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K W Brunson

Publications and source records attributed to K W Brunson.

30 records · Page 2Linked to original sources
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↗
PubMed1974

Pyrogenic specificity of streptococcal exotoxins, staphylococcal enterotoxin, and gram-negative endotoxin.

Streptococcal exotoxin and staphylococcal enterotoxin share several biological properties, including pyrogenicity, lymphocyte mitogenicity, and enhancement of gram-negative endotoxin lethality. These analogies of the toxins prompted comparative pyrogenic studies. When American Dutch rabbits were immunized by repeated intravenous injections of small amounts of staphylococcal enterotoxin, they exhibited a decreased febrile response upon challenge when compared with control animals not previously injected. The same animals responded similarly to control groups when challenged with streptococcal exotoxin A, B, or C. No cross-reactivity was observed in reciprocal cross-tests, using animals immune to the streptococcal toxins and challenging with staphylococcal enterotoxin. No cross-reactivity between either the streptococcal or staphylococcal toxins and bacterial endotoxin was observed.

Animals↗
PubMed1968

A selective-differential medium for detection of Streptococcus agalactiae.

A practical culture medium which allows direct plating of milk samples for detection and differentiation of Streptococcus agalactiae within 48 hours is described. Most other micro-organisms likely to be present in these samples are inhibited. Although some strains of Staphylococcus species and ofStreptococcus faecalis are able to grow, they may be differentiated on the basis of reaction in the medium surrounding the colonies.

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↗
PubMedDate not supplied

Enhanced anti-metastatic efficacy of IL-2 activated NK (A-NK) cells with novel benzothiazoles.

We have previously shown that A-NK cells when locoregionally administered accumulate within established cancer metastases and establish direct contact with both tumor cells and microvascular endothelial cells. Nevertheless, the accumulation of adoptively transferred A-NK cells into established cancer metastases is not sufficient for therapeutic efficacy in the B16 melanoma model. We have therefore attempted to enhance the anti-metastatic therapeutic efficacy of adoptively transferred A-NK cells with standard anticancer chemotherapeutic agents. We have found that chemoimmunotherapy with A-NK cells plus cyclophosphamide to be more effective than A-NK cell adoptive immunotherapy alone. We have now built on these findings, by examining the ability of novel biologic response modifiers (low molecular weight benzothiazole compounds) to augment adoptive immunotherapy with A-NK cells. Two compounds KB-R4107 (4-methoxy-2-(4-t-butylphenyl)benzothiazole) and KB-R4250 (4-methoxy-2-(4-trifluoromethylphenyl)benzothiazole) enhanced reduction of B16 melanoma pulmonary metastases mediated by A-NK cell adoptive immunotherapy. Both compounds were administered for 5 days prior to administration of A-NK cells at 100 mg/kg p.o. All experimental groups initially contained at least 7 animals and were examined for tumor burden on day 10. With B16 melanoma cells administered on day 0 and A-NK cells administered on Day 4, KB-R4107 and KB-R4250 yielded on average a 64% and 52% reduction in metastatic burden, respectively compared to an average 17% reduction using A-NK cells alone. In contrast these compounds did not diminish metastatic burden when administered alone. KB-R4107 and KB-R4250 are therefore low molecular weight, heterocyclic, biological response modifiers which can augment the anti-metastatic therapeutic effect of adoptively transferred A-NK cells.

Animals↗
PubMedDate not supplied

Neuroendocrine modulation of tumor metastases. I. Effect of adrenalectomy on B16 melanoma metastases.

There is increasing evidence to suggest a link between the neuroendocrine system and the immune system. Since it is well known that the immune response influences the establishment, progression or elimination of malignancy, we have examined the effects of adrenalectomy on B16 melanoma pulmonary tumor metastases and immune function in C57BL/6 mice to investigate the role of adrenal corticosteroids. Adrenalectomized mice were injected with 10(5) B16 melanoma cells on day 0. On day 9 the mice were sacrificed and the number of lung colonies counted. Adrenalectomized animals had a greater than 3 to 4-fold increase in the number of metastases as compared with sham operated animals. Steroid replacement therapy using dexamethasone delivered at 1 microgram/hr did not lead to any reduction in tumor metastases in adrenalectomized animals. These studies indicate that normal levels of adrenal steroids may influence the ability of tumor cells to colonize target organs and/or the ability of the immune system to mount an effective response.

Adrenalectomy↗
PubMedDate not supplied

Interleukin-2 (IL-2) activated natural killer (A-NK) cells: binding to microvascular endothelial cells and BRM enhancement of cytolytic activity.

