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Biomedical subjects

E Bonmassar

Publications and source records attributed to E Bonmassar.

At least 91 records · Page 5Linked to original sources
PubMed1990

IL-2 reverses the inhibition of cytotoxic T-cell responses induced by 5-(3,3' dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) in vitro.

One of the major limitations in the use of triazene compounds for inducing increased immunogenicity of tumor cells in vivo (i.e. chemical xenogenization) is the profound immunodepressive activity of these drugs. The present study analysed the inhibitory effects of DTIC on various T-dependent immune responses in mice in an attempt to determine the mechanism of action and appropriate treatments for reverting the immune damage produced by the agent. Results obtained show that treatment with DTIC in vivo produced: (a) inhibition of spleen cell proliferation; (b) reduced IL-2 production in response to allogeneic stimuli; (c) reduction of the generation of IL-2R + CD8 + cells in allogeneic MLC; (d) inhibition of allo-CTL generation. The addition of IL-2 to MLC on day 2 of the co-culture restored full allogeneic CTL responses. These data suggest that exogenous IL-2 could be used to counteract DTIC-induced depression of T-cell reactivity, which is presumably involved in hosts' responses against autochthonous xenogenized tumor cells.

Animals↗
PubMed1990

Selection of HTLV-I positive clones is prevented by prostaglandin A in infected cord blood cultures.

Type A prostaglandins (PGA1 and 16,16-dimethyl-PGA2-methyl ester) were found to block the proliferation of HTLV-I infected cord blood lymphocytes (CBL) in vitro, thus preventing the clonal immortalisation that is considered as a predisposing condition to HTLV-I positive leukaemia. PGA1 and di-M-PGA2 did not affect the long-term survival of normal non-infected CBL, whereas they suppressed the proliferation of an established cord-blood derived HTLV-I positive cell line, MT-2. As shown by the number of HTLV-I infected p19+ cells, the block of the selection of immortalised, infected clones by PGAs did not appear to be due to an inhibition of early stages of HTLV-I infection. The possibility that the effect of PGAs could be mediated by an action on the immune response was also examined. PGAs regulated the cell-mediated cytotoxic function of CBL to a different extent when normal non-infected or HTLV-I exposed CBL were compared. In fact, PGAs down-regulated the natural killing and macrophage/lymphocyte cytotoxic response of normal CBL, whereas they did not modify the already depressed immune response of CBL challenged with HTLV-I. These results suggest that the protective effect of PGAs against HTLV-I infection in vitro is mostly related to the direct suppression of the clonal expansion of virus-infected cells, rather than to the anti-viral activity or modulation of the cell-mediated immunity.

Cells, Cultured↗
PubMed1990

Role of biological response modifiers in immunochemotherapy of solid tumors and retroviral-induced leukemia.

Modulation of the immune response by the use of biological response modifiers (BRM) is aimed at amplifying the host resistance against cancer. Studies on inhibition of tumor growth on an in vitro model, in which human breast carcinoma (HBL-100) and human lung carcinoma (H125) cells were used as target tumor cells, confirmed that interferons (IFNs) alpha and beta can amplify the antineoplastic effects of immunochemotherapy by enhancing the cytotoxic activity of effector cells and by antagonizing the immunodepressive effects of radiation or anticancer drugs. Moreover, data obtained from a pilot clinical trial, designed to test the effect of low concentrations of beta-IFN on natural cell-mediated cytotoxicity, pointed out a good correlation between the in vitro and in vivo responsiveness to beta-IFN in cancer patients. The immunomodulating and antiproliferative effects of BRM were also evaluated in a model of viral leukemogenesis in vitro, after infection of cord blood derived mononuclear cells (CB-MNC) with the human leukemic retrovirus HTLV-I. Alpha-and beta-IFN were previously shown to regulate differentially the antiviral competence of recipient CB-MNC, by interfering with viral replication and delaying the emergence of the transformed clone(s). One of the mechanisms of IFN action that contributes to control HTLV-I infection in vitro can be ascribed to their property of partially counteracting the depression of cell-mediated cytotoxicity that follows exposure to HTLV-I. In the light of data previously and herein described, it seems that alpha- and beta-IFN can be considered potential candidates to define combined therapy with antiviral drugs, to control the early stages of retrovirus-associated disease in human pathology.

