5-S RNA: biosynthesis and association to immature ribosomal particles in the nucleus of lymphocytic mouse leukemia cells, L5178 Y.
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Comparison of quantitative structure-activity relationships of the inhibition of leukemia cells in culture with the inhibition of dihydrofolate reductase from leukemia cells and other cell types.
A set of 2,4-diamino-5-(3-X-phenyl)-s-triazines was used to inhibit the growth of tumor cells (L5178 leukemia) in culture. The molar concentration (C) of triazine causing 50% reduction in the rate of cell growth was used to develop a quantitative structure-activity relationship: log 1/C = 1.32 pi - 1.70 log (beta.10 pi + 1) + 0.44I + 8.10, where pi is the hydrophobic constant for X, beta is a disposable parameter, and I is an indicator variable for congeners containing a -CH2Z-C6H4-Y moiety (Z = O or NH). This equation is compared with similar equations derived for the inhibition of dihydrofolate reductase from leukemia cells and bovine liver.
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Action of the antileukemic and anti-HTLV-III (anti-HIV) agent avarol on the levels of superoxide dismutases and glutathione peroxidase activities in L5178y mouse lymphoma cells.
The antileukemic and anti-HTLV-III (anti-HIV) agent avarol, a sesquiterpenoid hydroquinone, was determined to be converted into its corresponding quinone derivative avarone via the semiquinone free radical. Its g-value was 2.0047; after hyperfine splitting the energy levels revealed 16 isotropic Hfs. The redox reaction products were identified at the pH values 4.0, 7.0 and 12.0 and the overall reaction pathways were formulated. In vivo experiments with L5178y mouse lymphoma cells in the ascites of mice revealed that the cytostatic potencies of avarol and avarone cannot be augmented by lowering the pH value. Incubation studies with L5178y cells in vitro showed that the intracellular levels of superoxide dismutases (SODases) and of glutathione (GSH) peroxidase activities significantly change after avarol administration. While both the Mn-SODase and the Cu/Zn-SODase activities dropped significantly, the GSH peroxidase activity increased inversely. From these experiments we assume that the anti-tumour and the antiviral effects of avarol/avarone may be due to an increase, induced by the drug, of the intracellular concentrations of superoxide radicals.
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Identification and immunogenic properties of an 80-kDa surface antigen on a drug-treated tumor variant: relationship to MuLV gp70.
Highly immunogenic tumor variants are generated by in vitro or in vivo treatment of L5178Y murine lymphoma cells with triazene derivatives. Most of these variants express new transplantation antigens which are not present on the original L5178Y tumor cells. In this study, a polyclonal syngeneic antiserum raised to one such variant (L5178Y/DTIC) was employed in immunoprecipitation studies of cell surface and metabolically labeled L5178Y/DTIC cells. One- and two-dimensional electrophoretic analyses of the immunoprecipitates detected a surface antigen of approximately 80 kDa. Additionally, a 45-kDa component was detected in the lysate of [35S]methionine-labeled cells. Anti-xenotropic MuLV gp70 serum precipitated material whose electrophoretic pattern was similar to that of the 80-kDa surface antigen. Sequential immunoprecipitation analysis revealed that the molecules reactive with the variant-specific antiserum were removed by the anti-xenotropic gp70 antibodies, whereas immunodepletion was only partial when the cell extract was first treated with the variant-specific antibodies. After Western blotting, the 80- and 45-kDa antigens precipitated by the variant-specific antibodies were injected intrasplenically into recipient mice. Only the animals sensitized with the 80-kDa antigen developed specific immunity to L5178Y/DTIC cells in that they displayed an increased frequency in CTL precursors (CTLp) to the variant cells. Sera from mice sensitized to the 80-kDa protein specifically inhibited the development of a primary CTL response to L5178Y/DTIC cells.
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Reactivity of catecholamines and related substances in the mouse lymphoma L5178Y cell assay for mutagens.