A syngeneic in vitro system was developed for investigation of the binding of purified murine interleukin-2 (IL-2) activated natural killer (A-NK) cells to murine microvascular endothelial cells. This system is potentially useful as a model to investigate biochemical and molecular events underlying the binding of A-NK cells to microvascular endothelial cells within metastases in vivo that we have previously noted using electron microscopy. A-NK/endothelial cell binding in the syngeneic system was compared with the binding of allogeneic A-NK cells to the endothelial cells. Among test agents used to pretreat the A-NK cells for modulation of binding, lipopolysaccharide (LPS) most consistently enhanced binding. Additionally, test agents were also used in concurrent assays of A-NK cytolytic activity versus YAC-1 and P815 tumor cell targets. Polyinosinic: polycytidylic acid (poly IC), and gamma interferon (gamma IFN) were among the test agents which enhanced A-NK cell cytolytic activity.

Animals↗
PubMedDate not supplied

Stromal cell involvement in leukemogenesis and carcinogenesis.

There is increasing evidence that the supportive cells (stromal cells) in nearly all organs containing cellular self-renewal systems are involved in carcinogenesis. One body of evidence specific to irradiation leukemogenesis documents the role of irradiated murine stromal cells in the cell biologic changes associated with evolution of leukemia in cocultivated, nonirradiated stem cells. Stem cell phenotypic changes that have been documented include upregulation of cell surface c-fms, downregulation of growth requirement for obligatory growth factors, and the appearance of novel transcripts detected by differential display. A second body of evidence documents the potential role of stromal cells functioning as biologic tumor promoters through their release of reactive oxygen species (ROS), and production of altered adhesion molecules or growth factors during the chronic response to chemical or physical carcinogens. These molecular biologic mechanisms, potentially operative in stromal cells, can block apoptosis and induce DNA strand breaks in closely associated self-renewing stem cells. In an in vivo model of irradiation effects on lung stromal cells, we have irradiated the lungs of control C57BL/6J mice or other mice with orthotopic Lewis lung tumors and shown that TGF-beta release is increased following irradiation. The TGF-beta increase by irradiation may specifically be inhibited by administering an inhalation plasmid liposome mixture containing a transgene for human manganese superoxide dismutase prior to irradiation. An appreciation of the role of stromal cells in leukemogenesis and carcinogenesis may also be very relevant to the design of new therapeutic strategies for treatment of cancer, particularly since current strategies focus on eradication of stem cell transformants and do not rigorously address the persistence of surviving stromal cells.

Animals↗
PubMedDate not supplied

Augmentation of IL-2 activated natural killer cell adoptive immunotherapy with cyclophosphamide.

UNLABELLED: We have previously documented that adoptively transferred, IL-2 activated natural killer (A-NK) cells can accumulate within established pulmonary metastases. Since we have observed that increases in the accumulation of A-NK cells do not always lead to increases in therapeutic efficacy, we examined the ability of cyclophosphamide to enhance the therapeutic efficacy of A-NK cells. Animals with established B16 melanoma or Lewis lung carcinoma pulmonary metastases were treated with A-NK cell adoptive immunotherapy, either alone or following treatment with chemotherapeutic doses of cyclophosphamide. Adoptive immunotherapy studies with A-NK cells yielded at most a 30% reduction in the number of pulmonary metastases; however, cyclophosphamide (300 mg/kg) consistently reduced the size of metastatic colonies. In contrast, the combination therapy of A-NK cells plus cyclophosphamide was more effective than adoptive immunotherapy alone. In addition, polyethylene glycol IL-2 is superior to IL-2 in these studies. CONCLUSIONS: Our studies suggest that chemoimmunotherapy with A-NK cells plus cyclophosphamide may be more effective than adoptive immunotherapy alone since it results in the reduction in both the size and number of pulmonary metastases.

Adoptive Transfer↗
PubMedDate not supplied

Flavone acetic acid enhances accumulation of IL-2 activated NK cells within established metastases.

Flavone acetic acid, an agent which has been implicated in both tumor vasculature collapse and NK cell activations, has been tested recently as a potential anti-cancer chemotherapeutic agent. We have tested this agent in combination with adoptive immunotherapy using IL-2 activated natural killer (A-NK) cells in a metastatic B16 melanoma model in C57BL/6 mice. By using rhodamine-labeled A-NK cells we have been able to quantitate both the number of A-NK cells that localize within each tumor section and the percentage of the tumor area occupied by A-NK cells. This has been accomplished using an image analysis system. Flavone acetic acid (200 mg/kg, i.p.) given one day prior to the injection of A-NK cells increased the area of the tumor occupied by A-NK cells and the area of individual A-NK cells approximately 2-fold; however, it did not appear to increase the number of A-NK cells per tumor cross-section. Nevertheless, this increase did not lead to any significant change in the therapeutic efficacy of A-NK cell adoptive immunotherapy. Our studies therefore suggest that mere enhancement of A-NK cell recruitment into tumor metastases does not necessarily translate into enhanced metastatic therapeutic efficacy. Moreover, this method may be a useful tool for pre-screening of compounds which enhance the accumulation of adoptively transferred cells into tumor metastases prior to in vivo screening for therapeutic efficacy.

Adjuvants, Immunologic↗