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PubMed1983

Studies on the induction and expression of T cell-mediated immunity. XIV. Antigen-nonspecific oxidation-dependent cellular cytotoxicity (ODCC) mediated by sodium periodate oxidation of cytotoxic T lymphocytes.

Alloimmune murine thymus-derived cytotoxic lymphocytes (CTL) generated in vivo or in vitro are shown to lyse antigen-nonspecific target cells (tumor cells, Con A, and LPS blasts) following treatment of CTL with an oxidizing agent, sodium periodate (NaIO4). It has been shown that NaIO4 oxidizes terminal sialic acid residues of cell surface macromolecules. The presence of reactive aldehyde groups, generated by NaIO4 modification, is required for the expression of antigen-nonspecific cytotoxicity because treatment of modified cells with a reducing agent such as potassium borohydride (KBH4) resulted in the abrogation of cytotoxicity. However, KBH4 treatment of unmodified or NaIO4-modified CTL has no effect on antigen-specific cytotoxicity. The modification of CTL by NaIO4 is sufficient to lead to the formation of lymphocyte-target cell conjugates and lysis of bound targets. Monoclonal antibodies directed against the Lyt-2 antigens of CTL, but not Lyt-1 antigens, in the absence of complement inhibited the nonspecific cytotoxicity resulting from NaIO4 modification of effector lymphocytes. These findings suggest that the mere interaction with or perturbation of appropriate cell surface molecule(s) of effector lymphocytes such as Lyt antigens by receptor-ligand interaction in SCMC or by NaIO4 modification in ODCC may lead to the expression of cytotoxicity. The present studies demonstrate a functional role of surface carbohydrates on CTL in cell-to-cell recognition and interactions. Furthermore, the results suggest that target cell modification is not a requisite for recognition and lysis in an antigen-nonspecific cytotoxic system such as ODCC. However, partial blocking of ODCC by alloantibodies directed against the H-2 of unmodified target cells suggests that NaIO4-modified CTL recognize unrelated target H-2 antigens. The implication of these findings on the molecular mechanism of cell-mediated cytotoxicity is discussed.

Animals↗
PubMed1984

Cytotoxicity of autologous and allogeneic lymphocytes against cultured human lung cancer cells: optimal conditions for the production of cytotoxic lymphocytes.

Optimal conditions for the in vitro production of cytotoxic lymphocytes against autologous lung cancer cells were studied. In the time-course experiments, fresh lymphocytes did not exhibit any cytotoxicity against autologous tumor cells, but, when cultured in the presence of T cell growth factor (IL2), the lymphocytes became cytotoxic against autologous tumor cells 3 days after the initiation of incubation and the cytotoxicity continued to increase, reaching a maximum at day 7. The study, conducted to compare the effects of IL2 and phytohemagglutinin (PHA), demonstrated that although lymphocytes cultured with PHA did exhibit a significant cytotoxicity, lymphocytes cultured with IL2 showed much higher activity. Peripheral blood, regional lymph node (RNL) and distal lymph node lymphocytes, and tumor infiltrating lymphocytes were tested as sources for the production of cytotoxic lymphocytes. Among these 4 sources, RNL proved the most consistently reliable source of cytotoxic lymphocytes. The results of in vitro stimulation by autologous tumor cells were ambivalent. Twenty-five experiments that compared in vitro stimulation by tumor cells and no stimulation revealed that 9 cases (36%) showed enhancement of cytotoxicity after stimulation with tumor cells, 5 cases showed inhibition, and the remainder no effect. Characterization of lymphocytes by using monoclonal antibodies indicated that cells lytic for autologous tumor cells are OKT3+, OKT8+, OKT4-, OKM1-.

Cells, Cultured↗
PubMed1984

Phorbol esters enhance spontaneous cytotoxicity of human lymphocytes, abrogate Fc receptor expression, and inhibit antibody-dependent lymphocyte-mediated cytotoxicity.

