Search PubMed⌕ Search

Biomedical subjects

H Umezawa

Publications and source records attributed to H Umezawa.

At least 55 records · Page 3Linked to original sources
PubMed1988

Antitumor activity of new morpholino anthracyclines.

Antitumor activity of 3'-deamino-3'-morpholino anthracyclines was examined. Morpholino derivatives of 13-deoxocarminomycins, MX2 (1), MX (2) and MY5 (3) shown in Fig. 1, administered iv showed increase in life span (ILS) values over 110% against ip-inoculated P388 leukemia. The ranges of effective doses of these compounds were broader than those of their parent drugs. The morpholino derivatives of doxorubicin and carminomycin, however, were not so effective as their parent drugs. Among these compounds, MX2 administered orally showed nearly the same effects as those obtained by iv administration against P388 leukemia. MX2 administered iv showed 89% ILS against intracerebrally-inoculated L1210 leukemia. The highly lipophilic nature of MX2 could contribute partly to achieving chemotherapeutic responses against intracerebrally-inoculated tumors or by oral administration.

Animals↗
PubMed1988

Strong binding of ditrisarubicin B to DNA.

DNA binding characteristics of ditrisarubicin B were studied by the fluorescence titration technique. Ditrisarubicin B bound to calf thymus DNA with an affinity higher than any we have ever seen among anthracyclines. The apparent association constant (Kapp) of ditrisarubicin B was 2.36 X 10(8) M-1, which is 22.7 times larger than that of doxorubicin. The apparent number of binding sites (napp) of ditrisarubicin B per nucleotide of DNA was 0.164, and this value is identical with that of doxorubicin. Betaclamycin A, which has a trisaccharide chain at C-7 but no carbohydrate at C-10 in the aglycone, interacted with DNA to give a Kapp of 5.92 X 10(6) M-1 and napp of 0.178. These results suggest to us that the high affinity of ditrisarubicin B for DNA is caused by the existence of a glycosidic chain at C-10.

Animals↗
PubMed1988

Antitumour activity of new semi-synthetic anthracyclines containing fluorotalopyranose.

The authors have synthesized 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) adriamycinone (FT-ADM) which exhibited strong antitumour activity and weak toxicity. These characteristics of FT-ADM are partly due to the presence of a 2'-fluoro atom which strengthens the glycoside bond. FT-ADM, however, is sparingly soluble in water because of lack of the 3'-amino group of adriamycin. To increase the solubility of FT-ADM, a hydrophilic group was added at the 14-OH group. Then, the 14-hemisuccinate, 14-hemiglutarate, 14-hemiadipiate, 14-hemipimelate and 14-hemisuberate derivatives of FT-ADM were synthesized. Among them, the 14-hemipimelate derivative (FAD-104) was selected for further development because of its potent antitumour activity and weak toxicity. When drugs were injected intraperitoneally every day from day 1 to 9, FAD-104 showed an apparently stronger antitumour effect against mouse L-1210 leukaemia than adriamycin with lower toxicities. FAD-104 was also more effective than adriamycin on L-1210 using other administration schedules. A characteristic feature is that FAD-104 is effective over a very broad range, which will be advantageous for safe clinical use. FAD-104 also showed marked antitumour effect against L-1210 when it was injected intravenously either once on day 1 or three times on days 1, 5 and 9. Thus, FAD-104 may be a more potent antitumour anthracycline than adriamycin.

Animals↗
PubMed1988

Specific inhibition of aspartase by S-2,3-dicarboxyaziridine.

Aspartase of Escherichia coli was inhibited in a competitive manner by S-2,3-dicarboxyazirdine (DCAZ), an antibacterial substance against Aeromonas salmonesida. The inhibition constant (Ki) was 55 microM, which was as low as less than one tenth that of the Km value for the substrate, L-aspartate. In view of the fact that both aspartase and fumarase (J. Greenhut et al. (1985) J. Biol. Chem. 260, 6684-6686) were inhibited by DCAZ in competitive manners, common features of the reaction mechanism of the two enzymes were discussed.

Ammonia-Lyases↗
PubMed1987

Synthesis of antitumor-active 7-O-(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl)-daunomycinone and -adriamycinone.

