Biomedical subjects
Publications and source records attributed to A Matsuda.
2-Fluoro- and 2-chloroneplanocin A's (2 and 3) were synthesized as an adenosine deaminase resistant-equivalent of neplanocin A, and evaluated for their antitumor and antiviral activities. Of these, 2 was completely resistant to adenosine deaminase and showed more significant antitumor and antiviral activities than neplanocin A.
Thymidine was converted into 5-formyl-2'-deoxyuridine (1), which was incorporated into oligonucleotides, 5'd(GGAGA1CTCC)3' (I-1) and 5'd(GCTGC1GCGAAAGCTG)3' (II-1). To avoid side-reactions and degradation, protection of the formyl group of 1 using a newly developed protecting group, N,N-di-(3,5-dichlorophenyl)ethylenediamine, was necessary. Compound 1 was unstable under the conditions employed for enzymatic complete digestion of oligonucleotides, so that a peak corresponding to 1 was not detected clearly by HPLC analysis of a nucleoside mixture obtained by complete hydrolysis of I-1. Therefore, the oligonucleotide I-1 was treated with cyanomethylene-triphenylphosphorane to give an oligonucleotide containing (E) and (Z)-5-(2-cyanovinyl)-2'- deoxyuridine, which was then hydrolyzed, and the newly generated nucleosides were detected by HPLC analysis. The Tm of the self-complementary oligonucleotide I-1 (40 degrees C) was higher than that of the parent oligonucleotide, 5'd(GGAGATCTCC)3', (31 degrees C) in a buffer containing 0.01 M sodium phosphate (pH 7.0) and 0.1 M NaCl. DNA replication study on a template-primer system [primer, 5'd(32P-CAGCTTTCGC)3'; template, 3'd(GTCGAAAGCGXCGTCG)5' (X = 1 or T)] showed that dATP was incorporated into the DNA strand at a site opposite to 1 by Klenow DNA polymerase, but with a reduced rate. The formyl group of 1 in the oligonucleotides reacted with amines to give Schiff base derivatives.
A 55-year-old woman developed Cushing's syndrome due to ACTH-independent bilateral adrenocortical macronodular hyperplasia. Plasma ACTH was undetectable, and was not stimulated by administration of metyrapone, CRH, or insulin. Hypercortisolism was not suppressed by a high dose of dexamethasone, but was responsive to ACTH. Both adrenal glands were enlarged with a total weight of 200 g, and contained multiple nodules composed of two cell types (large clear cells and small compact cells). In immunohistochemical studies, P450c17 immunoreactivity was predominantly observed in small compact cortical cells, while that of 3 beta HSD was observed exclusively in large clear cortical cells. This pattern of expression of steroidogenic enzymes as well as histological and clinical features is considered to be unique to ACTH-independent bilateral adrenocortical macronodular hyperplasia.
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Bucillamine has been reported to have beneficial effects in rheumatoid arthritis. This report concerns a case of RA in which agranulocytosis developed while on a course of bucillamine. A 52-year-old female with RA developed a rapid fall in white blood cell count after 4 weeks of bucillamine treatment at daily dose of 50 mg. Agranulocytosis was diagnosed (WBC 1300/mm3, granulocytes 5%). The administration of bucillamine was halted and she was treated with only prophylactic antibiotic regime. The peripheral granulocyte count result rapidly reversed within 3 days after discontinuation of the bucilamine treatment. Anti-leukocyte antibody was detected by the leukocyte lysis phenomenon method during the period of agranulocytosis. And high intrinsic G-CSF activities were detected in the patient serum before the recovery period of agranulocytosis. Agranulocytosis is a rare side effect of bucillamine but it is potentially more harmful than other side effects. In treatment with bucillamine, therefore, the drug should be carefully administered and regular blood examinations carried out to prevent the occurrence of this side effect.
We measured the manganese content of mononuclear blood cells and the manganese concentrations in whole blood and plasma from 31 healthy volunteers and 25 patients receiving total parenteral nutrition (TPN) (i.e., no dietary manganese). The manganese content (mean +/- 2 SD) of mononuclear blood cells and the manganese concentration in whole blood and plasma in the healthy volunteers were 8.84 +/- 4.18 ng/10(8) cells, 11.21 +/- 4.68 micrograms/L, and 1.21 +/- 0.72 micrograms/L, respectively. The manganese content of mononuclear blood cells from patients receiving TPN gradually decreased, falling below the lowest limit of the normal range by 21 weeks (95% confidence limits, 13-30 weeks) after starting TPN. Manganese concentrations in whole blood and plasma were within normal limits during our study period. These results suggest that the manganese content of mononuclear blood cells may better indicate manganese nutritional status than whole-blood or plasma concentrations.
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Design, synthesis, and tumor cell growth inhibitory effects of 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosyl derivatives of cytosine (1i, CNDAC), thymine (6a), uracil (6c), and adenine (6d) have been described. The synthesis of the target compounds was achieved from the corresponding 2'-keto nucleosides 2a-d. Cyanohydrins of 2a-d were converted to thionocarbonates, which were deoxygenated to give the desired 2'-beta-cyano-2'-deoxy derivatives 5a-d, followed by deprotection to furnish the target nucleosides. Of these nucleosides, CNDAC was the most potent inhibitor of cell growth with an IC50 value of 0.53 microM against L1210 cells. In vitro cytotoxicity of CNDAC against human tumor cell lines was also examined; compared with that of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-fluorouracil (5-FU), CNDAC was more cytotoxic to several cell lines refractory to ara-C. The in vivo effect of CNDAC on M5076 mouse reticulum cell sarcoma was very strong; 99% tumor volume inhibition on day 20 was achieved when it was administrated orally on days 1, 4, 7, 10, 13, and 16 at a dose of 400 mg/kg/day, while 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-FU caused only 50% inhibition at a dose of 500 mg/kg/day and 28% inhibition at a dose of 50 mg/kg/day, respectively, on the same schedule. These results indicated that CNDAC may have potential as a new antineoplastic agent with a broad antitumor spectrum.