Phorbol esters with tumor promoter activity enhance the spontaneous cytotoxicity of human lymphocytes against a variety of target cell lines, with an efficiency that correlates with their potency as tumor promoters or skin irritants. Analysis of surface marker expression of the lymphocytes cytotoxic after treatment with phorbol ester identified the cytotoxic cell subset as that containing natural killer cells. Although gamma-interferon (IFN gamma) is produced by T cells treated with phorbol esters, IFN gamma is probably not the mediator of enhancement of natural killer cell activity, because anti-IFN gamma antibodies failed to block this enhancement. Spontaneous cell-mediated cytotoxicity is inhibited when phorbol esters are present during the cytotoxic assay, but is enhanced when the effector cells are pretreated with these agents. On the other hand, antibody-dependent cytotoxicity mediated by lymphocytes is inhibited by phorbol ester pretreatment of the effector cells or by phorbol esters present during the cytotoxic assay. Treatment of lymphocytes with phorbol esters at 37 degrees C, but not at 4 degrees C, completely abrogates in 1 to 2 hr the expression of the receptor for the Fc fragment of IgG, as detected by rosette formation with IgG-sensitized erythrocytes and by reactivity with anti-Fc receptor antibodies. The inhibition of antibody-dependent cytotoxicity by phorbol esters is probably secondary to their effect on the Fc receptor.

Animals↗
PubMed1982

Inhibition of human antibody-dependent cellular cytotoxicity, cell-mediated cytotoxicity, and natural killing by a xenogeneic antiserum prepared against "activated" alloimmune human lymphocytes.

Xenogeneic antiserum (RH1) was prepared in Lewis rats by hyperimmunization with concanavalin A- (Con A) activated alloimmune human lymphocytes. The antiserum RH1 effectively inhibited human antibody-dependent cellular cytotoxicity (ADCC), cell-mediated cytotoxicity (CMC), and natural killing (NK) in the absence of complement (C). Inhibition by RH1 was dependent on the dilution of antiserum employed and the number of cytotoxic lymphocytes present during cytolysis. Pretreatment of lymphocytes with RH1 or the presence of RH1 in culture did not inhibit lymphocyte proliferation stimulated by Con A, phytohemagglutinin, or allogeneic cells; lymphokine production as measured by leukocyte-inhibiting factor production; antibody-dependent C lysis; or CMC mediated by murine cytotoxic T lymphocytes. Analysis of the mechanism of inhibition of cytotoxicity by RH1 revealed that 1) RH1 was not cytotoxic for human lymphocytes at 37 degrees C in the absence of C; 2) purified F(ab')2 fragments were equally inhibitory as whole serum; 3) pretreatment of lymphocytes with RH1 effectively inhibited their capacity to mediate ADCC, CMC, or NK, and this effect was reversible by culturing the cells overnight at 37 degrees C; 4) RH1 did not inhibit target cell binding by K cells, effector cells of ADCC, or alloimmune T cells, but did inhibit binding by NK cells; and finally, 5) the addition of RH1 to preformed lymphocyte-target conjugates in a single cell cytotoxicity assay inhibited killing of the bound target cells in all three systems without disrupting the conjugates. Collectively, these findings suggest that RH1 antiserum interacts with structures present on the surfaces of cytotoxic lymphocytes that are involved in the activation of the lytic mechanism(s) or with the actual lytic molecule or molecules themselves. Furthermore, the ability of RH1 to inhibit ADCC, CMC, and NK during the post-binding cytolytic phase of these reactions indicates that binding and cytolysis are distinct and separate events in all types of cell-mediated cytolysis.

Animals↗
PubMed1997

Microglial cells induce cytotoxic effects toward colon carcinoma cells: measurement of tumor cytotoxicity with a gamma-glutamyl transpeptidase assay.

