Ryozo Koshiura

Induction of cytotoxicity of peritoneal exudate cells by agrimoniin, a novel immunomodulatory tannin of Agrimonia pilosa Ledeb

SummaryThe cytotoxic activities of the PEC after an i.p. injection of agrimoniin, a tannin contained in Agrimonia pilosa Ledeb. were studied. The plastic nonadherent PEC had significantly higher NK cell activity than the untreated control, and the adherent PEC were cytostatic toward MM2 and MH134 cells. The adherent PEC did not cause tumor cell lysis by themselves, but were cytolytic against MM2 cells in the presence of anti-MM2 sera. In the course of these effects of PEC after the i.p. injection of agrimoniin, the augmentation of NK cell activity was the earliest reaction, reaching a peak at 2 days after the injection; then, cytostatic activity increased. The induction of antibody-dependent cell lytic activity was a later reaction, which reached a peak at 6 days after the injection.

Circumvention of multidrug resistance in P388 murine leukemia cells by a novel inhibitor of cyclic AMP-dependent protein kinase, H-87

A newly synthesized compound, H-87, N-[2-(p-bromo cinnamylmethylamino)ethyl]-5-isoquinolinesulfonamide was found to be a potent and selective inhibitor of cyclic AMP-dependent protein kinase. The effects of H-87 on in vitro sensitivities of various P388 murine leukemia cell lines resistant to several antitumor agents were examined. H-87 significantly potentiated the cytotoxic effects of Adriamycin (ADR), daunorubicin (DAU), vincristine (VCR) and vinblastine (VBL) on P388 cells resistant to these antitumor agents but hardly influenced the effects of mitomycin C (MMC), 5-fluorouracil (5-FU) and cisplatin (CDDP) on ADR-resistant P388 cells (P388/ADR) and P388 phenotypes resistant to the corresponding antitumor agents. H-87 promoted the accumulation of VBL much more in P388/ADR cells than in the sensitive cells by inhibiting the energy-dependent extrusion of the antitumor agent from the cells. These results suggest that this novel isoquinoline-sulfonamide derivative, H-87, overcomes the multidrug resistance by inhibiting the phosphorylation of an outward drug transport system through cyclic AMP-dependent protein kinase.

Correlation Between Hydrophobicity of N‐Alkylxanthine Derivatives and their Biological Activities on Guinea‐pig Isolated Tracheal Smooth Muscle

Abstract— Cyclic (c) AMP phosphodiesterase (PDE) inhibitory activities of N‐alkylxanthine derivatives (3‐methyl‐, 3‐ethyl‐, 3‐propyl‐, 3‐butyl‐, 1,3‐dimethyl‐, 1‐methyl‐3‐ethyl‐, 1‐methyl‐3‐propyl‐and 1‐methyl‐3‐butyl xanthines) and their relaxant effects on carbachol‐induced contraction and on resting tone guinea‐pig isolated tracheal smooth muscle have been investigated. The PDE inhibition constant (Ki) and the concentration producing 50% tracheal smooth muscle relaxation in‐vitro (EC50) were determined. Significant correlations between the ‐log Ki values and the ‐log EC50 values on the carbachol‐induced contraction or on the resting tone were found (r = 0·902 and 0·892). The apparent partition coefficient (P) between n‐octanol and pH 7·4 phosphate‐buffered saline (PBS) was measured as an index of hydrophobicity of the xanthine derivatives. There were significant correlations between log P and both ‐log EC50 values and between the log P and ‐log Ki values. These findings suggest that the cAMP PDE inhibitory activity of N‐alkylxanthine derivatives contributes to the mechanism of bronchodilatory action, and that an increase in hydrophobicity of the xanthine molecule enhances the biological activity.

A comparison of adrenergic receptors of rat ascites hepatoma AH130 cells with those of normal rat hepatocytes

The pharmacological specificity of adrenergic receptors in the plasma membrane of rat ascites hepatoma AH130 cells was compared with that in normal rat hepatocytes. The number of [125I]iodocyanopindolol-binding sites was much greater in AH130 cells than in the hepatocytes. We characterized the alpha-adrenergic receptor subtypes using the alpha 1-selective ligand [3H]prazosin and the alpha 2-selective ligand [3H]clonidine. AH130 cells had fewer prazosin-binding sites than the hepatocytes and about 8 times as many clonidine-binding sites of high affinity. The results showed that the adrenergic receptors in AH130 cells have pharmacological properties that are very different from those of the receptors in normal rat hepatocytes.

Cell Growth Inhibitory Compound from the Culture of Intestinal Lactic Acid Bacteria

The influence of the culture supernatants of 1000 strains of intestinal lactic acid bacteria on the growth of HeLa cells was examined. The compound from Enterococcus faecium 3463 showing the strongest cell growth inhibiting effect in these strains was isolated and identified as tyramine. The effect of tyramine was activated by the newborn bovine sera (NBS), but weakly by the fetal bovine sera (FBS). Benzylamine and beta-phenethylamine also showed the NBS-dependent cell growth inhibitory effect against HeLa cells.