2'-Deoxy-2'-isocyano-1-beta-D-arabinofuranosylcytosine (8, NCDAC) has been synthesized as a potential antitumor antimetabolite from a corresponding 2'-azido-2'-deoxy-1-beta-D-arabinofuranosyluracil derivative 2a. Uracil and thymine analogues 6a and 6b of 8 were also prepared. Attempts to synthesize 2'-deoxy-2'-isocyanocytidine (14b) failed due to the insertion of the 2'-alpha isocyano group into the 3'-OH group, affording the 2',3'-oxazoline derivative 15b. Stability of the isocyano derivative 6a and 2',3'-oxazoline derivative 15a under basic and acidic conditions were examined. The isocyano group in 6a was stable in basic conditions but unstable even in weakly acidic conditions to furnish the corresponding 2'-beta formamide derivative 17. Compound 15a was easily hydrolyzed the corresponding 2'-alpha formamide derivative 16 on treatment with H2O at room temperature. The cytotoxicity of 8, 6a, and 6b was examined in mouse and human tumor cells in vitro and compared with that of ara-C. Of these nucleosides, 8 was moderately cytotoxic to these cell lines. In vivo antitumor activity of 8 against Lewis lung carcinoma cells was also investigated and 8 showed only moderate tumor volume inhibition.
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A spin-trapping method combined with enzymatic digestion and high-performance liquid chromatography was employed to detect hydroxyl-radical-induced precursors of strand breaks in oligonucleotides ((dC)10 and (dT)10) as DNA models. Radicals produced as precursors of both strand breaks and base alterations were first trapped by the spin trap 2-methyl-2-nitrosopropane. The oligonucleotides containing spin adducts were subsequently digested by snake venom phosphodiesterase to release low-molecular-weight nitroxide fragments. In this way, several spin adducts were separated by high-performance liquid chromatography. In both oligonucleotides, ESR spectra attributable to the spin adducts derived from trapping of a precursor radical of strand breaks (the C4'-sugar radical) were observed. To further confirm this assignment, the induction of strand breaks was examined by polyacrylamide gel electrophoresis of 5'-32P-end-labeled oligonucleotides. Autoradiograms of the gels showed that the fragments corresponding to monomers to 9mers were formed in both oligonucleotides. When experiments were carried out under conditions in which hydroxyl radicals reacted with oligomers in the presence of the spin trap, the spin trap was found to suppress the fragmentation more than it did by scavenging hydroxyl radicals, indicating that the precursor radical of strand breaks (the C4' radical) was trapped. The present experiments showed that the spin-trapping method combined with gel electrophoresis was a good approach to identify sites of radical damage which cause strand breaks in oligonucleotides (probably in DNA).
In the IL-2-dependent murine cytotoxic T cell line CTLL-2, IL-2 induced a rapid and transient decrease in Co(2+)-trypsin-treated activity of protein phosphatase PP1. The PP1 activity declined to a minimum level, being 70% of control value, in 20 min after the addition of IL-2 but recovered to the control level within 45 min. The decrease of PP1 activity was dependent on IL-2 concentration and occurred specifically in cytosolic fraction. Similar alteration was observed in IL-2 sensitive murine T-lymphoblasts. Neither activity of protein phosphatase PP2A nor PP2C showed alteration during the IL-2 stimulation. These results suggest that PP1 plays an important role in early events of the intracellular growth signaling from the IL-2 receptor.
We examined the effects of adenosine analogues on the asthmatic reactions induced by the stimulation of capsaicin-sensitive afferent sensory nerves. Intravenous (i.v.) injection of adenosine A2 receptor agonists, 5'-(N-ethylcarboxamido)-adenosine (NECA) and 2-[p-(carboxyethyl)-phenylethylamino]-5'-N-ethylcarboxamido-adenos ine (CGS 21,680), dose dependently inhibited capsaicin-induced guinea-pig bronchoconstriction (1-1000 nmol kg-1), whereas i.v. administration of the adenosine A1 receptor agonist, N6-cyclo-hexyladenosine (CHA), did not affect it (1000 nmol kg-1). Intratracheal injection of NECA (0.05-5 nmol site-1) and CGS 21,680 (0.05-5 nmol site-1) also reduced capsaicin-induced constriction in a dose-dependent manner. However, NECA (1000 nmol kg-1) failed to inhibit substance P-induced guinea-pig bronchoconstriction. NECA (1-1000 nmol kg-1) dose-dependently inhibited cigarette smoke-induced rat tracheal plasma extravasation, but not substance P-induced reaction. NECA (0.1-10 microM) and CGS 21,680 (10 microM) significantly blocked the capsaicin-induced release of substance P-like immunoreactivity from guinea-pig lung, whereas CHA (10 microM) had no effect. This evidence suggests that adenosine A2 receptors modulate negatively the excitation of capsaicin-sensitive afferent sensory nerves and substance P release from their endings in airway tissues.
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