Activated macrophages have been shown to exert cytostatic and cytotoxic effects toward tumor cells via nitric oxide (NO) release. In the CNS, microglial cells are considered to be the main resident population of immune effector cells. In this study, cytotoxic activity of N11, an immortalized murine microglial cell line, toward rat progressive DHD/PROb and regressive DHD/REGb colon carcinoma cells was examined in parallel with NO production. Cytotoxicity was evaluated using a novel method, the gamma-glutamyl transpeptidase (gamma-GTP) assay, based on the fact that DHD tumor cells expressed high levels of gamma-GTP activity, while no gamma-GTP activity was found in cells of the monocyte/macrophage lineage. Results showed that activation of N11 cells by interferon-gamma plus either lipopolysaccharide or tumor necrosis factor-alpha induced high amounts of NO release and cytotoxic effects toward DHD/PROb as well as DHD/REGb cells. NO release by activated N11 cells was augmented by addition of tumor cell-conditioned medium. Both NO release by N11 cells and cytotoxicity were blocked by addition of N(G)-monomethyl-L-arginine (L-NMA), an inhibitor of NO synthase, suggesting that cytotoxicity was mediated by N11-derived NO. However, in the presence of L-NMA an increased production of interleukin-6 was also observed. In conclusion, in opposition to information obtained with brain-derived endothelial cells, brain-derived microglial cells did not differentiate between progressive and regressive clones of colon carcinoma cells. Our results point to a specific role for both endothelial and microglial cell types in the context of brain metastasis. Microglial cells can be cytotoxic for tumor cells, and this cytotoxicity is mediated by NO.

Animals↗
PubMed1976

Tumour-associated lymphocyte cytotoxicity superimposed on "spontaneous" cytotoxicity in melanoma patients.

Lymphocytes from 16 stage I, 6 stage II and 31 stage III melanoma patients (MP) and 51 healthy donors (HD) were tested as far as possible in parallel on a melanoma cell line (NKI-4), a bladder carcinoma cell line (T 24) and 18 different short-term melanoma cultures. Lymphocytes from MP and HD showed cytotoxic effects towards all three types of target cells. Lymphocytes from HD showed the strongest "spontaneous" cytotoxic effects on NKI-4 cells whereas, in general, weak cytotoxic effects were seen on short-term cultured melanoma cells. Within the different lymphocyte donor groups an enormous variation in cytotoxic effects was observed. However, the overall cytotoxic effects of stage I and II MP were significantly higher than those of the HD-group. Stage I MP showed significantly stronger cytotoxic effects on NKI-4 cells than on T 24 cells, indicating that tumour-associated lymphocyte cytotoxicity was superimposed on spontaneous cytotoxicity.

Adenocarcinoma↗
PubMed1996

Antibody-dependent cell-mediated cytotoxicity against orbital target cells in thyroid-associated ophthalmopathy and related disorders; close relationship between serum cytotoxic antibodies and parameters of eye muscle dysfunction.

We have carried out tests for antibody-dependent cell-mediated cytotoxicity (ADCC) against extra ocular muscle (EOM), Müller's muscle, orbital fibroblasts and skeletal muscle in patients with thyroid-associated ophthalmopathy (TAO) and related eye disorders. Cytotoxicity was measured as lactate dehydrogenase (LDH) release and results expressed as % cytotoxicity. Tests were positive, with EOM cells, in 65% of patients with TAO, 75% with ocular myopathy, a variant of TAO in which periorbital inflammation is minimal, 50% with euthyroid Graves' disease defined as ophthalmopathy associated with subclinical thyroiditis and in 50% of patients with stable lid lag and retraction but no other signs of progressive ophthalmopathy, but in only 13% of patients with Graves' hyperthyroidism without ophthalmopathy, 10% with Hashimoto's thyroiditis and 14% of patients with other thyroid disorders. Tests were positive, with Müller's muscle cells, in 40% of patients with TAO, 25% with ocular myopathy, 40% with euthyroid Graves' disease, 44% with lid lag, 19% with Graves'hyperthyroidism, 50% with Hashimoto's thyroiditis and in 37.5% of patients with other thyroid disorders. When skeletal muscle cells were used as target, tests were positive in 13% of patients with TAO, 31% with lid lag, 25% with Graves' hyperthyroidism and in 29% of patients with Hashimoto's thyroiditis, but in no patient with euthyroid Graves' disease or other thyroid disorders. Tests were negative in all patients and normals tested when EOM-derived fibroblasts were used as targets in ADCC. A significant positive correlation between % cytotoxicity against EOM cells and the severity of the eye muscle dysfunction expressed as an eye muscle index, was observed in patients with TAO. There was a significant negative correlation between the duration of eye disease and % cytotoxicity against EOM cells, suggesting higher titers of cytotoxic antibodies in the early stages of TAO. There was no correlation between % cytotoxicity and serum level of anti-TSH receptor antibodies, measured in a radioreceptor assay. These findings suggest that autoimmunity against Müller's muscle may play a role in the pathogenesis of persistent lid lag and retraction. The nature of the EOM and Müller's muscle autoantigens recognized by cytotoxic antibodies in the serum of patients with TAO and related eye disorders is unknown.

