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K W Brunson

Publications and source records attributed to K W Brunson.

17 recordsLinked to original sources
PubMed1992

Therapeutic agents for treatment of established metastases and inhibitors of metastatic spread: preclinical and clinical progress.

This article reviews recently described agents for the treatment of established metastases or inhibitors of metastatic spread. Recent progress in both preclinical models of experimental metastasis and clinical evaluation is highlighted. Where possible, distinctions are made between therapeutic agents for established metastatic tumors and those that merely interfere with the process of metastasis. The approaches emphasized include radiotherapy, cytotoxic chemotherapy, targeting the metastatic process and tumor metastases (adhesion, invasion, and angiogenesis), and modulation of the immune response, including chemoimmunotherapy. Emphasis has been placed on the necessity of using appropriate animal models of metastatic disease for the discovery and development of novel and effective antimetastatic therapeutic agents. Also addressed is the likelihood that future approaches to the metastasis problem will employ novel combined antimetastatic therapeutic modalities.

Adjuvants, Immunologic↗
PubMed1990

Differential cell surface antigen expression on metastatic variant lymphoma cell lines.

In the present investigation we have studied the cell surface antigenicity of a syngeneic murine metastatic lymphoma model system. This system is comprised of a highly malignant and metastatic RAW117-H10 subline and the less malignant/metastatic parental RAW117-P cell line. Using rabbit antisera raised against whole tumor cells we have been able to identify two major glycoprotein antigens which are differentially expressed on the cells. Although these antigens have a similar molecular weight (70 kD), they are antigenically distinct as determined by in vitro cytotoxicity assays. The levels of glycosylation on these glycoproteins were also found to be different. Increased expression of one of the antigenic components on the metastatic RAW117-H10 cells appeared to be associated with metastasis in this tumor model system.

Antigens, Neoplasm↗
PubMed1988

Regulated expression of the human mutant ras gene after transfection of BALB/c mouse embryo fibroblast cells.

Four continuous cell lines constructed by transfecting BALB/c mouse fibroblast cells with an expression system that has the mutant c-Ha-ras gene under control of a truncated version of the mouse metallothionein-1 (mt-1) promoter were characterized for zinc-induced phenotype switching. These cells were selected for transformation in the presence of zinc, a known inducer of the mt-1 promoter. When the transfected cells were grown in medium depleted of zinc, there was a dramatic reduction in their soft agar cloning efficiency. Adding zinc back to the medium restored the transformed phenotype in a dose-dependent manner. Analysis of the intracellular p21 levels of induced and uninduced cells showed that zinc was modulating the expression of the transfected ras gene. In vivo studies done with syngeneic mice showed that zinc-induced cells were tumorigenic and formed metastatic lesions in the lungs of the inoculated animals.

Animals↗
PubMed1988

Effects of differentiation inducing chemicals on in vivo malignancy and NK susceptibility of metastatic lymphoma cells.

In the present investigation we have determined the effects of the differentiation-inducing chemicals dimethyl sulfoxide (DMSO) and sodium butyrate on the growth and tumorigenicity of a highly malignant/metastatic cell line (RAW117-H10) and its less tumorigenic parental lymphoma cell line (RAW117-P). Both of these agents at doses shown to be nontoxic slowed the growth of these cells in suspension culture and significantly lengthened the doubling time while reducing colony formation in the agar tumor stem cell assay. Corresponding to these observations, the in vivo tumorigenicity of the highly malignant RAW117-H10 line was reduced by both chemicals but particularly by butyrate treatment. In addition, both agents increased the expression of some glycoproteins and the glycolipid asialo GM1. There was also a corresponding increase in the NK susceptibility of the normally NK resistant RAW117-H10 cells. To determine if the decreased malignancy of the highly malignant cells following treatment with the chemical agents was primarily due to the alteration in cell surface glycoconjugates or merely due to concomitant decreased growth potential, we transplanted highly glycosylated membrane fragments from normal syngeneic thymocytes to both RAW117-P and RAW117-H10 cells using a Sendai virus mediated membrane fusion technique. The in vivo tumorigenicity of the membrane altered RAW117-H10 cells was significantly decreased. These results strongly suggest that the decreased in vivo malignancy of RAW117-H10 cells resulting from treatment with chemical differentiation agents is caused by their increased susceptibility to NK cell mediated lysis which in turn results from cell surface changes involving altered, primarily increased, expression of certain glycosylated surface molecules. The cell surface glycoconjugates, such as receptors for certain lectins and glycolipid asialo GM1, can be used as markers for malignant potential and NK sensitivity of malignant lymphoid cells.

Animals↗
PubMed1987

Cell surface properties associated with malignancy of metastatic large cell lymphoma cells.