Antineoplastic Agents↗
PubMed1989

Two antiemetic regimens do not impair chemical xenogenization induced in vivo by 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide.

The possible interference with 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC)-mediated chemical xenogenization (CX) by antiemetic drugs was studied. DTIC was given alone or in combination with either dexamethasone or metoclopramide plus orphenadrine hydrochloride plus diazepam to CD2F1 mice bearing the histocompatible L1210 leukemia. Tumor cells were collected from treated animals and inoculated into histocompatible untreated and drug-treated recipients, for eight transplant generations. More than 50% of intact hosts rejected tumor cells between the fourth and sixth transplant generation, independently of antiemetic treatments. Positive controls treated with DTIC plus quinacrine (QC) confirmed that this antimutagenic compound entirely abrogates CX. The present results point out that the antiemetic regimens investigated in this study do not prevent CX. Since DTIC treatment requires intensive antiemetic support in man, these data are of clinical relevance for CX-oriented immunochemotherapy protocols.

Animals↗
PubMed1989

Natural resistance in mice against Friend leukemia cells. II. Studies with in vivo passaged interferon-sensitive and interferon-resistant cell clones.

Experiments were designed to test the presence of antitumor natural resistance (NR) in DBA/2 mice against highly oncogenic in vivo passaged histocompatible Friend leukemia cells (FLC-V). NR was measured in vivo as rapid clearance of radiolabeled cells from different organs or as growth inhibition in lethally irradiated mice. Interferon-sensitive (745) or interferon-resistant (3C18) lines were used. Organ clearance studies showed that young recipients eliminate cells more rapidly than old mice. Moreover, depressive (e.g., cyclophosphamide or carrageenen) or enhancing (e.g., poly (I:C) or Friend leukemia virus infection) agents of NR function modulate accordingly leukemia cell clearance. Similar results were obtained testing tumor growth in lethally irradiated hosts, although modulating agents were substantially less effective in this system. Both FLC-745-V and FLC-3C18-V lines were equally susceptible to NR. Therefore, these data provide further support to the hypothesis that exogenous IFN capable of suppressing the growth of both lines could act via enhancement of the NR function.

Animals↗
PubMed1989

Natural resistance in mice against Friend cells injected intravenously. III. Comparison between in vivo and in vitro passaged interferon-sensitive (745) and interferon-resistant (3Cl8) cell clones.

In vitro (FLC-Vt) or in vivo (FLC-V) passaged Friend erythroleukaemia cells of DBA/2 origin were tested for susceptibility to natural resistance (NR) in vivo or to NK cell activity in vitro. Scarcely oncogenic FLC-Vt cells were highly susceptible to in vivo NR (measured as rapid organ clearance or growth inhibition in lethally irradiated mice) or to in vitro NK attack. Conversely, highly oncogenic FLC-V cells were weakly susceptible to NR and to NK as well. These data seem to point out that natural immunity, which is up-regulated by endogenous or exogenous interferons, can play a significant role in surveillance against mouse leukaemic cells of retrovirus origin.

Animals↗
PubMed1989

Immunochemotherapy of advanced colorectal cancer with alpha-interferon and 5-fluorouracil. 1. Toxicological studies.