Using the L5178Y mouse lymphoma cell thymidine kinase locus and the Salmonella his locus assays, the mutagenic potentials of several catecholamines and related compounds were examined. No supplementary metabolic activation systems were used. In the mouse lymphoma assay, the dihydroxybenzenes catechol and hydroquinone had similar and appreciable mutagenic potentials, whereas resorcinol was less active. Derivatives of catechol, such as dopamine and epinephrine, were mutagenic, whereas the related monohydroxylated compounds tyramine and synephrine were inactive. The primary amine, arterenol, and the corresponding secondary amine, epinephrine, induced similar mutagenic responses. Carboxylation of the side chain of dopamine, giving L-dopa, reduced the maximum mutagenic response. The introduction of charged groups directly on to the aromatic ring also reduced mutagenic activity, while an intervening methylene reversed this effect. Thus, 3,4-dihydroxyhydrocinnamic acid was more active than 3,4-dihydroxybenzoic acid. The compound active at the lowest doses was 4-tert-butyl catechol. The activities of these compounds are highly dependent upon substituent groups. Experiments with superoxide dismutase gave circumstantial evidence for some of the mutagenic activity being due to superoxide anion. Active oxygen species might be responsible for some of the observed effects, but this cannot be concluded from the superoxide dismutase experiments. Mutagenic responses in Salmonella were very low but were significant for L-dopa in three strains and for epinephrine and arterenol in one strain. Limited DNA association studies of 14C-dopamine suggest interactions in L5178Y and Salmonella cells and in mouse liver. The mutagenicity of dopamine in L5178Y is reduced by high serum concentrations during the exposure period, while the apparent association with DNA is unaffected.
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Evaluation of di-(2-ethylhexyl)phthalate and its major metabolites in the Ames test and L5178Y mouse lymphoma mutagenicity assay.
Di-(2-ethylhexyl)phthalate (DEHP) and its two major metabolites, mono-(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (EH), were tested for genetic activity in both the Salmonella/mammalian microsome mutagenicity (Ames) assay and the L5178Y TK+/- mouse lymphoma cell mutagenicity assay. All chemicals were tested in both the presence and absence of Aroclor-induced liver microsomes prepared from male Sprague-Dawley rats. Dose levels for both assays were selected from preliminary toxicity studies for each chemical. Neither DEHP, MEHP, nor EH exhibited any significant mutagenic activity in strains TA-98, TA-100, TA-1535, TA-1537, and TA-1538 in the Ames test or when tested in the L5178Y TK+/- mouse lymphoma cell mutagenicity assay.
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Responses of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals.
Seventy-two chemicals were tested for their mutagenic potential in the L5178Y tk+/- mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector (Mutat Res 44:269-278, 1975) and Clive et al. (Mutat Res 59:61-108, 1979). Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 micrograms/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate, p-benzoquinone dioxime, benzyl acetate, 2-biphenylamine HCl, bis(2-chloro-1-methylethyl)ether, cadmium chloride, chlordane, chlorobenzene, chlorobenzilate, 2-chloroethanol, chlorothalonil, cytarabine.HCl, p,p'-DDE, diazinon, 2,6-dichloro-p-phenylenediamine, N,N-diethylthiourea, diglycidylresorcinol ether, 2,4-dimethoxy aniline.HCl, disperse yellow 3, endosulfan, 1,2-epoxyhexadecane, ethyl acrylate, ethyl benzene, ethylene thiourea, F D and C yellow Number 6, furan, heptachlor, isophorone, mercuric chloride, 4,4'-methylenedianiline.2 HCl, methyl viologen, nickel sulfate.6H2O, 4,4'-oxydianiline, pentachloroethane, piperonyl butoxide, propyl gallate, quinoline, rotenone, 2,4,5,6-tetrachloro-4-nitro-anisole, 1,1,1,2-tetrachloroethane, trichlorfon, 2,4,6-trichlorophenol, 2,4,5-trimethoxybenzaldehyde, 1,1,3-trimethyl-2-thiourea, 1-vinyl-3-cyclopetene dioxide, vinyl toluene, and ziram. Apart from 2-biphenylamine.HCl, 2-chloroethanol, disperse yellow 3, ethylene thiourea, FD and C yellow number 6, phenol, and 1,1,2-tetrachloroethane, rat liver S9 mix was not a requirement for these compounds. Chemicals not identified as mutagens were acid red, 11-aminoudecanoic acid, boric acid, 5-chloro-o-toluidine, coumaphos, cyclohexanone, decabromodiphenyl oxide, di(2-ethylhexyl)adipate, ferric chloride, fluometuron, melamine, monuron, phenesterin, phthalimide, reserpine, sodium dodecyl sulfate, 4,4-sulfonyldianiline, tetrachloroethylene, and zearalenone. The assay was incapable of providing a clear indication of whether some chemicals were mutagens; these were benzyl alcohol, 1,4-dichlorobenzene, phenol, succinic acid-2,2-dimethyl hydrazide, and toluene.