The highly malignant and metastatic RAW117-H10 cell line was developed by in vivo selection from the Abelson leukemia virus induced parental RAW117-P lymphoma. In this study we have characterized these cell lines with regard to their expression of lymphocyte and macrophage differentiation antigens, adherence, phagocytic properties, binding of various lectins, binding of antibodies to glycolipid asialo-monoganglioside, and the role of butanol extractable cell surface molecules to determine if any of these cell surface properties are associated with the malignant potential of RAW117-H10 cells. The only major difference in immunological phenotypes between RAW117-P and RAW117-H10 cells was an increased expression of Thy-1 molecules by the latter. However, the highly malignant RAW117-H10 cells bound significantly less concanavalin A, Ricinia communis agglutinin, succinylated wheat germ agglutinin, and particularly anti-asialomonoganglioside than their parental counterpart and were resistant to natural killer cell mediated cytolysis. Removal of butanol extractable cell surface molecules significantly decreased the malignancy of RAW117-H10 cells and increased their susceptibility to natural killer cell mediated cytolysis. The butanol treated RAW117-H10 cells regained high in vivo malignancy when recultured for 3 days to permit regeneration of their cell surface components. The butanol extracted RAW117-H10 cells still expressed high levels of Thy-1 indicating that this most probably represented "inappropriate" antigen expression. Since the expression of lymphocyte differentiation antigens did not correlate with the malignant behavior of the cells, we postulate that these antigenic differences merely represent phenotypic variation. The decreased malignant potential of the butanol treated RAW117-H10 cells did correlate with increased cell surface anti-asialomonoganglioside binding (glycolipid) and increased natural killer cell susceptibility.

Animals↗
PubMed1987

Differential growth characteristics of low and high metastatic variant RAW117 murine lymphosarcoma cells.

The Abelson-virus-induced murine lymphosarcoma cell line RAW117-P and its in vivo selected highly malignant and metastatic variant RAW117-H10 have been studied for their growth in vivo, in vitro and in semi-solid agar. The highly malignant metastatic variant RAW117-H10 cells killed syngeneic Balb/c mice rapidly and formed 100-200 times more gross liver tumor nodules than the less malignant parental RAW117-P cells. On the other hand, there were no differences between the in vitro growth kinetics of these cells as measured by various parameters such as metaphase arrest or cells in DNA synthetic phase on various days after the initiation of the culture. These cells could be grown in semi-solid agar and formed characteristic colonies. The parental cells formed many very small colonies, whereas the highly malignant cells formed fewer, but very large colonies in soft agar. These results suggest that differential interactions of highly malignant RAW117-H10 cells with the host, particularly the host immune system, are much more important for regulating the number of metastases than any intrinsic growth advantages. It appears that growth differences, potentially based on lack of response to feedback inhibition rather than on kinetic parameters, are responsible for highly malignant RAW117-H10 cells forming larger colonies both in agar in vitro and in the liver in vivo.

Animals↗
PubMed1979

Selection of malignant melanoma variant cell lines for ovary colonization.

Murine melanoma line B16-F1, which shows some specificity for metastatic organ colonization of lung but rarely metastasizes to ovary, was used to select variant cell lines with increased preference for experimental ovary metastasis. Ovary-colonizing melanoma cell lines were sequentially selected in syngeneic C57BL/6 mice by repeated intravenous administration and surgical recovery of ovarian melanoma tumors for tissue culture. After ten selections for experimental ovary metastasis, line B16-010 was established which formed experimental metastatic ovary tumors in almost every test animal. In tissue culture B16-010 cells grew in circular colonies with rounded, smooth cell peripheries compared to B16-F1 cells which were flatter, grew in irregular patterns, and exhibited long cellular projections. Ovary-selected B16 lines contained less melanin pigment (B16-010 less than B16-05 less than B16-01 approximately equal to B16-F1) compared to the parental melanoma line. Together with previous cloning and selection data, these results are consistent with the preexistence of highly malignant cells in the parental tumor population that possess the ability to metastasize to specific organs.

Animals↗
PubMed1978

Lipopolysaccharide effects on sensitive and resistant variant Chinese hamster ovary cell lines.

Chinese hamster ovary (CHO . K1 . PRO) cell growth was inhibited by addition of a gram-negative bacterial lipopolysaccharide (LPS) to the cell culture medium. Growth inhibition began after three or four days of incubation, was dose-dependent up to a maximum at an LPS concentration of 500 microgram/ml and was accompanied by cell shape changes and enhanced cytoplasmic vacuolization. Formation of bizarre CHO . K1 . PRO cell shapes and vacuole formation were most pronounced after seven days of incubation with LPS and could be observed by light and electron microscopy. An LPS-resistant cell population was obtained by intermittent in vitro exposure to high levels of LPS; these variant cells or clones derived from them failed to display growth inhibition in the presence of LPS. A clone from the LPS-resistant variant population showed altered cell properties compared to the parental cell line which included changes in cell morphology, adhesion, and endocytosis. Parental cells was markedly density-inhibited, whereas the cariant clone exhibited considerable growth after confluency. The LPS-resistant variant cells showed a more elongated morphology than the parental line. No significant differences were observed between rates of detachment of parental and variant cells when sparse cultures of either line were removed from tissue culture dishes by ethylenediaminetetracetate (EDTA). However, at confluency approximately 100% of the variant cells versus 35% of the parental cells were removed by EDTA in one hour. Measurements of 125I-ferritin uptake by parental and variant cells showed approximately twenty-fold and twofold increases, respectively, in uptake induced by LPS when compared to untreated control cultures.