Twelve patients with advanced colorectal cancer were subjected to alternating cycles of treatment with low immunomodulating doses of recombinant alpha-interferon (alpha IFN) + 5-fluorouracil (5FU) or with 5FU alone. Hematological, biochemical and physical evaluation of the patients showed that alpha IFN + 5FU cycles were well tolerated like 5FU alone, except for modest and transient fever following alpha IFN administration. At hematological nadir (day 15-18 of each cycle) lymphocytopenia and granulocytopenia were more pronounced during alpha IFN + 5FU than 5FU cycles. No difference was found for platelet nadir. At the beginning of each cycle complete leukocyte recovery was observed in all cases. Platelet recovery was also complete, although counts were higher after alpha IFN + 5FU than after 5FU alone. Clinical results showed 1 complete remission, 1 partial remission, 5 stable disease and 5 progressive disease. These data point out that low doses of alpha IFN can be safely associated with 5FU. However further studies are required to establish the possible therapeutic value of alpha IFN-mediated immunomodulation for immunochemotherapy of colorectal cancer.

Adult↗
PubMed1988

Comparative studies between in vitro and in vivo effects of human beta-interferon on natural killer activity and its relevance to immunochemotherapy.

A good correlation was found between in vivo and in vitro responses of peripheral MNC from breast cancer patients and the NK boosting effect of human beta IFN. In vitro immunochemistry studies showed that marked antitumor effects were obtained against cultured cancer cells when a widely used chemotherapeutic agent such as 5-FU was combined with nonsensitized spontaneously cytolytic MNC, preactivated in vitro with beta IFN. These results suggest that the in vitro susceptibility assay of MNC to IFNs could be used for predicting favorable responses to immunochemotherapy regimens employing IFNs as immunomodulating agents.

Cytotoxicity, Immunologic↗
PubMed1988

Sister-chromatid exchanges in human lymphocytes exposed to 1-p-(3-methyltriazeno)benzoic acid potassium salt.

The 1-p-(3-methyltriazeno) benzoic acid potassium salt (MTBA) is a triazeno analogue of dacarbazine, an antineoplastic agent capable of mediating the appearance of new antigenic specificities on cancer cells in mice, a phenomenon described as 'chemical xenogenization' (CX). Recently we reported the clastogenic potential of MTBA on human lymphocytes. Since sister-chromatid exchange (SCE) assay is more sensitive than clastogenic tests, at least at low drug concentrations, we assessed SCE frequencies induced by MTBA on human lymphocytes stimulated by PHA. Drug treatment at 2-500 micrograms/ml was performed in vitro prior to or after PHA addition. SCE values increased significantly in a dose-dependent manner up to 200 micrograms/ml. However, SCE frequencies, as well as chromosome breaks, did not increase dramatically. These data indicate that MTBA concentrations used for CX do not cause severe cytogenetic damage to immune cells at least in vitro.

Cells, Cultured↗
PubMed1988

Effect of hydrocortisone on human natural killer activity and its modulation by beta interferon.

It is well known that glucocorticoids depress the natural killer (NK) activity of human peripheral blood lymphocytes when used both in vivo and in vitro. Since interferons enhance natural cytotoxicity, potential interaction between beta-interferon and hydrocortisone hemisuccinate has been investigated using mononuclear cells of peripheral blood obtained from 17 healthy donors. At the end of in vitro treatment mononuclear cells were tested for NK activity against K562 cells in a 4 h 51Cr-release assay. The results suggest that beta-interferon at the optimal treatment schedule (i.e. before and after exposure to hydrocortisone) is capable of abrogating the hydrocortisone-mediated impairment of NK function. These findings provide valuable suggestions for optimal treatment schedules with beta-interferon (i.e. beta-interferon treatment before and after exposure of effector cells to hydrocortisone) for overriding the suppressive effects of glucocorticoid therapy on natural immunity.

Cytotoxicity, Immunologic↗
PubMed1988

Depression of early phase of HTLV-I infection in vitro mediated by human beta-interferon.