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High-frequency generation of new immunoresistant tumor variants during metastasis of a cloned murine tumor line (ESb).
A metastatic variant of a chemically induced lymphoma (ESb) from a DBA/2 mouse was found to activate in syngeneic hosts specific anti-tumor cytolytic T lymphocytes (CTL) which recognized on the tumor a distinct tumor-associated antigen. Upon metastasis of a cloned ESb tumor line from an s.c. site to the spleen, the tumor cells which were originally sensitive to lysis by anti-ESb CTL became specifically immunoresistant. The development of immunoresistant variants after tumor-cell transplantation followed a refined kinetic and organ pattern: they were first detected in the spleen, then also in the liver and in the late stage of tumor progression they were the predominant tumor type in all involved organs. No immunoresistant tumor variants were generated in immunoincompetent animals such as nude (nu/nu) mice. Immunoresistant variants also developed when immunosensitive ESb clones were inoculated into animals specifically preimmunized against ESb. In fact, these variants were the only type of cells eventually growing out from such animals causing death from metastasis in spite of the specific immune status of the host. The change of tumor antigen expression described here differs from antibody-induced antigenic modulation in that it is genetically transmitted and stable in tissue culture. The immunoresistant tumor variants which did not preexist in the starting, twice-cloned cell population represent a new type of immune escape variant.
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Natural cytotoxic cells against solid tumors in mice. IV. Natural cytotoxic (NC) cells are not activated natural killer (NK) cells.
Natural cell-mediated cytotoxicity (NCMC), measured against a variety of tumors, is mediated by at least two sub-populations of effector cells: natural cytotoxic (NC) and natural killer (NK). The studies described in this report show that target lysis by NC cells requires a prolonged (18- to 24 h) assay period, whereas NC-susceptible targets can be lysed in short-term (4h) [3H]-proline assays using allo-sensitized CTL or mitogen-activated cytotoxic populations. NC cells are not "activated" during the long-term assay as indicated by: (1) demonstrating that lysis of NC-susceptible targets in long-term (20 h) 51Cr assays is still the function of a Qa-5- effector cell (NC) and (2) the fact that preincubation of the NC effector cell with susceptible targets for 18 h did not result in the activation of an NK-like population (kinetics of target lysis were comparable to those noted with fresh NC cell preparations). We show that NC cell activity is preserved in both the beige mutant and the PL/J mouse strains, both of which exhibit low NK cell activity, even in long-term assays. These combined studies support the view that NC and NK cell activities are the function of distinct cell types and not the property of a single cell class under different states of activation.
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In vivo generation and selection of variants with altered sensitivity to natural resistance (NR): a model of tumor progression.
