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T Utsugi

Publications and source records attributed to T Utsugi.

At least 73 records · Page 4Linked to original sources
PubMed1991

Prostaglandin E2 does not inhibit tumoricidal activity of mouse macrophages against adherent tumor cells.

We determined whether endogenously produced PGE2 can down-regulate the tumoricidal properties of macrophages by a negative feedback mechanism. Peritoneal exudate macrophages or resident peritoneal macrophages of mice were incubated in medium (control) or in medium containing IFN-gamma and LPS. Activated macrophages were highly tumoricidal against syngeneic melanoma cells and secreted high levels of PGE2. Treatment with indomethacin or diclofenac sodium (voltaren) completely inhibited the production and secretion of PGE2 but not the tumoricidal activity of activated macrophages measured either immediately after activation or 1 to 3 days thereafter. Finally, the addition of exogenous PGE2 did not alter the ability of peritoneal exudate macrophages to respond to IFN-gamma or of LPS to produce high levels of tumor cell lysis. Collectively, these results show that PGE2 produced by activated macrophages is not a down-regulator of their tumoricidal activity against adherent tumor cells.

Animals↗
PubMed1991

In situ activation of mouse macrophages and therapy of spontaneous renal cell cancer metastasis by liposomes containing the lipopeptide CGP 31362.

We determined whether the intravenous administration of multilamellar vesicle liposomes (MLV) containing a lipopeptide analogue of a fragment from the cell wall of gram-negative bacteria (CGP 31362) can render BALB/c mouse alveolar macrophages tumoricidal in situ and reduce the incidence of spontaneous lung metastasis of syngeneic renal carcinoma (RENCA) cells. Alveolar macrophages (a) incubated in vitro with MLV containing CGP 31362 (MLV-31362) and (b) harvested from mice injected i.v. with MLV-31362 were rendered cytotoxic against the RENCA cells. Maximum cytotoxic activity of the macrophages was induced by injecting 5 mumol MLV consisting of 250 mg phospholipids and 0.5 mg CGP 31362. The single i.v. injection of 5 mumol MLV-31362 produced activation of macrophages that lasted for up to 4 days. Repeated i.v. injections of MLV-31362 produced a continuous antitumor activity in alveolar macrophages. To study the lipopeptide's effects on metastasis, we injected the left kidneys of BALB/c mice with RENCA cells. The kidney with growing tumor was resected 10 days later and, after a further 2 days, groups of mice were injected i.v. with MLV-31362 or with MLV-HBSS (twice weekly for 3 weeks). Treatment with MLV-31362 significantly decreased the median number of spontaneous lung metastases. These data demonstrate that the systemic administration of MLV-31362 can activate murine lung macrophages in situ and reduce the incidence of spontaneous RENCA lung metastases.

Adjuvants, Immunologic↗
PubMed1991

Comparative efficacy of liposomes containing synthetic bacterial cell wall analogues for tumoricidal activation of monocytes and macrophages.

We examined the activation to the tumoricidal state of normal mouse peritoneal exudate macrophages, bone marrow macrophages, and human blood monocytes by liposomes containing either lipophilic muramyl tripeptide (CGP 19,835) or a new synthetic analogue of lipoprotein from gram-negative bacteria outer wall, CGP 31,362, or combinations of the two. The superiority of liposomes containing the synthetic lipopeptide over liposomes containing lipophilic muramyl tripeptide for in vitro activation of monocytes and macrophages was demonstrated in several experiments. First, liposome-CGP-19,835 activated monocytes only in the presence of interferon-gamma, whereas activation with liposome-CGP 31,362 was interferon-independent. Second, activation of both mouse macrophages and human blood monocytes by liposome-CGP 31,362 occurred at a lower liposomal concentration than that by liposome-CGP 19,835. Third, monocytes incubated with liposome-CGP 31,362 released both tumor necrosis factor (TNF) and interleukin-1 activities, whereas monocytes treated with liposome-CGP 19,835 (in the absence of interferon-gamma) released only TNF activity. These data suggest that liposomes containing the synthetic lipopeptide CGP 31,362 are superior to liposomes containing CGP 19,835 for systemic activation of macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Optimization of the liposomes encapsulating a new lipopeptide CGP 31362 for efficient activation of tumoricidal properties in monocytes and macrophages.