Animals↗
PubMed1978

Selection and biologic properties of malignant variants of a murine lymphosarcoma.

A syngeneic tumor model system with the RAW117 lymphosarcoma cell line was developed for use in investigations of host and tumor cell properties associated with an enhanced state of malignancy. This BALB/c mouse model was found to be similar to human lymphosarcoma in that liver and spleen were the major organs involved. Sequential in vivo selections were performed by iv tumor cell inoculation, removal of resulting solid liver tumor nodules for growth in vitro, and reinjection of the cultured cells iv. After ten such sequential selections for implantation, invasion, survival, and growth in liver, a lymphosarcoma cell line was obtained (RAW 117-H10) that formed approximately 200-fold more gross liver tumor nodules than did the parental tumor cell line in comparative biologic assays and displayed enhanced malignant properties when monitored by time of host death. Very few lung nodules or tumors were present at other sites with either the parental or any of the selected RAW117 lines, which confirms previous reports in which in vivo sequential selection yielded stable cell lines with preferential tumor colonization at specific sites.

Animals↗
PubMed1978

Specificity of arrest, survival, and growth of selected metastatic variant cell lines.

Animal tumor models for blood-borne metastasis have been developed by in vitro cloning or in vivo selection of malignant tumor cell populations to obtain organ-preferring variant tumor cell lines with altered arrest, survival, invasion, and growth properties. Selection and some tumor cell characteristics of lung-, brain-, and ovary-colonizing metastatic B16 melanoma, liver-colonizing RAW114 lymphosarcoma, and lung-colonizing MSV3T3 vasoformative sarcoma variant lines will be discussed along with additional data, suggesting that tumor cells of varying malignant potential preeexist in the unselected tumor population.

Animals↗
PubMed1976

Cellular interactions in the metastatic process.

Tumor metastasis is a multistep process which is dependent on both host and tumor properties. It is proposed that the interaction of normal host blood and endothelial cells with circulating malignant cells result in tumor cell arrest leading to subsequent metastases at specific secondary sites. In experimental animal models the frequency and location of metastatic foci can be manipulated by repeated in vivo selection for tumor cell variants showing altered preference for organ-specific implantation and survival. These tumor cell variants can be used to determine the cell surface structures and enzymes involved in the various steps of the metastatic process.

Animals↗
PubMedDate not supplied

Characterization of metastasis-associated antigens on RAW117 lymphosarcoma cell lines.

A syngeneic murine model system was used to study the immunobiology of metastasis. The highly malignant RAW117-H10 cell line was compared to the less malignant parental RAW117-P cell line from which it was derived, for expression of cell surface antigens. Using rabbit antisera, two major glycoprotein antigens were detected on the tumor cell surfaces. Antigen-I was uniformly distributed over the surface of these cells whereas antigen-II had a patchy, punctate distribution. Antigen-I was displayed less on RAW117-H10 cells than on RAW117-P cells, while the expression of the other serologically distinct antigen (antigen-II) was increased on RAW117-H10 cells compared to the less malignant parental (RAW117-P) cells. This differential antigen expression was assessed by immunodiffusion, a 125I-labeled protein-A binding assay, flow cytometry and rocket immunoelectrophoresis. Both these antigens had a molecular weight of 70,000 daltons. Antigen-I bound the lectin concanavalin-A whereas antigen-II did not, suggesting that antigen-I might be the viral envelope glycoprotein gp70. The identity of antigen-II is presently unknown. Syngeneic Balb/c mice injected with highly malignant and metastatic RAW117-H10 cells coated with antiserum to antigen-I were protected from early death; this effect was not seen with RAW117-H10 cells coated with antiserum to antigen-II. The opsonizing qualities of these antisera may be different due to antibody to antigen-II being shed more rapidly than antibody to antigen-I.

Animals↗
PubMedDate not supplied

Enhanced antiproliferative activity by metastatic RAW117 lymphoma cells.

The highly malignant/metastatic murine large cell lymphoma cell line RAW117-H10 forms 100-200 times more liver metastatic tumors than its parental counterpart cell line RAW117-P. RAW117-H10 cells, but not the less malignant/metastatic parental cells, significantly inhibited the mitogen-induced proliferation of normal syngeneic Balb/c and allogeneic ICRC mouse spleen cells. Such an inhibition also occurred when mitomycin-C treated metastatic lymphoma cells were added 24 h after initiation of culture, indicating that no competition with mitogen binding sites on the lymphocytes was necessary for inhibition of proliferation. 'Antiproliferative' cell surface molecules were extracted non-cytolytically from the RAW117-H10 cells using butanol. The butanol extracts from the metastatic RAW117-H10 cells also inhibited the mitogen-induced proliferation and natural killer (NK) cell-mediated cytotoxicity of normal spleen cells. Our results indicate that these 'antiproliferative' cell surface molecules of metastatic murine RAW117-H10 lymphoma cells may have important role(s) in tumor-mediated host immunosuppression.

Animals↗