The stability of a cloned murine tumor for sensitivity to NR was examined following growth in vivo in order to test the hypothesis that tumor progression proceeds through the generation and selection of variants. Clonal sensitivity to the [131I]-dUrd elimination assay of NR was assessed for the L5178Y-F9 tumor grown in syngeneic DBA/2 mice or maintained solely in tissue culture. Subclones derived from a tumor obtained from the injection site 3 1/2 weeks after the s.c. inoculation of 25 cells were less sensitive to NR in comparison with subclones derived from cells grown only in vitro. Subclones from the cells grown in vivo exhibited increased heterogeneity in sensitivity to NR in addition to their expanded range of susceptibility to complement-mediated lysis by CBA serum natural antibodies. The extent of the heterogeneity argues against tumor "adaptation" forming the basis for the phenotypic alteration while chromosomal studies eliminate the possibility that a new tumor was induced. These data support the hypothesis that tumor progression proceeds through the random generation of variants and host-mediated selection for the proliferation of clones with an increased ability to survive.
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The mechanism of augmentation of natural killer cell activity by syngeneic tumor cells: role of macrophage-derived factor in NK boosting.
The role of natural killer (NK) cells in controlling tumor growth was investigated using an NK-susceptible (c127v-IC2) and an NK-insusceptible (c127av) subline of the lymphoma L5178Y. Syngeneic DBA/2 mice inoculated intraperitoneally with c127v-IC2 tumor cells survived significantly longer than did c127av-bearing mice. Similarly, c127v-IC2, but not c127av tumor cells, were found to augment NK activity of spleen and peritoneal exudate cells in both DBA/2 and BALB/c nu/nu mice when inoculated into the peritoneal cavity. C127v-IC2 tumor cells incubated with either DBA/2 or BALB/c nu/nu spleen cells in vitro boosted NK activity and induced the production of gamma-type interferon (IFN), whereas incubation with c127av tumor cells induced neither NK activity nor IFN. Two kinds of cells cooperated in the production of IFN in response to c127v-IC2 tumor cells, namely, cells which were nonadherent, bore asialo-GM1, NK-1.2 and a low level of Thy-1.2 antigen and thus closely resembled NK cells, and those which were adherent and phagocytic and lacked both asialo-GM1 and NK-1.2 markers, presumably macrophages. Further analysis strongly suggested that c127-v-IC2 tumor cells stimulate macrophages to produce factor(s) which can induce the production of IFN by NK cells. The induced IFN was shown to be of the gamma type by its lability at pH 2.0 and insusceptibility to anti-IFN alpha, beta serum. This suggests a novel pathway for NK cell activation, and strongly supports the importance of macrophages and NK cells in natural resistance against certain tumors.
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Selective inhibition by monosaccharides of tumor cell cytotoxicity mediated by mouse macrophages, macrophage-like cell lines, and natural killer cells.
A series of monosaccharides were tested for their ability to inhibit the effector phase of macrophage-mediated cytolysis against two susceptible murine tumor target cells, L5178Y and RL male I. Two monosaccharides, D-mannose and N-acetyl-D-galactosamine, were found to decrease cytotoxicity consistently in a dose-dependent manner. However, D-mannose preferentially inhibited lysis of RL male I target cells with little effect on lysis of L5178Y target cells, while the reverse was found with N-acetyl-D-galactosamine. Neither monosaccharide interfered with the activation of macrophages by polyinosinic:polycytidylic acid. Natural killer cell activity was decreased by a 25 mM concentration of D-mannose but not by N-acetyl-D-galactosamine, although increasing concentrations of N-acetyl-D-galactosamine were inhibitory. Neither monosaccharide affected cytotoxicity by alloimmune T cells. Cytotoxicity of macrophage-like cell lines against tumor target cells was also decreased by monosaccharides but the pattern of inhibition was different from that seen with activated macrophage effector cells. Both D-mannose and N-acetyl-D-galactosamine inhibited glucose oxidation by activated macrophages but only D-mannose significantly decreased protein synthesis of activated macrophages. These results indicate that monosaccharides can inhibit macrophage-mediated cytotoxicity in a selective manner with the pattern dependent on the tumor target cell used in the assay.
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Adoptive immunotherapy of intracerebral murine lymphomas: role of different lymphoid populations.