The title compounds (17 and 23) were prepared by coupling 3,4-di-O-acetyl-2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl bromide (15) with daunomycinone. The key step in the preparation of 15 was the epoxide-ring opening of methyl 2,3-anhydro-4-O-benzyl-6-deoxy-alpha-L-gulopyranoside with KHF2 in ethylene glycol, whereupon 2-fluoro-alpha-L-idopyranoside was obtained. Compounds 17 and 23 showed strong antitumor activity.

Animals↗
PubMed1987

Sulfhydryl modification and activation of phenylalanine hydroxylase by dinitrophenyl alkyl disulfide.

A new family of asymmetric thiol-disulfide exchange reagents, the dinitrophenyl alkyl disulfides (DNPSSR), was used to modify rat liver phenylalanine hydroxylase. The results indicate that the enzyme has two different types of reactive sulfhydryl (SH) residues per subunit. One SH residue was modified selectively by a DNPSSR having a neutral and hydrophilic alkyl group, and this modification was accompanied by appreciable activation of enzyme; the other SH residue was modified only by an anionic DNPSSR, and this modification did not result in activation. The catalytic properties of phenylalanine hydroxylase activated by DNPSSR were similar to those of the N-ethylmaleimide- (NEM-) modified enzyme, but the process of activation by DNPSSR was quite different from modification with NEM. An analysis of the reaction kinetics of the modification and of catalysis by the modified enzyme suggests that DNPSSR modification causes a change in the subunit interaction leading to a loss of the negative cooperativity normally seen with phenylalanine hydroxylase.

Animals↗
PubMed1987

Analgesic effect of actinonin, a new potent inhibitor of multiple enkephalin degrading enzymes.

Actinonin, previously isolated as an antibiotic and shown to be an inhibitor of aminopeptidase M (EC 3.4.11.2), has now been shown to inhibit three enkephalin-degrading enzymes from guinea-pig striatum. The values of IC50 were 0.39 microM for striatal membrane aminopeptidase ("enkephalin-aminopeptidase") and 5.6 microM striatal membrane neutral endopeptidase ("enkephalinase A"). Furthermore, soluble dipeptidylaminopeptidase in a rat whole brain homogenate was also inhibited by actinonin with the IC50 value of 1.1 microM. Actinonin administered intracisternally (i.cist., 50 micrograms) or intraperitoneally (i.p., 100 mg/kg), potentiated the analgesic action of met-enkephalin (50 micrograms i.cist.). analgesia by a tail-flick test. The potentiating activity of actinonin i.p. to met-enkephalin analgesia was almost the same potency as that of thiorphan, whereas the inhibitory activity of actinonin against enkephalinase A was 1/1000 that of thiorphan. Actinonin alone, administered either i.cist. or i.p., showed an analgesic action as estimated by the tail-flick test.

Aminopeptidases↗
PubMed1987

Involvement of cytotoxic T-lymphocytes in the antitumor activity of spergualin against L1210 cells.

Spergualin exhibited a strong antitumor effect against L1210(IMC), a tumor cell line which has been maintained in BALB/c X DBA/2 F1 (hereafter called CD2F1) mice in the Institute of Microbial Chemistry. Mice inoculated i.p. with 10(5) cells of L1210(IMC) survived more than 60 days by daily i.p. administration of spergualin for 9 days at 5 mg/kg/day, which was started 1 day after the tumor inoculation. These cured mice rejected a second inoculation of 10(6) cells of L1210(IMC), but they did not reject the inoculation of 10(2) P388 cells. In Winn's tumor neutralization assay and in the 51Cr release assay, the T-cell fraction prepared from the spleens of the cured mice had higher cytotoxic activity against L1210(IMC) than whole spleen cells. The cytotoxic activity of spleen cells was diminished by treatment with anti-Thy-1.2 or anti-Lyt-2.1 antibody and complement. Therefore, the effector cells involved in the immunological rejection should be regarded as cytotoxic T-lymphocytes. The cytotoxic activity of these T-lymphocytes was measured during and after the spergualin administration for 9 days, and high activity was observed from 1 day after the final spergualin administration. The antitumor effect of spergualin against L1210(IMC) was much lower in T-cell-deficient athymic mice. These results suggest that cytotoxic T-lymphocytes are involved in the antitumor action of spergualin against L1210(IMC) in vivo.