Adult↗
PubMed1985

Natural cytotoxicity of human blood lymphocytes and monocytes and their cytotoxic factors: effect of interferon on target cell susceptibility.

The effect of interferon (IFN) on target cell susceptibility to human natural killer (NK) cells and monocytes was analyzed in direct cell-mediated and their cytotoxic factor-mediated cytotoxicity assays. Treatment of K562 cells with IFN resulted in a decrease in their sensitivity to lysis by nonadherent lymphocytes and Percoll-purified large granular lymphocytes (LGL) when tested in a 4-hour 51Cr release assay. In contrast, the treatment did not affect the target susceptibility to monocytes purified by adherence to autologous serum-coated plastic surfaces. In the target-binding assay with LGL or monocytes the number of conjugates was not altered after IFN treatment of K562. Lymphocytes and monocytes were induced to release soluble cytotoxic factors, termed "natural killer cytotoxic factors (NKCF) and monocyte cytotoxic factors (MCF)," respectively, when co-cultured with K562. Both NKCF and MCF lysed K562 in a 48-hour microcytotoxicity assay or in an 18-hour 51Cr release assay in the presence of dactinomycin. IFN-treated K562 reduced or completely lost their ability to stimulate the release of NKCF, whereas they triggered MCF secretion as effectively as did the untreated K562. When lymphocytes or monocytes were pretreated with IFN, they released NKCF or MCF with augmented lytic activity. In contrast to the sensitivity to NK cell-mediated lysis, IFN pretreatment of K562 induced no change in their susceptibility to NKCF and MCF. When IFN was added to NKCF and MCF assays, the cytotoxicity was enhanced. The addition of IFN to K562 that had been pretreated with NKCF or MCF and washed resulted in no increase in lysis. The capacity of K562 to absorb the lytic activity of NKCF and MCF was not altered by IFN. These results indicate that IFN treatment of target cells can be used to distinguish the two distinct types of blood mononuclear cells with natural cytotoxicity, NK cells and monocytes, and that each effector cell type is stimulated to release cytotoxic factors by the different target determinant after the initial effector-target cell binding.

Cytotoxicity, Immunologic↗
PubMed1985

The mechanism of the inhibitory effect of progesterone on lymphocyte cytotoxicity: II. Relationship between cytotoxicity and the cyclooxygenase pathway of arachidonic acid metabolism.

In the previous paper we have demonstrated that progesterone-treated lymphocytes of healthy pregnant women produce a 34,000 MW protein that inhibits cytotoxic activity and prostaglandin F2 alpha synthesis. Since recently it has been shown that certain leukotrienes have a stimulatory effect on natural killer activity, in this study an attempt was made to determine whether there is a relationship between cytotoxicity and PGF2 alpha synthesis or if alterations in the values of these parameters are independent. Arachidonic acid increased cytotoxic activity of healthy pregnant women's peripheral blood mononuclear cells (PBMC) in a concentration-dependent manner. Exogenous arachidonic acid was able to counteract the blocking effect of the above-mentioned protein produced by progesterone-treated lymphocytes. To determine whether the products of the cyclooxygenase or the lipoxygenase pathway of arachidonic acid metabolism are responsible for increased cytotoxicity, both enzyme systems were blocked separately. Both indomethacin and the lipoxygenase inhibitor BW 755C reduced cytotoxicity in a dose-dependent fashion. However, the lipoxygenase inhibitor prevented prostaglandin synthesis to the same extent, or even more than indomethacin, in all concentrations used; so, its blocking effect cannot be considered as supportive evidence for the role of leukotrienes in cytotoxicity. On the other hand, lipopolysaccharide, with a selective stimulatory effect on prostaglandin synthesis, increased cytotoxicity. Lipopolysaccharide had no effect on progesterone-pretreated PBMC. The above data allow the assumption that besides leukotrienes, cyclooxygenase products may also increase cytotoxicity.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1975

The cytotoxic activity of mouse T lymphocytes against allogeneic cytotoxic T cells.