In an attempt to elucidate the cellular mechanisms responsible for the therapeutic activity of systemic immunotherapy in an adoptive transfer system, lymphoma cells were implanted i.c. It was found that, upon peripheral injection of cytotoxic T-lymphocytes with specificity for the tumor, the cells reached and infiltrated the diseased brain but did not accumulate selectively in the malignant graft. In order to accomplish significant tumor inhibition, the infused lymphocytes, largely expressing the Lyt-1+2+ phenotype, apparently cooperated with radioresistant phagocytic cells present in histocompatible hosts and athymic mice.
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Humoral response against murine lymphoma cells xenogenized by drug treatment in vivo.
Treatment of murine lymphomas with triazene derivatives may lead to the appearance of novel drug-mediated tumor antigens, a phenomenon known as chemical xenogenization. Such antigens, which are capable of eliciting specific transplantation resistance in histocompatible mice, have been previously detected by in vivo and in vitro cell-mediated immune responses. In the present report we address the question of the humoral antibody response to a chemically xenogenized lymphoma. Histocompatible mice were given several injections of live cells of the xenogenized tumor. Ten days after each immunization, pooled sera from different animals were analyzed for Ab content by means of flow microfluorometry analysis and CEL-ISA assay. The results reveal that antibodies of both IgG and IgM classes capable of binding the xenogenized tumor can already be detected after one single sensitization. However, the Ab titer gradually increases through subsequent immunizations, reaching a peak level after 3-4 injections at a time when most of the humoral response is made up of antibodies of IgG class. The specificity of the anti-xenogenized tumor hyperimmune sera was subsequently investigated by its reaction with the parental, non-xenogenized line and with normal tissue cells of the same or allogeneic haplotypes. The data obtained point out that cross-reactivity with the parental line could be completely removed by absorption of the hyperimmune sera on parental cells, which removed most of the IgM antibodies. Moreover, the presence of an excess of anti-parental antibodies on the xenogenized tumor cells does not prevent the subsequent binding of the hyperimmune absorbed serum, thus indicating that the novel determinant(s) recognized on xenogenized cells are not spatially related to those shared with the original parental tumor. In addition, the hyperimmune absorbed serum does not cross-react with normal hemopoietic or lymphoid cells of the same (H-2d) or allogeneic H-2b and H-2k haplotypes. Furthermore, no alien histocompatibility antigens of H-2b or H-2k haplotypes could be detected on the xenogenized tumor cell surface. Taken together, these data provide evidence that chemical xenogenization of a murine lymphoma leads to the appearance of novel determinant(s) detectable by specific antibodies.
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Delayed-type hypersensitivity to tumor antigens co-expressed with immunogenic determinants induced by xenogenization.
Previous work has shown that murine lymphoma cells antigenically altered ("xenogenized") by drug treatment elicit strong in vivo resistance to the original cells. Moreover, splenocytes immune to a drug-treated variant (L5178Y/DTIC) of a murine lymphoma exert anti-parental tumor activity in an adoptive transfer system, an effect mediated by L3T4+ lymphocytes and associated with the detection of an anti-L5178Y delayed-type hypersensitivity (DTH) response. We now report that the in vivo activity of the tumor-immune L3T4+ lymphocytes is a radio-sensitive (2,500 rad in vitro) phenomenon that requires collaboration with radio-resistant, silica-sensitive syngeneic cells in the host, and is inhibited by treatment of recipient mice with monoclonal antibodies (MAbs) to the L3T4 antigen or murine interferon-gamma (IFN-gamma). In vitro, the tumor-immune L3T4+ lymphocytes produce interleukin 2 (IL-2), lymphotoxin (LT) and IFN-gamma activities on incubation with L5178Y cells and spleen-adherent cells. These results suggest that the mechanisms of anti-parental tumor protection by xenogenized cells involve specific induction of a DTH response mediated by the "inflammatory" (THI) subset of L3T4+ T lymphocytes and IFN-gamma activated macrophages.
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Recruitment and activation of tumor-specific immune T cells in situ: functional studies using a sponge matrix model.
