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F R Balkwill

Publications and source records attributed to F R Balkwill.

At least 55 records · Page 3Linked to original sources
PubMed1990

Investigation of cytokine gene expression in human colorectal cancer.

RNA was extracted from 28 samples of colorectal cancer and 26 samples of adjacent normal bowel. Northern blotting analysis showed the presence of mRNA for tumor necrosis factor (TNF) in 15 of 28 cancer samples and 6 of 26 matched normal areas. In 10 patients, TNF mRNA was found only in the tumor; in 5, TNF mRNA was seen in tumor and normal areas; and in only 1 was TNF mRNA seen in the normal, but not the malignant, area. The expression of TNF mRNA was not related to the stage of disease, degree of lymphocyte infiltration, or necrosis in the tumor. Blots were reprobed for gamma-interferon, interleukin (IL) 1 alpha and beta, IL-6, and transforming growth factor beta 1 mRNA. One tumor sample was positive for IL-1 beta, and one normal sample expressed interferon gamma mRNA. All samples had transforming growth factor beta 1 mRNA, and there was no obvious difference between levels in tumor tissues or adjacent normal areas. In situ hybridization studies with a TNF riboprobe showed that TNF mRNA was only detectable in a small minority of mononuclear and predominantly stromal cells. Immunohistochemistry on sequential sections showed that CD4- and CD8-positive lymphocytes, and macrophages, were present in the stroma. An antibody to the macrophage C3b receptor identified a minority population whose distribution corresponded closely to the cells labeled with the TNF riboprobe.

Biological Factors↗
PubMed1990

In situ detection of tumour necrosis factor in human ovarian cancer specimens.

In situ hybridisation was used to study the local expression of tumour necrosis factor (TNF) mRNA in human ovarian tumours. In 8 of 14 ovarian cancers studied, a minority of cells in the epithelial areas of the tumour contained TNF mRNA. In individual high-power fields as many as 8% of cells were positive for TNF mRNA. Immunohistochemical studies on sequential sections and the morphology of the positive cells led to the conclusion that the ovarian tumour cells were transcribing the TNF gene. There was immunohistochemical evidence of the production of TNF protein by the tumour cells and TNF protein in a tumour lysate. The production of TNF by human ovarian cancer cells may influence the biology of the tumour, contribute to neoplastic progression and alter the response to therapy.

Antibodies, Monoclonal↗
PubMed1990

Cells secreting tumour necrosis factor show enhanced metastasis in nude mice.

A tumour cell may acquire the ability to invade and metastasise via heritable changes in its genome and/or changes in the local environment. Chinese hamster ovary (CHO) cells transfected with the gene for human TNF (CHO/TNF cells) showed a greatly enhanced ability to invade peritoneal surfaces and metastasise in nude mice compared with cells transfected by the vector alone. In situ hybridisation with a riboprobe for human TNF showed that the CHO/TNF cells were actively transcribing this cytokine after in vivo injection. Neutralising antibodies to human TNF, both whole IgG and F(ab)2 fragments, abrogated the enhanced metastatic activity of the TNF-secreting cells. Thus transfection of a cytokine/growth-factor gene can confer a metastatic phenotype on the recipient cell.

Animals↗
PubMed1989

Paradoxical effects of tumour necrosis factor in experimental ovarian cancer.

Recombinant human tumour necrosis factor (rhTNF) had anti-tumour activity against 2 of 3 human ovarian cancer xenografts growing intraperitoneally (i.p.) in nude mice, producing a moderate (2- to 3-fold) increase in mouse survival time. rhTNF therapy caused a marked influx of polymorphonuclear neutrophils into the peritoneal cavity during the first few days of daily therapy. This was accompanied by a decrease in the number of peritoneal macrophages and lymphocytes. rhTNF also caused an increase in peripheral blood neutrophils. With continuation of daily therapy, the peritoneal neutrophil influx diminished, with restoration of the macrophage and lymphocyte populations. After 2 to 3 weeks there was a small but significant increase in peritoneal Thy 1.2+ cells. In the peripheral blood, the neutrophilia was less marked than at the start of therapy. Mild myelosuppression was indicated by significant falls in haemoglobin and platelet counts. Within 24 hr of the start of therapy in the 2 responsive xenografts (HU and LA) tumour clumps in the peritoneum were surrounded by host inflammatory cells, and tumours fixed to the omentum were infiltrated by neutrophils and mononuclear cells. In both instances necrosis was evident by 4 to 7 days. The third xenograft (OS) grew although the rhTNF therapy induced the same inflammatory changes in the peritoneum. In contrast to its positive effect on the survival of tumour-bearing mice, rhTNF promoted the adhesion of tumour cells to the peritoneum and their establishment as tumour nodules below the mesothelial surface. This phenomenon was seen in all 3 xenografts including the OS xenograft which did not respond in any other way to rhTNF therapy.