The purpose of this study was to optimize a suitable liposomal carrier for CGP 31362, a new synthetic lipopeptide analogue of gram-negative bacterial cell walls. CGP 31362 was inserted into the membranes of different liposomes with different phospholipid composition. We determined the ability of these liposomes to activate tumoricidal properties in mouse peritoneal and bone marrow macrophages, and in human monocytes. The ideal liposome carrier for CGP 31362 consisted of phosphatidylcholine and phosphatidylserine in a 7:3 molar ratio. Subsequent to efficient binding and endocytosis, CGP 31362 in liposomes of this composition rendered mouse macrophages and human monocytes highly tumoricidal. Moreover, even in the absence of interferon-gamma, human monocytes released significant levels of tumor necrosis factor and interleukin-1. These data show that in a suitable liposomal carrier, the new synthetic lipopeptide in liposomes is a potent activator of tumoricidal properties in macrophages.

Animals↗
PubMed1991

In situ activation of mouse lung macrophages by coadministration of liposomes containing the lipopeptide CGP 31362 and interleukin 2 involves interaction with T lymphocytes and natural killer cells.

These studies were undertaken to determine the mechanism for augmented tumoricidal activity of alveolar macrophages (AM) in mice injected intravenously with multilamellar liposomes containing a lipopeptide analogue of Gram-negative bacteria cell wall (MLV-CGP 31362) and intraperitoneally with interleukin 2 (IL-2). BALB/c mice were injected into the kidney with syngeneic renal carcinoma cells. Ten days later, this kidney was resected, and the mice were treated intravenously with MLV-CGP 31362 and/or intraperitoneally with IL-2. Treatment with MLV-CGP 31362 led to a reduction in the number of lung metastases, whereas treatment with IL-2 alone did not. The coadministration of intravenous liposomes and intraperitoneal IL-2 produced significant eradication of lung metastases. MLV-CGP 31362 (iv) and IL-2 (ip) were injected both into control immune-competent and nude mice or into mice whose natural killer (NK) cells had been depleted by systemic administration of anti-asialo GM1 antibodies. MLV-CGP 31362 activated tumoricidal properties in AM of all groups of mice. The additive tumoricidal activation of AM by IL-2 was associated with its effects on both T cells and NK cells.

Animals↗
PubMed1990

Potentiation of topoisomerase inhibitor-induced DNA strand breakage and cytotoxicity by tumor necrosis factor: enhancement of topoisomerase activity as a mechanism of potentiation.

A combination of tumor necrosis factor (TNF) and the topoisomerase I inhibitor, camptothecin, or the topoisomerase II inhibitors, teniposide and amsacrine, produced dose-dependent synergistic cytotoxicity against the murine L929 fibrosarcoma cells. Similar synergy was not observed with a combination of TNF and bleomycin. To define the role of TNF in the augmentation of tumor cell killing by topoisomerase I or II inhibitors, the effect of TNF on the production of enzyme-linked DNA strand breaks induced in cells by topoisomerase inhibitors was investigated. L929 cells incubated for 1 h with the topoisomerase inhibitors contained protein-linked strand breaks. In contrast, TNF alone did not induce DNA strand breakage. However, when cells were incubated simultaneously with TNF and camptothecin, amsacrine, Adriamycin, actinomycin D, teniposide, or etoposide, increased numbers of strand breaks were produced. Preincubation of the cells with TNF for 30 min or 3 h before the addition of camptothecin or etoposide resulted in no more strand breaks than that observed in cells incubated with the drugs alone. TNF treatment of L929 cells produced a rapid and transient increase in specific activity of extractable topoisomerases I and II. These increases were maximum at 2-5 min of TNF treatment and by 30 min the activities of extractable enzymes were equal to or less than those detected in extracts from untreated cell controls. The transient nature of the increase in extractable topoisomerase activity may explain the kinetics and significance of the order of addition of TNF and inhibitors for maximal synergistic activity. These data are consistent also with a role for topoisomerase-linked DNA lesions in the TNF-mediated potentiation of killing of L929 cells by topoisomerase inhibitors.