The activation of tumor-specific precursor cytotoxic T lymphocytes (CTLP) into cytotoxic T cells (CTL) was demonstrated in situ using the well-defined, highly metastatic ESb tumor as murine model system. Ten days after optimal immunization of syngeneic mice with a sublethal dose of live ESb tumor cells in the pinna, tumor-sensitized non-cytotoxic CTLP were recovered from the spleen and lymph nodes. These cells mature into tumor-specific CTL upon restimulation in vitro. Using a confined sponge matrix compartment, in combination with a specific tumor vaccine (autologous inactivated tumor cells), we induced a CD8+ (Lyt 2+) T-cell-mediated, highly cytotoxic anti-tumor immune response in situ in immunized mice. It was not possible to activate a similar response directly in lymphoid organs such as the spleen. The cytotoxic CD8+ T cells, recovered by simple mechanical pressing of the sponge, were active against the specific tumor cells in a 51Cr-release assay in vitro and also in a Winn neutralization assay in vivo. CTL activity was increased and remained in the non-adherent fraction when the cell mixture, squeezed out of the sponges, was passed over nylon wool. In a cell recruitment assay, the delayed-type hypersensitivity (DTH) potential of the activated sponge-infiltrating T cells was demonstrated by their capacity to recruit circulating host lymphocytes to sites of tumor-cell location in situ.
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Alterations of drug-induced toxicity in the mouse lymphoma assay by a rat hepatic microsomal metabolizing system (S-9).
Large differences in induced cellular toxicity were observed in the presence or absence of a rat liver microsomal metabolizing system (S-9) during drug testing in the mouse lymphoma assay. After studying the fate of three drugs in this test system, several mechanisms were demonstrated whereby S-9 reduced cellular toxicity. For N-(4-hydroxyphenyl)retinamide (HPR), fenoctimine sulfate and methyl palmoxirate, the drug concentrations (EC50) in the presence of S-9 were, respectively, 11.5, 14.3 and 4.1 times the concentrations required to achieve comparable levels of toxicity in the absence of S-9. HPR was metabolized by the S-9 and sequestered in the microsomal membranes. This was associated with a marked reduction in the cellular accumulation of the drug. The reduced toxicity of fenoctimine sulfate in the presence of S-9 was associated with extensive biotransformation to polar metabolites. This was accompanied by a reduction of radioactivity associated with the cells from 5.7% to 0.4% of the administered drug. Methyl palmoxirate was rapidly converted to its acid, palmoxirate, by horse serum enzymes present in the treatment medium. This provides an example of metabolism by a test system component other than the S-9 or lymphoma cells. The reduced toxicity of this drug in the presence of S-9 was attributed to further metabolism of palmoxirate and a reduction of the proportion of total radioactivity associated with the cells from 3.1% to 0.4%. These results emphasize the need for pilot toxicity studies, especially when components of the test system are varied, to assess the effect of drug concentration on the toxic response.(ABSTRACT TRUNCATED AT 250 WORDS)
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Inhibition of calcium and glucose uptake by murine leukemia L5178Y cells treated with antiserum.
Studies were performed to determine whether decreases in transport of calcium and glucose might be among the earliest changes triggered by the antigen-antibody reactions occurring on the cell surface of murine leukemia L5178Y cells after treatment with rabbit antisera. After treatment with antisera, in the absence of complement, these cells exhibited a decreased uptake of 45Ca, 2-deoxy[3H]glucose, and 3-0-methyl[3H]glucose. These changes occurred rapidly, within 2 minutes after the addition of antiserum, in contrast to the previously reported inhibitory effects of antiserum on DNA, RNA, and protein synthesis, which became demonstrable only after 4 to 8 hours. The kinetics of uptake of the radioactive substrates was biphasic, with a very rapid initial uptake followed by less rapid linear uptake. The precise mechanism of cell growth inhibition remains to be elucidated, but one of the initial effects of antiserum treatment may be a perturbation at the cell membrane such that transport of specific nutrients is decreased, resulting in the observed effects on macromolecular synthesis.
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