Using a 51Cr cytotoxicity assay, the sensitivity of murine cytotoxic T cells to T cell mediated cytotoxicity has been tested. Two experimental approaches have been used. First, cytotoxic T-blast-lymphocytes (CTBL), enriched by the velocity sedimentation at 1 g were used both as cytotoxic effector cells and as 51Cr-labelled target cells. It was found that murine CTBL are capable to lyse directly and specifically allogeneic CTBL within 200 minutes. The second approach used was to incubate CTBL together with CTBL, the cytotoxic activity of which was directed against the transplantation antigens of the added allogeneic CTBL population. After 10 hours, the residual cytotoxic activity was tested. Again it was found that CTBL were capable of functionally inactivating allogeneic CTBL. Therefore the results obtained are incompatible with the concept that target cell lysis by cytotoxic T lymphocytes is mediated by a non specific "lymphotoxin", secreted by activated T cells after the antigen-recognition phase in the confined space between T cells and target cells.

Animals↗
PubMed1978

Cell types involved in cytotoxicity induced by heated cells and inhibition of this cytotoxicity by anti-human B cell sera.

We have studied the induction of cytotoxic activity in human peripheral blood lymphocytes by heated allogeneic cells. By separating T and B cells from the responder and stimulator cell populations we found that cytotoxic cells are generated in responder T cell populations by both T and the B stimulator cells. Rabbit antisera to a membrane glycoprotein complex (33,000 and 27,000 m.w. by SDS-gel electrophoresis) isolated from a human B cell line were utilized to explore further the nature of the effector cells in this type of cytotoxicity. This antiserum, present during the 6-day-culture period, blocked generation of cytotoxic effector cells. Depletion of cells bearing the B cell antigen from the responder cell population by anti-B cell serum and complement (C) eliminated cytotoxicity. Furthermore, heated cell-induced cytotoxicity was blocked by simply pretreating the responder or the stimulator cell populations with anti-B cell serum in the absence of C. Apparently the human lymphocyte that functions as the effector cell in heated cell-induced cytotoxicity bears the Ia-like antigen that might be important in triggering this type of cytotoxicity.

Antilymphocyte Serum↗
PubMed1979

Direct cytotoxicity against chicken erythrocytes in mice. II. Nature of immunoglobulin on cytotoxic T lymphocytes.

Direct cytotoxicity raised at an early interval after immunization with chicken erythrocytes (CRBC) has been ascribed to O-positive, immunoglobulin (Ig)-bearing lymphocytes. Cytotoxicity of such effector cells was not affected by trypsinization. Cytotoxity was reduced by the treatment of effector cells with anti-IgG serum and complement or by the addition of anti-IgG serum to culture medium for cytotoxicity test. When the effector cells were treated with trypsin before cytotoxicity test, such procedures with anti-IgG serum did not affect their cytotoxicity. Ig molecules on cytotoxic T lympohcytes may not be an essential element for antigen recognition. This explanation may be supported by the fact that cytotoxicity against CRBC could be raised in 600 rad irradiation, thymus-cell transferred mice in the absence of antibody production.

Animals↗
PubMed1986

Cytotoxicity by human adherent cells: oxygen-dependent and -independent cytotoxic reactions by different cell populations.

Human adherent cells, obtained by EDTA reversible adherence to plastic, are potent effectors in cell-mediated cytotoxicity. Spontaneous cytotoxicity in a 2-hr assay against K562 target cells was shown to be largely mediated by contaminating natural killer (NK) cells. Treatment of adherent cells with NK-specific monoclonal antibody anti-Leu-11 plus complement abolished almost completely the spontaneous cytotoxicity. Spontaneous cytotoxicity by adherent cells was also reduced when the phorbol ester PMA was present in the assay. On the other hand, PMA induced a cytotoxic response in NK-cell depleted adherent cells after prolonged 18 hr incubation. The cell population responsible for this dichotomous effect of PMA on adherent cell-mediated cytotoxicity was shown to be monocytes, as revealed by monoclonal antibody treatment. Pure NK cell preparations were not affected by PMA in their cytolytic capacities. Reactive oxygen species are not involved in NK-cell mediated cytotoxicity, while PMA stimulated the monocytes to exert cytolysis and suppressed NK cells by the generation of these highly toxic oxygen products. Hydrogen peroxide especially seemed to be the mediator in this oxygen-dependent monocyte-mediated cytotoxicity and NK-cell suppression.