Amsacrine↗
PubMed1990

Tumor cytotoxicity and interleukin 1 production of blood monocytes of lung cancer patients.

The effects of lung cancer on the abilities of blood monocytes to produce interleukin-1 and to mediate antitumor activity were examined. The functional integrity of blood monocytes was determined by their capacity to respond in vitro to a variety of activating agents and become tumoricidal, as assessed by a radioactive release assay and ability to produce interleukin-1 in vitro. The results show that the presence of lung cancer significantly increased the number of harvested blood monocytes and that the spontaneous tumoricidal activity of these monocytes was slightly high as compared to monocytes obtained from healthy donors. The production of interleukin-1 by monocytes of healthy donors and lung cancer patients was similar. Blood monocytes obtained from lung cancer patients were less cytotoxic against allogeneic A375 melanoma cells as compared with those of healthy donors subsequent to incubation with a soluble muramyl dipeptide analog or lipopolysaccharide, but were as tumoricidal as those from healthy donors when activated with lipophilic muramyl tripeptide (MTP-PE) entrapped in multilamellar liposomes. The finding that monocytes of patients with lung cancer can respond to MTP-PE encapsulated in liposomes, recommends the use of these liposomes in therapy of human lung cancer.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Differential release of TNF-alpha, IL 1, and PGE2 by human blood monocytes subsequent to interaction with different bacterial derived agents.

The purpose of these studies was to determine whether the tumoricidal phenotype of human blood monocytes would be affected by different activation signals. Human monocytes obtained by elutriation of buffy coats were cultured in vitro in medium containing LPS, muramyltripeptide phosphatidylethanolamine (MTP-PE), or a lipopeptide analogue of gram-negative bacteria cell wall. These immunomodulators were added to monocytes in the presence or absence of IFN-gamma. Incubation with LPS, lipopeptide, and MTP-PE rendered the monocyte cytotoxic against allogeneic melanoma cells. Monocytes treated with LPS and lipopeptide (in the absence of IFN-gamma) secreted IL 1, TNF, and PGE2. In contrast, monocytes incubated with MTP-PE (in the absence of IFN-gamma) secreted only TNF. When the monocytes were coincubated with IFN-gamma (human but not mouse) and the immunomodulators, IL 1, TNF, and PGE2 were secreted at all test groups. These data show that some immunomodulators can regulate the release of TNF independently of IL 1 and that not all "activated tumoricidal macrophages" share identical phenotypes.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Synergistic antitumor effects of topoisomerase inhibitors and natural cell-mediated cytotoxicity.

The mechanism of augmentation of tumor cell killing by immune effector cells and chemotherapeutic drugs was studied. The effect of treating tumor cells with various antineoplastic drugs on their sensitivity to murine natural cell-mediated cytotoxicity in vitro was investigated. Pretreatment with actinomycin D at nontoxic concentrations rendered L929 and WEHI-164 tumor cells more susceptible to killing by mouse spleen lymphocytes in a dose-dependent manner. Similarly, enhancement of L929 tumor cell killing by natural cell-mediated cytotoxicity was observed following treatment of the target cells with the topoisomerase II inhibitors, Adriamycin, amsacrine, bisantrene, etoposide, and teniposide, as well as with topoisomerase I inhibitor, camptothecin. In contrast, drugs which induce their cytotoxic effects by mechanisms that do not involve topoisomerase inhibition such as bleomycin, vinblastine, vincristine, and mitomycin C failed to exhibit synergism with natural cell-mediated cytotoxicity. However, moderate synergy was consistently observed with cis-platinum. The effector cells responsible for the cytotoxicity in the present system are natural cytotoxic cells since they kill WEHI-164 but not YAC cells, are resistant to treatment with anti-asialo-GM1 antibody, and their activity is abolished by anti-tumor necrosis factor antibodies. Indeed, tumor necrosis factor-mediated cytotoxicity of WEHI-164 or L929 was enhanced by treatment of the target cells with topoisomerase II inhibitors. Moreover, WEHI-164 cells selected for tumor necrosis factor resistance were resistant to natural cell-mediated cytotoxicity, and no synergy could be observed with topoisomerase inhibitors.