Animals↗
PubMed1989

Interferons.

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Animals↗
PubMed1989

Action of recombinant alpha interferon against experimental and spontaneous metastases in a murine model.

The therapeutic potential of rHuIFN-alpha A/D, a hybrid human IFN molecule with equal activity on murine cells, was studied in experimental and spontaneous metastatic models of a murine colon carcinoma COLON 26. rHuIFN-alpha A/D inhibited experimental pulmonary metastases of COLON 26 and prolonged the survival of BALB/c mice. Dose scheduling, survival and tumour-cell clearance studies showed that the first 5 days were critical in the inhibition of pulmonary metastases. However, it is unlikely that lung NK cells were involved in the anti-metastatic effect of rHuIFN-alpha A/D because inhibition of pulmonary metastases and a decrease in radio-labelled tumour-cell survival was seen in BALB/c mice depleted selectively of their NK cells by prior treatment with rabbit antiasialoGMI serum. Although rHuIFN-alpha A/D stimulated NK-cell activity in BALB/c mice, it was ineffective in abrogating the NK suppressant action of rabbit anti-asialoGMI serum on murine lung NK cells. Thus, IFN may mediate its early antimetastatic effect via a mechanism independent of NK-cell stimulation. IFN also inhibited the development of lung metastases from s.c. COLON 26 tumors in normal, NK-depleted and T-cell-deficient mice.

Animals↗
PubMed1989

The cytokine network.

The availability of pure recombinant cytokines and molecular probes for their genes has generated an avalanche of scientific information. These data show that cytokines have a broad and overlapping range of cell regulatory activity both in vitro and in vivo. New factors are added to the cytokine list, and new functions reported for existing cytokines, with such frequency that it is difficult to retain an overall picture. With this problem in mind, a large wallchart was designed and was displayed at the second meeting of the British Cytokine Group* whose members pooled their collective knowledge, to list the known biological activities of these cytokines. This wallchart of cytokine activity, now referenced, is reproduced for Immunology Today. It is not a final list: new information and cytokines are continually reported and space has been left for readers to make their own additions. A neutrophil-activating peptide variously named monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil-activating factor (NAF), lymphocyte-derived neutrophil-activating peptide (LYNAP), which has been suggested as a candidate for interleukin 8 (IL-8), is included.

Biological Factors↗
PubMed1989

Interferons alpha and gamma differ in their ability to cause tumour stasis and regression in vivo.

We have studied the antitumour activity of human lymphoblastoid interferon-alpha [HuIFN-alpha(N)] and human recombinant interferon-gamma (rHuIFN-gamma) on 12 early passage (passages 2-7) human tumour xenografts derived from primary malignancies. Systemic daily therapy of established (approx. 0.5 cm diameter) subcutaneous xenografts with HuIFN-alpha(N) resulted in significant tumour stasis, and occasionally regression, in nine of 12 breast, bowel, and ovarian cancers studied. A significant decrease in tumour mitotic index was seen in three HuIFN-alpha(N) sensitive breast tumours. In contrast, none of nine of the same tumours responded significantly to rHuIFN-gamma therapy. Direct administration of rHuIFN-gamma into the tumour did not improve its therapeutic efficacy. However, when tumour cells from xenografts were dissociated and grown as colonies in soft agar, both IFNs, used at doses that are found circulating in vivo after therapy, inhibited colony development in three of three lines tested. Combinations of rHuIFN-gamma and HuIFN-alpha(N) had no synergistic benefit in four of four xenografts studied.

Animals↗
PubMed1989

Tumour necrosis factor.