Animals↗
PubMed1987

Composite effects of actinonin when inhibiting enkephalin-degrading enzymes.

Actinonin which has been found to be an inhibitor of aminopeptidase M (EC 3.4.11.2) also inhibited enkephalinase A (EC 3.4.24.11) and enkephalin aminopeptidase which were partially purified from the corpus striatum membrane of guinea-pig brain. The IC50 values were 5.6 microM for enkephalinase A and 0.39 microM for enkephalin aminopeptidase. Actinonin also inhibited with an IC50 value of 1.1 microM dipeptidyl aminopeptidase tested on whole brain homogenate of rats in the presence of thiorphan and bestatin. Analgesia was assessed by measuring the tail-flick latency of mice. The analgesic effect of [Met5]enkephalin injected intracisternally (i.cist., 50 micrograms) was potentiated by an intraperitoneal (i.p., 100 and 300 mg/kg) as well as an i.cist. (25 micrograms) injection of actinonin. Actinonin was found to inhibit all three enzymes of enkephalin metabolism and, when given peripherally, to potentiate enkephalin analgesia.

Aminopeptidases↗
PubMed1987

Nucleotide sequence of the streptomycinphosphotransferase and amidinotransferase genes from Streptomyces griseus.

Genes for streptomycin phosphotransferase and inosamine-P-amidinotransferase from a streptomycin-producing Streptomyces griseus were cloned on a 3.8kb BamHI-SphI fragment in S. lividans using the multicopy cloning vector pIJ702. The nucleotide sequence of this 3.8kb fragment was determined and the coding sequences for the two genes were identified by comparison with the amino-terminal sequences of the two enzymes purified from S. lividans clones.

Amidinotransferases↗
PubMed1987

Relative deficiency of serine proteinase activities in spleens of aged mice.

We examined the relation of hydrolytic enzymes in spleen to the aging process in mice over a period of 30 months. When the enzymatic activities were expressed as activities per milligrams protein, those of serine proteinases and dipeptidyl peptidase IV (Gly-Pro-AP) significantly decreased with age, whereas that of L-leucine aminopeptidase (Leu-AP) increased significantly. However, when expressed as total activities, the enzymatic activities in spleen generally tended to increase with age, except in the case of serine proteinases, because of the age-related increase in spleen weight. The results were taken to indicate that the activities of serine proteinases become relatively more deficient in the spleen as age increases. The results of a multivariate study maintained this peculiarity of serine proteinases in comparison with other enzymes. The relative deficiency of serine proteinases in spleen may be somehow related to immunodeficiency in aged animals, as judged from similar findings in animal models of systemic erythematodes.

Aging↗
PubMed1987

Morphometrical observations on the mandible of five strains of rabbits and strain identification using mandible measurements.

In order to clarify the relationships between five strains of rabbits and to identify the strains, principal component and discriminant analyses were carried out using 12 mandibular measurements of three inbred strains (JW-NIBS/Y (JW/Y), NW-NIBS/Y (NW/Y) and Dutch-NIBS/Y (D/Y)) and two outbred strains (JW-NIBS (JW) and NW-NIBS (NW] which were maintained at the Nippon Institute for Biological Science. The results obtained were as follows. (1) Principal component analysis revealed that in the males the mandible of JW was the largest but with considerable variation. D/Y was the smallest of all strains examined. The mandibles of NW and NW/Y were similar to the JW mandibles but had a shape which was shorter and higher. In the females the mandible of NW was the largest of all strains and, as in the males, D/Y was the smallest and JW varied markedly. (2) Discriminant analysis showed the probability of erroneous discrimination to be 14.8% (34/229) when the inbred and outbred strains were combined. In both sexes erroneous discrimination mostly occurred between NW and NW/Y, which have the same origin, and between JW and NW, which have a common ancestor. However, when the inbreds and outbreds were identified separately by discriminant analysis, the probability of erroneous discrimination was low in both cases (4.5% (5/112) and 7.7% (9/117) respectively). These results indicate that strain differences are found in the size and shape of rabbit mandibles and that mandible analysis is effective for strain identification of laboratory rabbits.

Animals↗