Animals↗
PubMed1989

Effector mechanism of human monocyte-mediated cytotoxicity: role of a new tumor cytotoxic factor distinct from interleukin 1 and tumor necrosis factor alpha.

Human blood monocytes activated to the tumoricidal state were previously found to release a factor(s) responsible for tumor cell killing. The activity of the tumor cytotoxic factor(s) (TCF) was determined by release assay of radioactivity from human A375 melanoma cells. On fractionation of the supernatant of activated monocytes by Ultrogel AcA34 and TSK-G3000SW gel chromatographies two major peaks of the material with TCF activity with MWs of 30,000 and 15,000, called TCF-I and TCF-II, respectively were obtained. TCF-II could be neutralized by polyclonal anti-IL-1 beta antiserum, but anti-IL-1 alpha antiserum did not neutralize either factor. TCF-I was separated by ampholine column electrofocusing into three major fractions with TCF activity at pI 5, 6 and 6.8, named TCF-1 alpha, TCF-1 beta and TCF-1 gamma, respectively. The cytotoxic and IL-1 activities of TCF-1 alpha were neutralized by anti-IL-1 alpha serum, whereas those of TCF-1 beta and TCF-1 gamma were not completely neutralized by anti-IL-1 alpha or anti-IL-1 beta antiserum. On DEAE ion-exchange chromatography (TSK DEAE 5PW) TCF-I beta gave two peaks with TCF activity (TCF-I beta 1 and TCF-I beta 2). TCF-I beta 1 was slightly neutralized by anti-TNF alpha antibody, but TCF-I beta 2 was not affected by antisera against IL-1 alpha and IL-1 beta, or anti-TNF alpha antibody, thus ruling out the possibility that tumor necrosis factor (TNF alpha) might be involved in tumor cell killing mediated by TCF-I beta 2. These results indicate that human monocyte-mediated cytotoxicity against human A375 melanoma cells is mediated in part by a tumor cytotoxic factor (TCF; MW, 30,000; pI 6), differing from IL-1 and TNF alpha.

Cell Survival↗
PubMed1989

Value of vectorcardiography in predicting progress in dilated cardiomyopathy.

Sixteen of 75 patients with dilated cardiomyopathy (DCM) died during a mean follow-up period of 39.7 months. In non-survivors, the cardiothoracic ratio and the left ventricular end-diastolic dimensions were greater, the left ventricular end-diastolic pressures were more elevated, and the cardiac index was lower than in the survivors at the time of initial diagnosis. There were no significant differences between survivors and non-survivors in the magnitude of the maximum QRS and T vectors or in the maximum T angle. In the non-survivors, the maximum QRS vector was directed more posteriorly and the width/length ratio of the loop in the horizontal plane was smaller than in survivors. The QRS loop in the horizontal plane was often distorted in non-survivors or showed a bizarre figure-of-eight configuration. It appears that in DCM a marked posterior displacement of a QRS loop that is narrow and distorted or is in a bizarre figure-of-eight configuration in the horizontal plane indicates an unfavorable prognosis.

Adult↗
PubMed1988

Differential effects of recombinant interferons alpha, beta, and gamma on induction of human lymphokine (IL-2)-activated killer activity.

The effects of three classes of recombinant interferons (IFN-alpha A, IFN-beta, and IFN-gamma) on maximal induction of lymphokine (IL-2)-activated killer (LAK) activity were studied. Highly purified lymphocytes (greater than 99%) were obtained by counter-flow centrifugal elutriation from peripheral blood of healthy donors. After incubation for 4 days with IL-2 (1 U/ml), purified lymphocytes showed maximal LAK activity against NK cell-resistant target (Daudi) cells, as assessed by 4-hour 51Cr release assay. Addition of exogenous IFN-alpha A or IFN-beta to cultures of lymphocytes plus IL-2 resulted in significant inhibition of LAK activity, but addition of IFN-gamma had no effect on LAK induction by IL-2. IFN-alpha A caused greatest inhibition of LAK activity when added at the start of culture of lymphocytes with IL-2, and was less inhibitory when added 1 day later. Similar inhibition by IFN-alpha A or IFN-beta was observed with nine lines of human tumorigenic cells as targets of LAK activity. IFN-alpha A and IFN-beta also inhibited the proliferative responses of lymphocytes to IL-2 stimulation, and the expression of IL-2 receptors on their surface, whereas IFN-gamma did not. These results suggest that IFN-alpha A and IFN-beta may be important in in situ regulation of LAK cell induction against neoplasms.