Catalase↗
PubMedDate not supplied

Antibody-dependent cellular cytotoxicity (ADCC) and lymphocyte-mediated cytotoxicity (LMC) in patients with vascular disease and guinea pigs immunized with human vascular extracts.

Antibody-dependent cellular cytotoxicity (ADCC) and lymphocyte-mediated cytotoxicity (LMC) were studied in vitro in patients with myocardial infarction, peripheral arterial disease or thrombophlebitis. LMC was also investigated in guinea pigs immunized with human vascular extracts. 51-Chromium-labelled chicken erythrocytes were used as target cells. In LMC tests human aortic or venous extracts were coated on the surface of sensitized erythrocytes. Cytotoxicity of separated lymphocyte populations was expressed by cytotoxic capacity. ADCC was decreased and LMC was increased both in patients and in immunized animals compared with controls. T-cells induced the largest cytotoxic effect. O (null)-cells also had cytotoxic capacity against vascular antigen coated targets in patients and in immunized animals. Cytolytic T-lymphocytes are thought to be responsible for cytotoxicity both of T- and O-cells. The LMC test seems to be useful for in vitro detection of cellular sensitization against vascular or other specific antigens.

Adult↗
PubMed1997

Cytotoxic effects of acrylates and methacrylates: relationships of monomer structures and cytotoxicity.

Thirty-nine acrylates and methacrylates that had been used in dental resin materials were evaluated by a cytotoxicity test, and the relationships between their structures and cytotoxicity were studied to predict cytotoxic levels of dental resin materials in order to develop new low-toxic resin materials. All the acrylates evaluated were more toxic than corresponding methacrylates. In both the acrylates and methacrylates, a hydroxyl group seemed to enhance cytotoxicity. Dimethacrylates with 14 or fewer oxyethylene chains showed similar cytotoxicity while dimethacrylates with 23 oxyethylene chains showed lower cytotoxicity. The cytotoxicity ranking of monomers widely used in dental resin materials was bisphenol A bis 2-hydroxypropyl methacrylate (bisGMA) > urethane dimethacrylate (UDMA) > triethyleneglycol dimethacrylate (3G) > 2-hydroxyethyl methacrylate (HEMA) > methyl methacrylate (MMA). In acrylates, methacrylates, and ethylmethacrylates with either substituents, the lipophilicity of substituents affected their cytotoxicity, and an inverse correlation between IC50 and logP was observed. These results will be useful in developing new resin materials with low toxic monomer compositions.

Acrylates↗
PubMed2001

Synergistic cytotoxic effect between serine-threonine phosphatase inhibitors and 5-fluorouracil: a novel concept for modulation of cytotoxic effect.

PURPOSE: The present study was undertaken to look for an agent or agents able to modulate the cytotoxic effect of 5-fluorouracil (FUra) and to investigate the role of serine-threonine phosphatase inhibitors on the cytotoxic effect of FUra. METHODS: The cytotoxicities of FUra and protein phosphatase inhibitors (PPIs) were evaluated by two different methods: a clonogenic assay and a proliferation assay. In the clonogenic assay, cancer cells were treated with various concentration of FUra with or without PPIs for 72 h. The drug-containing medium was replaced by fresh medium, the cultures incubated for an additional 10 days, and the colonies enumerated. In the proliferation assay the cells were treated with FUra alone or in combination with PPIs for 96 h and cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay based on the uptake of the tetrazolium dye. Thymidine kinase (TK) activity was determined based on the catalytic phosphorylation of [(3)H]d-thymidine to [(3)H]dTMP. Incorporation of FUra into DNA and RNA was determined by treating the cells with [2-(14)C]fluorouracil for 72 h and measuring the radioactivity in the isolated DNA and RNA fractions. RESULTS: The serine-threonine phosphatase inhibitors caliculin A (CAL), okadaic acid (OA) and microcystin-LR (MCLR) dose-dependently inhibited the growth of Clone 20 and Clone 5 cells of Colon 26 murine colon adenocarcinoma cells, human cervical cancer HeLa cells, human gastric cancer MKN 7 cells, and murine sarcoma S-180 cells in vitro. Among the compounds tested, MCLR at non-toxic concentrations was found to increase FUra incorporation into RNA and DNA in Clone 20 cells by 60% and 127%, respectively, to increase TK activity alone (twofold) as well as in combination with FUra (threefold), and to potentiate the cytotoxicity of FUra synergistically and cytospecifically in vitro. The cytotoxicity of FUra alone or in combination with MCLR, but not that of PPIs alone, was abrogated almost completely by exogenous thymidine (dThd), suggesting that inhibition of thymidylate synthetase (TS) is the growth-limiting event in the cytotoxic action of FUra even in combination with MCLR. CONCLUSIONS: The findings presented here suggest that MCLR synergistically and cytospecifically potentiates the antitumor activity of FUra with substantial improvement in the therapeutic index of FUra via enhancement of both DNA- and RNA-directed cytotoxicity.