Natural human interferon beta (beta-IFN) was tested during the early phase of in vitro infection with HTLV-I virus of human cord blood mononuclear cells (CBL), to evaluate whether its antiviral and immunomodulating effects might prevent spreading of infection in the host. beta-IFN was found to reduce HTLV-I transmission and integration in CBL cultures. Moreover, beta-IFN had no effect in preventing virus transmission and integration in K562 and a very limited effect in HL60 and Molt-4 human tumour lines, suggesting a cell-type specific mode of action. beta-IFN induced a 'priming' response on CBL, since overnight pretreatment of recipient cells or one single treatment at the onset of the coculture were almost equally effective in protecting against HTLV-I infection. During the early days post infection (p.i.), IFN-treated CBL showed a pattern of phenotypic markers that was closer to that of non-infected CBL. In contrast, untreated CBL exposed to HTLV-I showed a percent increase of Tac+, M3+ and Leu 11+ subpopulations. Cell-mediated immune responses of CBL were depressed after coculturing with HTLV-I producer MT-2 cells. beta-IFN was able to boost the cell-mediated cytotoxicity of fresh and infected CBL against both K562 and MT-2 target cells. Leukocyte blastogenesis in mixed lymphocyte/tumour cell cultures, evaluated in terms of 3H-thymidine incorporation during the first week p.i., was also enhanced by IFN when macrophages and lymphocytes were reconstituted at an optimal 1:20 ratio. It is conceivable that this overall enhancement of the immune response induced by beta-IFN could contribute to reduce HTLV-I infection in vitro.

Antigens, Surface↗
PubMed1987

In vitro susceptibility of different human T-cell subpopulations and resistance of large granular lymphocytes to HTLV-I infection.

T4 subpopulation of T lymphocytes is the preferential target of infection with human T leukemia/lymphoma virus of subgroup I (HTLV-I). In this study we attempt to determine whether different T-cell subsets exhibit differences in susceptibility to virus infection. T cells from cord or peripheral blood were separated according to cell densities and T-cell surface markers by Percoll gradient and Sepharose anti-Fab immunoadsorbent affinity column (IAC), respectively. Separated T-cell subpopulations were infected with HTLV-I, by means of co-cultivation with irradiated virus producer cell lines (MT-2, TK). Percentages of HTLV-I-infected cells were assayed by immunofluorescence assay (IFA), using highly specific mouse monoclonal antibody (MAb) directed against HTLV-I p19 core protein. The results showed that different T-cell subpopulations separated either by Percoll or by IAC were susceptible to HTLV-I infection with the exception of large granular lymphocytes (LGL), which exhibit high cell-mediated natural cytotoxicity (CMNC). The susceptibility to HTLV-I infection of T cells with CMNC activity was further studied on established cell clones with LGL morphology. The results showed again that these cells were resistant to the virus infection. The present studies indicate that different T-cell subpopulations, irrespective of their size and of cell-surface markers, are susceptible to HTLV-I infection, with the exception of functionally mature LGL or of immortalized LGL clones.

Cell Separation↗
PubMed1987

Influence of low-dose beta-interferon on natural killer cell activity in breast cancer patients subjected to chemotherapy.

The present study was designed to test whether immunomodulating doses of human beta-interferon would affect the natural cell-mediated cytotoxic function in untreated breast cancer patients or in those subjected to antitumor therapy. Analyses were performed on 11 breast cancer patients, 3 at stage 1 and 8 at stage 2, the latter being subjected to cyclophosphamide, methotrexate, 5-Fluorouracil (CMF) adjuvant chemotherapy. Five patients treated with CMF and 3 patients not subjected to adjuvant chemotherapy, received human beta-interferon (IF, 2 X 10(6) IU/patient, i.m.), on days 0,7, and 15 for 6 cycles of 31 days each. The natural killer (NK) activity (NKA) of peripheral blood mononuclear cells (MNC) was tested 24 and 48 h after low-dose IF administration. The results of NKA determinations carried out for the 6 cycles of treatment show that (1) chemotherapy alone depressed NKA; (2) IF alone increased NKA in stage 1 patients not treated with CMF; (3) IF antagonized the depressive activity of CMF on NK function and significantly augumented NKA in the case of low "basal" cytotocix activity detectable in MNC collected before IF administration. Parallel in vitro studies showed that the inhibitory effect on NKA provoked by CMF is due to cyclophosphamide present in the association and is effectively antagonized by IF. These data provide rational bases for using IF in immunochemotherapy regimens, when tumor cells are supposed to be susceptible to host control by the natural resistance function.

