. However, in preliminary studies the DNA-non-binding adriamycin analogue N-trifluoroacetyladriamycin-14-valerate (AD 32) showed somewhat greater inhibition of DNA and RNA synthesis than adriamycin under identical conditions. The kinetics of macromolecule synthesis inhibition induced by adriamycin and AD 32, and the two principal DNA-non-binding metabolites of AD 32, N-trifluoroacetyladriamycin (AD 41) and N-trifluoroacetyladriamycinol (AD 92), have now been subjected to comparative study in cultured CEM (human leukemic lymphoblastic) cells. At equimolar concentrations (10 microM), or at concentrations related to their 50% growth-inhibitory values vs CEM cells, AD 32 was consistently found to be more inhibitory than adriamycin of DNA and RNA synthesis, as measured by the incorporation of tritiated thymidine and uridine, respectively, into acid-precipitable fractions relative to untreated controls. Marked inhibitory activity was apparent with 10 microM AD 32 even at the earliest sampling time (15 min); with adriamycin at the same concentration the maximal effect was not achieved until 3 h. AD 32 at 4.8 microM concentration continued to show strong inhibition of nucleic acid synthesis, whereas adriamycin at 1.0 microM was essentially inactive. Like AD 32, AD 41 and AD 92 showed greater inhibition than adriamycin of DNA and RNA synthesis at the early sampling times, although in all instances the effects of AD 32 were more profound. AD 32 at 10 microM concentration produced a moderate but significant inhibition of the incorporation of tritiated methionine into protein compared with adriamycin, which at this concentration was not active. Parallel HPLC analytical studies with similar drug-treated cultures indicated that, while small amounts of adriamycin were found in cells treated with 10 microM AD 32, the amount of adriamycin present at 15 min was only a small fraction (less than 5%) of the amount of adriamycin achieved at 3 h in cultures treated with 1.0 microM adriamycin, a concentration already shown to be only slightly inhibitory of nucleic acid synthesis under the culture conditions. The present study thus confirms the marked DNA and RNA synthesis-inhibitory effects of AD 32, and establishes that this inhibitory activity is not due to conversion of AD 32 into adriamycin. These findings accordingly call into question the validity of the drug-DNA binding mechanism as the explanation for the nucleic acid synthesis inhibitory effects seen with ADR.

Cell Survival↗
PubMed1987

Prolactin regulation of estrogen and progesterone receptors in normal and neoplastic mouse mammary tissue.

The transplantable mouse mammary tumor, TPDMT-4, is pregnancy-dependent and requires prolactin (PRL), estradiol (E2) and progesterone (Pg) for growth. To examine the role of PRL in regulating tissue growth and the levels of estrogen receptor (ER) and progesterone receptor (PgR), tumor-bearing mice were ovariectomized, hysterectomized and then injected with ergocornine hydrogenmaleate (ERG), ERG + PRL, or ERG + PRL + E2 + Pg. Total (nuclear + cytoplasmic) ER and PgR in normal and neoplastic mammary tissues were measured. In addition, tumor size and tritium-labeled thymidine [( 3H]dThd) incorporation into nuclei of the tumor and mammary gland were determined. PRL alone caused a 2- to 3-fold increase in ER and PgR levels in normal mammary gland but not in the tumor. PRL alone caused a modest increase in the number of 3H-thymidine-labeled nuclei in both tissues. PRL combined with E2 and Pg increased the percent of labeled nuclei 5- to 10-fold in both tissues, and increased the PgR levels in normal but not in tumor tissue. Thus, PRL alone can increase ER in normal mammary tissue but this increase is not required for growth since ER levels are unchanged when PRL + E2 + Pg are injected and mammary cell growth is stimulated. The ability of PRL to up-regulate ER has been lost in the tumor. Since basal levels of ER and PgR are not altered in the tumor when PRL + E2 + Pg are given, an increase in ER and PgR levels is not required for the three hormones to stimulate tumor growth.

Animals↗
PubMed1985

Systemic changes in hydrolytic enzyme activities in mice affected with murine leprosy.

In order to investigate the behavior of hydrolytic enzymes in chronic infections, the activities of 17 hydrolytic enzymes were tested in limb muscles, heart muscle, spleen, liver, and kidney of lepromatous mice infected with Mycobacterium lepraemurium (M. lepraemurium) and their controls. Typical increases in those enzymatic activities were seen in spleen and liver, where pathological changes were the most pronounced, especially at the 11th week after the inoculation of the bacilli. At the 16th week, the enzymatic changes became less remarkable probably because of the decreased viability of tissues in these organs. The enzymatic changes observed could not be explained as due to bacterial enzymes. These findings are compatible with the notion that the increases in hydrolytic enzyme activities are related to tissue damage caused by murine leprosy.

