Ubenimex is a low molecular biological response modifier (BRM) which has been demonstrated to have antitumor and immunomodulatory activities. In this study, the effect of ubenimex on infection with Candida albicans was investigated in normal and immunosuppressed mice, and it showed a prophylactic effect. In normal mice, ubenimex prolonged survival time in a dose-dependent manner. In immunosuppressed mice treated with cyclophosphamide 4 days before infection, ubenimex at 5 mg/kg for 5 days significantly increased the number of survivors. Significant improvement in peritoneal leukocyte counts and in function of neutrophils including phagocytosis and release of activated oxygen was observed in ubenimex-treated mice. These results indicate that ubenimex is a potent BRM for prevention against opportunistic infections.

Animals↗

PubMed1992

Inhibition of tumor invasion and extracellular matrix degradation by ubenimex (bestatin).

We have investigated the effect of the immunomodulator ubenimex (hereafter referred to as bestatin) on the enzymatic degradation of the extracellular matrix by human renal cell carcinoma SN12M cells during the invasive process. The invasion of SN12M cells into reconstituted basement membrane (Matrigel) was inhibited by the presence of bestatin in a concentration-dependent manner. However, bestatin did not have any effect on tumor cell adhesion and migration to the extracellular matrices which may be involved in tumor cell invasion. Bestatin inhibited the degradation of type IV collagen by tumor cells, but not by tumor-conditioned medium (TCM), in a concentration-dependent manner. We also found that bestatin inhibited hydrolysing activities towards substrates of aminopeptidases in SN12M cells. Since bestatin was found to inhibit aminopeptidase activity, the inhibition of tumor invasion by bestatin is likely to be associated with its action as an enzyme inhibitor. Bestatin only slightly inhibited tumor cell plasmin activity, which can lead to the conversion of the latent collagenase to the active form, but this slight effect was not significant. The zymography of TCM from SN12M cells showed that the treatment of tumor cells with bestatin resulted in the disappearance of the 68 kDa type IV collagenase-enzyme level (active form) and slight reduction of the 72 kDa type IV collagenase-enzyme level (latent form). These results indicated that bestatin may inhibit tumor cell invasion through a mechanism involving its inhibitory action on aminopeptidases in tumor cells, suggesting that the aminopeptidase may partly be associated with the conversion of a latent form of type IV procollagenase to an active form or the secretion of the collagenases from tumor cells.

Adult↗

PubMed1992

Deoxyspergualin, a novel immunosuppressant, markedly inhibits human mixed lymphocyte reaction and cytotoxic T-lymphocyte activity in vitro.

Deoxyspergualin (DSG) has demonstrated potent immunosuppressive activities in vivo. However, because of its lability in culture medium, the mechanism of activity has not yet been identified in vitro. In this study, a more stable analogue, deoxymethylspergualin (MeDSG), was used to investigate the in vitro immunosuppressive activity of DSG. MeDSG suppressed both human mixed lymphocyte reaction (MLR) and cytotoxic T-lymphocyte (CTL) activity at doses greater than 0.1 micrograms/ml in vitro. In kinetics studies, MeDSG was found to suppress a MLR when added on day 3 of a 7 day MLR incubation but cyclosporin A (CYA) suppressed a MLR only when added during the initial stage of a MLR (i.e. on day 1). In studies of cell surface phenotype in the MLR, MeDSG treatment decreased the numbers of CD8+ lymphocytes but those of CD4+ lymphocytes were not affected. In addition, MeDSG had no significant effect on interleukin-2 (IL-2) receptor expression or IL-2 production. These results suggest that MeDSG suppresses the T-cells which are proliferating competent cells such as cytotoxic T-cells (CD8+), but has a different mode of immunosuppressive action compared with CYA.

Cyclosporine↗

PubMed1992

Myeloprotective activity of deoxyspergualin: influence on splenic colony-forming cell injury and antitumor activity of mitomycin C in mice.

We have examined the efficacy of deoxyspergualin (DSG) in protecting splenic colony-forming cells (CFU-S) from mitomycin C (MMC)-induced damage. The main findings of the study are as follows. (1) When DSG was administered at doses of 1.5 and 3 mg/kg for 7 days before the MMC injection, the decrease of the femoral CFU-S caused by MMC was diminished on the day after the MMC injection. The optimal dose was found to be 3 mg/kg. (2) In animals receiving 3 mg/kg DSG for at least 3 days preceding the MMC injection, the femoral CFU-S was more than 200% of that in the MMC alone group one day after the MMC injection. (3) The number of femoral CFU-S in the mice which received 3 mg/kg DSG for 3 days prior to MMC was significantly restored day by day and reached 70% of normal at 5 days after the MMC injection, while it was only 13% of normal in the MMC alone group. Moreover, the prior DSG administration significantly diminished the MMC toxicity to circulating platelets. (4) DSG administration (3 mg/kg) 3 days prior to MMC did not weaken the antitumor activity against colon 26 adenocarcinoma or P388 leukemia when compared with MMC alone. These findings have shown the ability of DSG specifically to protect the animals against bone marrow toxicity caused by MMC without interfering with the antitumor activity.

Adenocarcinoma↗

PubMed1992

Oxygenated anodendrosins from the seeds of Anodendron affine (studies on Anodendron. XI).

Explore the source record for details and available documents.