Adult↗
PubMed1987

In vivo natural antitumor resistance against murine EL-4 lymphoma cells in lethally irradiated syngeneic C57Bl/6 mice.

Natural resistance has been detected in lethally irradiated C57Bl/6 (B6) mice inoculated intravenously with the ascites form of a syngeneic B6 leukemia. EL-4 cells were injected into lethally irradiated (800 R) B6 mice and tumor cell proliferation was evaluated by 125IUdR uptake in different organs 4 days after the challenge. Differential growth of lymphoma cells was observed when young mice were injected as compared with older mice and when mice were treated with agents known to interfere with natural resistance (e.g., poly(I:C), FLV-P, carrageenan, cyclophosphamide, high doses of irradiated cells). Similar results were obtained by measuring rapid clearance of 125IUdR-labeled EL-4 cells from lungs of intact B6 mice. In vivo cold competition studies, employing EL-4 and several other tumor lines of the same or different haplotype, showed that only EL-4 and RBL-5 cells were capable of inhibiting syngeneic resistance against EL-4 tumor. On the contrary, YAC-1 lymphoma cells, the most susceptible target to natural killer-mediated cytotoxicity in vitro, did not compete. These results suggest that EL-4 cells express membrane determinants not detectable on normal H-2b parental bone marrow cells and are susceptible to natural resistance against hemopoietic tumor cells in lethally irradiated syngeneic B6 mice.

Animals↗
PubMed1987

Cytogenetic effects of 1-p-(3-methyltriazeno)benzoic acid potassium salt on human lymphocytes in vitro.

The triazene derivative 1-p-(3-methyltriazeno)benzoic acid potassium salt (MTBA) shows pharmacological properties similar to those of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC, trade name dacarbazine), which is known to induce antigenic modulation in tumor cells (xenogenization) and is currently used in cancer therapy. Mutagenic, teratogenic and cancerogenic properties of triazene derivatives have been demonstrated but there is no report on their possible clastogenicity. We describe here the in vitro cytogenetic effects of MTBA on human peripheral blood lymphocytes. The drug was tested at different culture times in a range of concentrations from 2 to 500 micrograms/ml. MTBA caused a dose-dependent increase in the frequency of chromosomal breaks. Different blood donors showed different sensitivity to the treatment. Cell proliferation, as evaluated by [3H]thymidine incorporation, was inhibited at the highest concentrations of the drug. These data might be relevant for comparison with in vivo effects of the drug in clinical trials and to investigate the possible relations between xenogenization induced by MTBA and its genetic and cytogenetic effects in human lymphocytes.

Cell Division↗
PubMed1987

Low concentrations of suramin can reduce in vitro infection of human cord blood lymphocytes with HTLV-I during long-term culture.

In vitro infection of human cord blood lymphocytes (CBL) with human T-cell leukemia/lymphoma virus type I (HTLV-I) was found to be reduced by suramin treatment at a concentration ranging from 10-100 micrograms/ml. At higher concentrations (500 micrograms/ml) suramin was toxic to the cells and even resulted in an increased percentage of cells positive for the p19 viral core protein. Suramin treatment at the onset of the CBL coculture with a lethally irradiated HTLV-I donor cell line (MT-2) reduced virus transmission, evaluated as number of p19+ cells, and the consequent amount of integrated provirus in the host genome. The amount of viral RNA transcripts was not reduced in CBL cocultures. On the other hand, suramin affected HTLV-I replication in infected MT-2 cells, when used at a concentration of 50 micrograms/ml, and this might contribute to the reduced infectivity of suramin-treated MT-2 cells. In addition to its antiviral effects, suramin exerted a modest positive regulation on the natural killing activity of CBL and their early proliferative response in mixed lymphocyte/tumor cell culture.

Antiviral Agents↗