Humans↗
PubMed1988

Up- and down-regulation of human lymphokine (IL-2)-activated killer cell induction by monocytes, depending on their functional state.

Studies were made to determine whether freshly isolated monocytes from healthy donors could influence the induction of lymphokine (IL-2)-activated killer (LAK) activity. Highly purified lymphocytes (greater than 99%) and monocytes (greater than 90%) were isolated by counter-flow centrifugal elutriation from peripheral blood. Lymphocytes incubated for 4 days with IL-2 showed significant LAK activity against natural killer (NK) cell-resistant target (Daudi) cells, whereas monocytes treated for 4 days with IL-2 and/or IFN-gamma were not cytotoxic. Under the experimental conditions used, addition of monocytes to the lymphocyte cultures resulted in significant augmentation of the LAK activity, depending on the density of monocytes added. In contrast, monocytes stimulated by lipopolysaccharide (LPS) markedly suppressed LAK activity induced by IL-2, depending on the dose of LPS added. Similar up- and down-regulations of LAK cell induction by monocytes were observed with 4 lines of human lung cancer cells as targets for LAK activity. Although supernatants from untreated monocytes did not increase LAK induction, supernatants from LPS-stimulated monocytes suppressed LAK induction. The regulatory role of monocytes could not be replaced by the addition of exogenous interleukin I (IL-I) or tumor necrosis factor (TNF). Prostaglandin E did not seem to play a regulatory role, since addition of indomethacin did not affect the regulation of LAK cell induction by monocytes. These results clearly indicate that human monocytes may cause up- or down-regulation of the expression of IL-2-induced LAK activity, depending on their functional state.

Adenocarcinoma↗
PubMed1988

Dose-response relationship for translocation induction in spermatogonia of the crab-eating monkey (Macaca fascicularis) by chronic gamma-ray-irradiation.

The induction of reciprocal translocations in spermatogonia of the crab-eating monkey (Macaca fascicularis) by chronic gamma-irradiation (1.8 x 10(-5) Gy/min, about 0.024 Gy/22 h/day) was examined. The frequencies of translocation per cell were 0.15% at 0.3 Gy, 0.27% at 1.0 Gy and 0.33% at 1.5 Gy. The dose-response relationship for translocation yield was a linear one with a regression coefficient (b) of 0.16 x 10(-2). When the slope (b) of the regression line was compared with that at a high dose rate (0.25 Gy/min, b = 1.79 x 10(-2), it was clear that the induction rate of translocations after chronic gamma-irradiation was only about one-tenth of that after high-dose-rate irradiation. Thus, there was evidence for a pronounced dose-rate effect in the crab-eating monkey.

Animals↗
PubMed1987

Effects of human alveolar macrophages on the induction of lymphokine (IL 2)-activated killer cells.

Normal human alveolar macrophages (AM) significantly and reproducibly suppress induction of IL 2-activated killer (LAK) cell activity against allogeneic Burkitt's lymphoma (Daudi) cells. Incubation of purified peripheral blood lymphocytes for 4 days with autologous AM and 1 U/ml of IL 2 resulted in AM-mediated suppression of LAK activity, whereas peripheral blood monocytes isolated freshly by centrifugal elutriation from the same donor potentiated induction of LAK activity by IL 2. The suppression of LAK cell induction by human AM was dependent on the density of AM added to the lymphocyte cultures. Recombinant IFN-gamma did not affect AM-mediated suppression of LAK cell induction by IL 2. Both AM and monocytes stimulated with lipopolysaccharide markedly suppressed LAK cell induction by IL 2. AM-mediated down-regulation was seen only when AM were added immediately after the start of incubation of lymphocytes with IL 2; AM potentiated LAK activity when added 1 day later. Similar AM-mediated suppression of LAK cell induction was observed with four lines of allogeneic lung cancer cells as targets for LAK activity. These results indicate that AM may be important in regulation of in situ induction of LAK activity in the lung.