Carbohydrate Sequence↗

PubMed1992

Relationship between oxygen sensitivity and oxygen metabolism of Bifidobacterium species.

Bifidobacteria, which are obligate anaerobes, were studied to determine the relationship between their sensitivity to oxygen and oxygen metabolism. Among the four species tested, Bifidobacterium infantis, Bifidobacterium breve, and Bifidobacterium longum differed from Bifidobacterium adolescentis in sensitivity to oxygen. The former three species showed marked growth under conditions of partial aeration, whereas the growth of B. adolescentis was suppressed by low concentrations of oxygen. Bifidobacteria express reduced NAD-oxidase and -peroxidase activities, which function in a pathway for two-electron reduction of molecular oxygen, producing hydrogen peroxide and, subsequently, water. Activities of reduced NAD-oxidase and -peroxidase were inversely correlated with their sensitivities to oxygen. Bifidobacterium adolescentis exhibited lowered activities of these two enzymes; the activities were 10 to 20% of those observed with B. infantis, B. breve, and B. longum. These observations are compatible with the hypothesis that reduced NAD-oxidase and reduced NAD-peroxidase in Bifidobacterium species play a role in prevention of oxygen toxicity. Superoxide dismutase activity was also detected in Bifidobacterium species. Superoxide dismutase is probably not involved in detoxification of oxygen, because the activity of this enzyme was extremely low, and the sensitivity to oxygen varied independently of superoxide dismutase activity.

Bifidobacterium↗

PubMed1992

Enhancement by ubenimex (bestatin) of host resistance to Candida albicans infection.

Ubenimex is a low molecular weight microbial metabolite which has been demonstrated to have antitumor and immunomodulatory activities. In this study, the protective effect of ubenimex on Candida albicans infection was investigated in normal and immunosuppressed mice. In normal mice, treatment with ubenimex at 0.5, 5 and 25 mg/kg for 5 days prior to infection prolonged survival time in a dose-dependent manner. In immunosuppressed mice treated with a single dose of cyclophosphamide 4 days prior to infection, ubenimex treatment at 5 mg/kg for 5 days significantly increased the number of survivors. Ubenimex-treated mice had a significant increase in number of peritoneal exudate cells with neutrophils as well as enhanced functions, including phagocytosis and active oxygen production. These results suggest the potential usefulness of ubenimex as a prophylactic agent for the management of patients with opportunistic fungal infections.

Animals↗

PubMed1992

[Creatine kinase activity and its isozyme levels in cord blood].

We measured creatine kinase (CK) levels of cord blood and evaluated them in relation to the degree of maturity and distress. The reference value of CK of cord blood in normal neonates was 209 +/- 99 U/l (mean +/- SD) and the percent values of the isoenzymes, CK-MM, CK-MB and CK-BB, were 86.7 +/- 6.2%, 5.1 +/- 2.6%, and 8.1 +/- 5.4%, respectively. There was a positive correlation between the birth weight and CK, CK-MM, CK-MB and CK-BB levels of cord blood. The CK and CK-MM levels of cord blood in the neonates who were prematurely delivered and small-for-date were significantly lower than those in normal controls. The CK and CK-MM levels of cord blood in the neonates with low Apgar scores, 6-4 and 3-0, were 172 +/- 74, 145 +/- 73 and 104 +/- 63, 92 +/- 55 U/l, respectively, which were significantly lower than those in the neonates with the high scores (10-7), 208 +/- 104, 183 +/- 92 U/l. The neonates with distress showed the low CK and CK-MM values, 76 +/- 12 and 61 +/- 8 U/l. The CK and CK-MM levels of cord blood tended to decrease with prolongation of labor, but did not differ from each other among the neonates delivered by different modes. These results suggest that the CK and its isoenzyme levels are good indicators for the degree of maturity of neonates and the severity of neonatal distress.

Creatine Kinase↗

PubMed1992

Therapeutic activity of deoxyspergualin in comparison with cyclosporin A, and its combined use with cyclosporin A and prednisolone in highly allogeneic skin transplantation in the rat.

The present paper demonstrates the efficacy of a novel immunosuppressive agent, deoxyspergualin (DSG), in rat skin transplantation despite major histocompatible antigen differences, both by itself and in combination with cyclosporin A (CyA) and prednisolone (PD). DSG significantly prolonged the median survival time (MST) of WKAH skin on F344 rats, when given at daily doses of 1.5-12 mg/kg i.p. for 10 days starting from day one after grafting. A significant increase of the MST has been observed also in the rats orally receiving CyA at daily doses of 12.5-50 mg/kg according to the same dosing protocol. DSG was as effective as CyA in prolonging the MST. In contrast, when treatment started 4 days after grafting (at the time of the rejection crisis), DSG (6 mg/kg) was able to reverse the rejection, whereas CyA (50 mg/kg) was not. When DSG (1.5 mg/kg) and CyA (6.25 or 12.5 mg/kg) were given together from day one after grafting, the combined therapy was superior to each monotherapy. Similarly, when DSG (1.5 mg/kg) and PD (10 mg/kg) were given simultaneously from the rejection crisis, the combined therapy was demonstrated to have stronger activity than any of the monotherapies. Moreover, the skin-allografted rats could be switched successfully either from CyA to DSG treatment or from DSG to CyA treatment.

Animals↗

PubMed1991