Specific receptors for glucocorticoid in the cytoplasm of the liver of AH 130 tumor-bearing rats.
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Specific receptors for dexamethasone (11beta, 17alpha, 21-trihydroxy-9alpha-fluoro-16alpha-methyl-1,4-pregnadiene-3,20-dione) in the cytoplasm of the liver from AH 130 (solid type) tumor-bearing rats markedly increased in the advanced stage of tumor growth. The cytoplasmic receptors of the livers of normal and tumor-bearing rats differed in their affinities for dexamethasone, and their apparent equilibrium (dissociation) constants (K) for dexamethasone were 4.0 and 2.6 X 10(-9) M, respectively. The rates of dissociation of dexamethasone-receptor complexes and the heat denaturations of the receptors in the livers of normal and tumor-bearing rats were similar. The glucocorticoid receptors of tumor-bearing rat liver had slightly higher affinities than did those of normal liver for all the steroids tested. Only a trace amount of receptors for dexamethasone could be detected in the cytoplasm of AH 130 ascites cells. (+info)
Differences in benzo(a)pyrene metabolism between rodent liver microsomes and embryonic cells.
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Differences in benzo(a)pyrene metabolite pattern have been shown by rodent liver microsomes (Sprague-Dawley) and rodent embryo cells from Syrian hamsters and NIH Swiss mice. Rodent liver induced by methylcholanthrene shows marked quantitative variation between species. Additional pattern changes were found in mouse and hamster embryo secondary cultures with a reduction of the K-region metabolites and a marked increase in 9-hydroxybenzo(a)-pyrene. These results are indicative of a region-specific attack on the carcinogen by the cell monooxygenases which is distinct from the liver attack of microsomal enzymes on benzo(a)pyrene. These results suggest that activation and detoxification of benzo(a)pyrene may be species and tissue variable, and susceptibility and resistence to malignant transformation may be predicted on induction of a fortuitous combination of intermediate metabolic steps. (+info)
Long-term transplantability and morphological stability of three experimentally induced urinary bladder carcinomas in rats.
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Three transitional cell carcinomas induced in Fischer 344 rats by a methylcholanthrene pellet or a foreign body inserted locally into the bladder have been serially transplanted in the syngeneic strain for up to 6.5 years. There have been no changes in the individual morphological characteristics of the tumors during this time. Cells cultured in vitro for varying numbers of passages reproduce regularly the morphology of each tumor when they are injected back into the animals and results from a microcytotoxicity assay for cellular immunity indicate that they retain a common, bladder tumor-specific antigen. These tumors are useful for research in turmo biology and are offered to other scientists seeking transplantable carcinomas for experimentation. (+info)
Ambiguity of the thymidine index.
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The observed thymidine indices of seven experimental tumor lines are compared as a function of duration of emulsion exposure. The effects of dose level of tritiated thymidine and background threshold are also evaluated. The results indicate that an arbitrary high background threshold discriminates against "lightly" labeled cells at short periods of exposure but that the chosen threshold becomes less critical with longer exposure. The observed thymidine index increases with increasing duration of emulsion exposure but appears to approach a plateau for all tumor systems. The "thymidine index curves" are significantly different for each tumor. There is an inverse relationship between the dose of tritiated thymidine and the duration of exposure required to recognize the same fraction of cells as labeled in a given tumor. Similar experimental conditions do not necessarily guarantee a valid basis for comparison of observed thymidine indices among tumors. (+info)
Carcinogenicity of triethanolamine in mice and its mutagenicity after reaction with sodium nitrite in bacteria.
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Mice fed a diet containing 0.3 or 0.03% triethanolamine developed malignant tumors. Females showed a high incidence of tumors in lymphoid tissues, while this type was absent in males. Tumors in other tissues were produced at a considerable rate in both sexes, but no hepatoma was found. Triethanolamine was not mutagenic to Bacillus subtilis by itself, but it became mutagenic after reacting with sodium nitrite under acidic conditions or when the mixture was heated. Although N-nitrosodiethanolamine, a known carcinogen and mutagen, was detected in the reaction mixture by thin-layer chromatography, it may not be the main mutagenic product, because the product was a stable and direct mutagen and its mutagenic activity was destroyed by liver enzymes, unlike N-nitrosodiethanolamine. The lethal and mutagenic DNA damages produced by this unidentified product were susceptible to some extent to the repair functions of the bacteria. (+info)
Antitumor effect of allogenic fibroblasts engineered to express Fas ligand (FasL).