Tumour necrosis factor, TNF, possesses the attributes of a typical cytokine, being a pleiotropic cell regulatory protein whose activity is largely determined by the cell type to which it binds and the presence of other protein regulators. Thus TNF can be a growth factor, cytotoxin, cytostatic agent or inducer of differentiation. This cytokine is also an important inflammatory mediator regulating the activity of neutrophils, eosinophils, T and B lymphocytes and modulating the properties of the vascular endothelium. All of these actions may play a role in the ability of TNF to induce necrosis of experimental animal tumours, but the potential of this cytokine in therapy of human cancer is uncertain. The increasing evidence for a role for TNF in the pathophysiology of acute and chronic disease makes the use of specific TNF antagonists an equally interesting therapeutic possibility.

Animals↗
PubMed1989

The relevance of animal tumour models to the preclinical screening of cytokines.

This article assesses the value of animal models in determining the mechanism of action and spectrum of activity of cytokines. It examines the merits of animal models of transplantable and metastatic tumours and the value of human xenografts grown in immunodeficient mice and discusses how well they compare with the human situation. Results from the use of five cytokines in animal models of cancer are presented.

Animals↗
PubMed1988

An autoimmune aetiology for hypothyroidism following interferon therapy for breast cancer.

Alpha-interferon has been administered as an adjuvant treatment for women with loco-regional relapse of breast cancer. During the course of treatment 5/10 (50%) of women receiving interferon developed de novo thyroid autoantibodies. Three patients became clinically myxoedematous, with biochemical evidence of hypothyroidism which responded to thyroxine replacement therapy. The leucocyte alpha-interferon preparations used in the trial enhanced Class I but not Class II MHC antigens on thyrocytes in vitro. These data strongly suggest that patients receiving alpha-interferon therapy should be closely monitored for the possible development of thyroid dysfunction and that thyroid antibody determination can greatly help to predict overt thyroid clinical abnormalities.

Autoantibodies↗
PubMed1988

Human interferons inhibit experimental metastases of a human melanoma cell line in nude mice.

Therapy with human lymphoblastoid interferon HuIFN-alpha(N1), or recombinant human interferon gamma, rHuIFN-gamma, inhibited experimental pulmonary metastases of the human melanoma cell line, DX3-azac, in BALB/c nude mice and significantly prolonged survival. The human IFNs had no effect on nude mouse lung and spleen NK cell activity, lung macrophage activity, haemoglobin or white cell counts. HuIFN-alpha(N1) had no effect on the levels of the IFN induced enzyme 2-5A synthetase in nude mouse lungs although the rHuIFN-gamma caused some elevation. In addition, clearance of radiolabelled DX3-azac cells was identical in control or human IFN treated mice, and there was no histological evidence of an increase in immune effector cells associated with the metastatic lesions in treated mice. Human IFN therapy did not affect the state of differentiation of the melanoma cells in vivo as measured by melanin content, but both IFNs inhibited the development of colonies of DX3-azac cells in vitro. We conclude that in this model system IFNs have direct anti-proliferative effects on metastatic cells.

Animals↗
PubMed1987

Enhanced metastases of a mouse carcinoma after in vitro treatment with murine interferon gamma.

We have studied the influence of interferons (IFNs) on the metastatic potential of mouse colon adenocarcinoma, COLON 26, cells. Pre-treatment of the cells in vitro for 24 hr with recombinant murine IFN-gamma (rMuIFN-gamma) significantly increased the number of lung tumour nodules when cells were injected i.v. into immunocompetent BALB/c mice and BALB/c nude mice. However, when MuIFN-gamma-pre-treated cells were injected into beige (NK-deficient) nude mice or anti-asialoGM 1 (asGM 1)-serum-treated BALB/c mice (NK-depleted) no enhancement of metastatic potential was seen. Pre-treatment of COLON 26 cells with recombinant human IFN-alpha A/D (Bg1 I), an IFN with equal activity on human and mouse cells, did not significantly enhance their subsequent metastases in immunocompetent or immunodeficient mice. In fact, there was a small but significant decrease in the number of tumour nodules in the lungs of beige nude and asGM 1-treated mice. The effects of rMuIFN-gamma on COLON 26 cells did not appear to be related to an alteration in MHC expression. COLON 26 cells constitutively express H-2D and H-2K antigens and both IFNs had equal enhancing (approx. 2-fold) activity on the expression of these antigens at the doses used in this experiment (10(3)U/ml). We conclude that pre-treatment with rMuIFN-gamma renders COLON 26 cells resistant to in vivo NK-cell lysis via a mechanism that does not involve changes in MHC expression.

Adenocarcinoma↗