Animals↗
PubMed2003

In vitro cytotoxicity of aplidin and crossresistance with other cytotoxic drugs in childhood leukemic and normal bone marrow and blood samples: a rational basis for clinical development.

To determine the potential of aplidin as a cytotoxic agent in pediatric leukemia, we tested bone marrow (BM) and peripheral blood (PB) samples (n=72) of children with different types of leukemia and healthy children in the methyl-thiazol-tetrazolium assay. Also, we compared these results with other cytotoxic drugs. Aplidin was cytotoxic in vitro at nanomolar concentrations, in a dose-dependent fashion. L-carnitine, that is applied in clinical studies to prevent myotoxicity caused by aplidin, had no effect on aplidin cytotoxicity in vitro. Aplidin cytotoxicity in vitro was not different when initial and relapsed acute lymphoblastic leukemia (ALL) or initial ALL and initial acute myeloid leukemia were compared. However, normal BM (n=19) and PB (n=13) cells were more resistant to aplidin than leukemic cells (median two- to seven-fold, P=0.001 and median four- to 11-fold, P&<0.0001, respectively). In leukemia samples, no significant crossresistance between aplidin and other cytotoxic drugs was found, except for a trend for correlation with 2',2'-difluorodeoxycytidine (rho=0.71, P=0.02). In normal BM samples, significant crossresistance with the epipodophyllotoxins was found, which is not readily explained by the currently known mechanisms of action of aplidin. In conclusion, we show that aplidin has selective cytotoxicity in vitro towards childhood leukemia cells and generally lacks crossresistance with other known cytotoxic drugs, which warrants clinical studies.

Antineoplastic Agents↗
PubMedDate not supplied

In vitro assessment of cytotoxicity and carcinogenic potential of chemicals: evaluation of the cytotoxicity induced by 58 metal compounds in the Balb/3T3 cell line.

A new, mechanistically based, in vitro strategy involving Balb/c 3T3 clone A 31-1-1 mouse embryo fibroblasts has been proposed for the determination of the carcinogenic potential of inorganic chemicals, in order to establish priority of metal compounds to be tested and, whenever possible, to compare the in vitro results with the corresponding in vivo data. As a first step in this research, this study reports on the cytotoxic effects of 58 metal compounds in the Balb/3T3 cell line. After harmonisation and standardisation of the Balb/3T3 protocol, cells were exposed for 72 hours to a fixed dose (100 microM) of 58 individual compounds. The cytotoxicity induced by some metal compounds was found to be related to their chemical form (for example, Cr(NO(3))(3) and Na(2)CrO(4)), suggesting that the Balb/3T3 cell line is a valuable cellular model in relation to this aspect of metal speciation. The results of the systematic study on the metal-induced cytotoxic effects in the Balb/3T3 cell line could be arbitrarily classified into three groups according to the degree of cytotoxicity. Group I includes 26 species that induced no observable effect or only a slight cytotoxic effect; Group II includes 13 metal compounds that exhibited an obvious degree of cytotoxicity; and Group III includes 19 metal species that displayed a strong cytotoxic response. Metal compounds of Groups II and III are considered to be of the highest priority for setting of dose-effect relationships for a subsequent in vitro study on metal-induced concurrent cytotoxicity and morphological transformation in the Balb/3T3 cell line.

3T3 Cells↗