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Fas ligand is a type II transmembrane protein which can induce apoptosis in Fas-expressing cells. Recent reports indicate that expression of FasL in transplanted cells may cause graft rejection and, on the other hand, tumor cells may lose their tumorigenicity when they are engineered to express FasL. These effects could be related to recruitment of neutrophils by FasL with activation of their cytotoxic machinery. In this study we investigated the antitumor effect of allogenic fibroblasts engineered to express FasL. Fibroblasts engineered to express FasL (PA317/FasL) did not exert toxic effects on transformed liver cell line (BNL) or colon cancer cell line (CT26) in vitro, but they could abrogate their tumorigenicity in vivo. Histological examination of the site of implantation of BNL cells mixed with PA317/FasL revealed massive infiltration of polymorphonuclear neutrophils and mononuclear cells. A specific immune protective effect was observed in animals primed with a mixture of BNL or CT26 and PA317/FasL cells. Rechallenge with tumor cells 14 or 100 days after priming resulted in protection of 100 or 50% of animals, respectively. This protective effect was due to CD8+ cells since depletion of CD8+ led to tumor formation. In addition, treatment of pre-established BNL tumors with a subcutaneous injection of BNL and PA317/FasL cell mixture at a distant site caused significant inhibition of tumor growth. These data demonstrate that allogenic cells engineered with FasL are able to abolish tumor growth and induce specific protective immunity when they are mixed with neoplastic cells. (+info)
Systemic administration of rIL-12 synergistically enhances the therapeutic effect of a TNF gene-transduced cancer vaccine.
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Interleukin-12 (IL-12) is a potent antitumor cytokine, which induces and enhances the activity of natural killer (NK) cells, lymphokine activated killer (LAK) cells and cytotoxic T lymphocytes (CTL). IL-12 also stimulates IFN-gamma production from both T cells and NK cells. In this study, we transfected methylcholanthrene-induced fibrosarcoma (MCA-D) with TNF gene and investigated the therapeutic effect of TNF gene-transduced cancer vaccine and whether the vaccination effect is enhanced by systemic administration of recombinant IL-12 (rIL-12), in a murine model. TNF gene-transduced cancer vaccine or systemic administration of rIL-12 showed slight or moderate inhibition of pre-established tumor. However, simultaneous application of the vaccine and rIL-12 resulted in complete eradication. The cytotoxicity of CTL against parental tumor cells was enhanced with the combination of the vaccine and rIL-12, and IFN-gamma production from spleen cells also increased synergistically. Our findings show that synergistic enhancement of CTL activity and IFN-gamma production could play an important role in the antitumor effect of combination therapy using TNF gene-transduced cancer vaccine and rIL-12. (+info)
The role of homophilic binding in anti-tumor antibody R24 recognition of molecular surfaces. Demonstration of an intermolecular beta-sheet interaction between vh domains.
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The murine antibody R24 and mouse-human Fv-IgG1(kappa) chimeric antibody chR24 are specific for the cell-surface tumor antigen disialoganglioside GD3. X-ray diffraction and surface plasmon resonance experiments have been employed to study the mechanism of "homophilic binding," in which molecules of R24 recognize and bind to other molecules of R24 though their heavy chain variable domains. R24 exhibits strong binding to liposomes containing disialoganglioside GD3; however, the kinetics are unusual in that saturation of binding is not observed. The binding of chR24 to GD3-bearing liposomes is significantly weaker, suggesting that cooperative interactions involving antibody constant regions contribute to R24 binding of membrane-bound GD3. The crystal structures of the Fabs from R24 and chR24 reveal the mechanism for homophilic binding and confirm that the homophilic and antigen-binding idiotopes are distinct. The homophilic binding idiotope is formed largely by an anti-parallel beta-sheet dimerization between the H2 complementarity determining region (CDR) loops of two Fabs, while the antigen-binding idiotope is a pocket formed by the three CDR loops on the heavy chain. The formation of homophilic dimers requires the presence of a canonical conformation for the H2 CDR in conjunction with participation of side chains. The relative positions of the homophilic and antigen-binding sites allows for a lattice of GD3-specific antibodies to be constructed, which is stabilized by the presence of the cell membrane. This model provides for the selective recognition by R24 of cells that overexpress GD3 on the cell surface. (+info)