Animals↗
PubMed1982

Failure to validate the growth of Mycobacterium leprae on M-Y 14b agar medium.

Confirmation experiments on colony formation of M. leprae on the M-Y 14b agar medium developed by Murohashi and Yoshida were carried out for two years independently by individual members of an organized research group, according to the method described by Murohashi and Yoshida. The results obtained can be summarized as follows: a) No colony production by M. leprae on M-Y 14b agar medium was seen. b) No increase in the number of cells of M. leprae on M-Y 14b agar medium during cultivation was seen. c) Light and electron microscopic observation indicated that there was an increase in the number of non-solid bacterial cells and ghost cells with time of cultivation. d) It was found by mouse foot pad inoculation that four of six samples of M. leprae used as inocula were definitely viable. e) By means of mouse foot pad inoculation, it was shown that viability of M. leprae inoculated onto M-Y 14b agar medium was lost within approximately seven weeks of cultivation. From these results, can be definitely concluded that there is no evidence indicating that multiplication of M. leprae took place on M-Y 14b agar medium.

Agar↗
PubMed1979

Prolactin receptors in primary cultures of carcinogen-induced rat-mammary tumors.

7,12-Dimethylbenz[alpha]anthracene-induced rat mammary tumors were dissociated with collagenase and hyaluronidase and placed into primary culture. In most cultures, specific binding of 125I-labeled ovine prolactin was (i) lower than that for the original tumors unless bovine prolactin (1 microgram/ml) had been added to the dissociation medium, and (ii) varied with the type of growth medium used. The level of prolactin binding in cultured cells was relatively constant for the first 7-10 days. Prolactin binding in cultured cell homogenates was maximal at pH 7.0, proportional to cell protein, specific for prolactin, and reached a steady state by 12 h at 22 degrees C. The half-maximum inhibition of 125I-labeled prolactin binding by unlabeled prolactin was 100 ng/ml for cells grown in 5-1000 ng of prolactin/ml. After prolactin was removed from the growth medium, the level of available binding sites progressively increased, reached a maximum at 48 h and then declined. At 48 h, the dissociation constant for prolactin binding (Kd approximately 1 x 10(-10) M) was comparable to that in tumors. In some cultured tumors, a 48-h treatment with 0.5 or 1.0 ng of prolactin/ml caused an apparent increase in the level of prolactin binding. Prolactin increased DNA synthesis and its removal caused a reduction in [3H]estradiol and [3H]-R5020 binding to cultured cell cytosols.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1978

Estrogen control of progesterone receptor in human breast cancer: role of estradiol and antiestrogen.

Estrogen antagonists are widely used in the treatment of breast cancer, and studies of their mechanism of action may provide clues to an understanding of tumor growth regulation and mechanisms of normal estrogen action. We have used human breast cancer cells in long term culture as an in vitro model to study the roles of estradiol and the antiestrogens, tamoxifen and nafoxidine, on cell growth and progesterone receptor (PgR) induction. Tamoxifen is found to have dual dose-dependent estrogenic/antiestrogenic properties. With 1 micrometer tamoxifen, cell growth and PgR induction are suppressed. These effects are reversed by estradiol. At lower doses (less than 0.1 micrometer), however, tamoxifen is a potent estrogen and rapidly induces (24--48 h) PgR, which increases 4- to 10-fold after 4--6 days and falls if tamoxifen is removed. Induction of PgR by estradiol is weaker but follows a similar time course. Tamoxifen-induced PgR is similar to that induced by estradiol; it sediments at 8S on sucrose density gradients, is a tight binder (R5020 Kd, 1.7 micrometer at 4 C and 0.87 nM at 15 C), and can be translocated to the nucleus by R5020. The dual properties of tamoxifen are not due to metabolic formation of an active antiestrogen from a prohormone precursor. In contrast, the action of the antiestrogen nafoxidine is not biphasic in MCF-7 cells; it does not induce PgR over a wide dose range and at high doses, the compound inhibits cell growth.

Breast Neoplasms↗
PubMed1977

Progesterone interaction with estrogen and antiestrogen in the rat uterus--receptor effects.

Daily injections of estradiol or the antiestrogen tamoxifen initially stimulate uterine weight increase and progesterone receptor synthesis, though continued tamoxifen fails to maintain the increased weight. The stimulatory actions of both estradiol and tamoxifen are inhibited or reversed by a single injection of progesterone. It has been hypothesized that progesterone antagonizes estrogen action by reducing estrogen receptor levels, but in the present experiments neither cytoplasmic nor nuclear estrogen receptor was affected. We conclude that progesterone acts at a point beyond estrogen receptor availability or translocation to antagonize estrogen action.

Animals↗