Cells, Cultured↗
PubMed1986

Synergism of recombinant human interferon gamma with liposome-encapsulated muramyl tripeptide in activation of the tumoricidal properties of human monocytes.

Freshly isolated human peripheral blood monocytes from healthy volunteers are not cytotoxic to allogeneic A375 melanoma cells, but they were rendered tumoricidal by incubation in vitro with either liposomes containing 5 micrograms/mumol phospholipid of muramyl tripeptide phosphatidylethanolamine (liposome-MTP-PE; optimal dose, 500 nmol/ml) or recombinant human interferon gamma (rIFN-gamma; optimal dose, 100 U/ml). A combination of sub-threshold concentrations of liposome-MTP-PE (50 nmol/ml) and rIFN-gamma (1 or 10 U/ml) also induced significant tumor-cell killing, indicating that the effects of rIFN-gamma and liposome-MTP-PE in monocyte activation are synergistic. In contrast to rIFN-gamma, recombinant IFN-alpha and IFN-beta had additive effects with liposome-MTP-PE in human monocyte activation. Since recombinant human IFN-gamma has a synergistic effect with liposome-MTP-PE in monocyte activation, unlike IFN-alpha or IFN-beta, and liposome-MTP-PE as well as rIFN-gamma is available at standardized concentrations, this combination could be of clinical value in the treatment of disseminated malignant disease.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Comparative analysis of the priming effect of human interferon-gamma, -alpha, and -beta on synergism with muramyl dipeptide analog for anti-tumor expression of human blood monocytes.

Freshly isolated human peripheral blood monocytes from healthy volunteers were not cytotoxic to allogeneic A375 melanoma cells, but they were activated to the cytotoxic state by incubation in vitro with either des-methyl muramyl dipeptide (norMDP; minimal effective dose, 0.5 micrograms/ml) or recombinant human interferon-gamma (rIFN-gamma; minimal effective dose, 1 U/ml). A combination of subthreshold concentrations of these agents (norMDP, 0.5 micrograms/ml; rIFN-gamma, 10 U/ml) also induced significant cytotoxicity, indicating that the effects of norMDP and rIFN-gamma in monocyte activation are synergistic. Natural human IFN-gamma (nIFN-gamma) and norMDP also had similar synergistic effects. Pretreatment of rIFN-gamma with anti-IFN-gamma antibody completely inhibited its synergistic effect with norMDP in monocyte activation. Because pretreatment of rIFN-gamma and norMDP with polymyxin B did not interfere with their effects in monocyte activation, the preparations were not contaminated with lipopolysaccharide. Moreover, because pretreatment of monocyte monolayers with anti-Leu-11b antibody (anti-natural killer (NK) cell antibody) and complement did not interfere with the synergistic effects of norMDP and rIFN-gamma, whereas pretreatment with anti-Leu-M1 antibody (anti-monocyte antibody) caused complete inhibition of their effects, the observed tumor cytotoxicity of monocyte-rich monolayers was probably not due to a small number of adherent NK cells, but to the stimulation of the monocytes. Natural and recombinant IFN-alpha and IFN-beta at concentrations of greater than or equal to 100 U/ml also induced tumoricidal activity of monocytes, but unlike IFN-gamma, their effects were additive with norMDP, and they had less priming effect than IFN-gamma when they were added before norMDP to monocytes. These findings suggest that recombinant human IFN-gamma has much more synergistic potential with norMDP than IFN-alpha or IFN-beta, and this synergism of rIFN-gamma and norMDP for monocyte activation could be of clinical value in treatment of disseminated malignant diseases, because these compounds are readily available at standardized concentrations.

Acetylmuramyl-Alanyl-Isoglutamine↗