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Biomedical subjects

F R Balkwill

Publications and source records attributed to F R Balkwill.

At least 73 records · Page 4Linked to original sources
PubMed1987

Therapeutic potential of tumor necrosis factor-alpha and gamma-interferon in experimental human ovarian cancer.

We have studied the activity of recombinant human gamma-interferon and recombinant human tumor necrosis factor alpha against four human ovarian cancer i.p. xenografts OS, LA, HN, and DO derived from primary tumor material. In the OS xenograft all control mice died by 42 days and therapy starting 7 days after tumor cell injection with 5 X 10(4) units recombinant human gamma-interferon or 1 microgram recombinant human tumor necrosis factor alpha alone had no significant effect on cumulative survival in three separate experiments. However, a combination of the two agents resulted in 85% cumulative survival at 150 days. This combination therapy also significantly increased survival of mice treated as late as 21 days after tumor cell injection. In the LA xenograft (where control mice were all dead by 23 days) therapy with either agent alone, or a combination, more than doubled survival time of mice. In the HN xenograft all control mice were dead at 22 days whereas either therapy alone or in combination gave +85% cumulative survival at 100 days. In a fourth xenograft, DO, survival of mice in the combination therapy group was significantly increased. Thus these two biological therapies, alone or in combination, show significant activity against human ovarian cancer cells.

Animals↗
PubMed1987

Intraperitoneal xenografts of human epithelial ovarian cancer in nude mice.

Using continuous human ovarian cancer cell lines, i.p. xenografts were successfully established in nude mice from four of four attempts. When primary tumor material was used, xenografts grew in 8 of 10 attempts. From these eight, three passageable xenograft cell lines have been established. To our knowledge, this is the first report published of such xenografts. I.p. xenografts closely mimic the clinical behavior of human ovarian cancer, and those developed from primary tumor material maintain close morphological similarity to the parent primary tumor. When expression of placental alkaline phosphatase and the tumor associated antigens defined by the monoclonal antibodies HMFG1, HMFG2, AUA1, and F36/22 by these models was determined, those i.p. xenografts derived from primary tumor material exactly matched the original tumor, while none of the xenografts derived from the cell lines expressed these antigens. These models will be useful for investigating the biology and treatment of ovarian cancer.

Animals↗
PubMed1987

Induction and suppression of glutathione transferases by interferon in the mouse.

The administration of interferon-alpha/beta to female nude (nu/nu) mice caused significant changes in the levels of the cytosolic hepatic glutathione transferases. Antibodies raised against rat subunits, Ya, Yc, Yb1, Yb2, and Yk, and the subunits of the human transferases, mu (YbYb), lambda (YfYf), and epsilon (B1B1) all reacted with enzymes in the mouse and were used to demonstrate suppression and induction of transferase levels. Western blot analysis followed by semiquantitation by laser scanning showed the Ya, Yb1, Yb2, Yc, Yk, mu, and B1 subunits to be suppressed by 11, 11, 44, 30, 12, 14, and 47%, respectively, by interferon treatment. In contrast to these findings, the Yf subunit was induced 5-7-fold. A concomitant 220% increase was observed in the specific activity of the hepatic cytosol for ethacrynic acid, a substrate for the Yf subunit. Changes in the levels of transferase enzymes in normal and tumor cells may have significant implications when cytotoxic drugs are used in combination with interferons in cancer therapy. The Yf subunit, an enzyme found in human tumors and in placenta (Polidoro, G., Di Mio, C., Del Boccio, G., Zulli, P., and Fererici, G. (1980) Biochem. Pharmacol. 29, 1677-1680) has also been shown to be elevated in hepatic preneoplastic lesions (Kitahara, A., Satoh, K., Nishimura, K., Ishikawa, T., Ruike, K., Sato, K., Tsuda, H., and Ito, N. (1984) Cancer Res. 44, 2698-2703). These data indicate that the Yf subunit represents a potentially important interferon-inducible gene product.

Animals↗
PubMed1987

Effects of tumour necrosis factor on human tumour xenografts in nude mice.

Recombinant human tumour necrosis factor (rHuTNF) when injected intraperitoneally into nude mice bearing subcutaneous tumour xenografts (breast and bowel) had no significant antitumour activity (six different tumours were tested). The same dose administered locally at the tumour site resulted in complete regression and cure of the majority of tumours. Macroscopic evidence of tumour necrosis was rarely seen but microscopically a peritumoral cuff of host inflammatory cells surrounded the dying tumour cells within four days of the start of therapy. The combination of rHuTNF (i.p.) with recombinant human gamma-interferon (rHuIFN-gamma) (i.p.) led to significant tumour inhibition in only one of three xenografts tested. Combination of rHuTNF (i.p.) and HuIFN-alpha (s.c.) resulted in significant inhibition in all of three xenografts tested. Human ovarian tumours were grown in the peritoneal cavity of nude mice. The biological behaviour of this cancer closely resembled the human disease, the xenografts growing as solid tumours and/or ascites. When rHuTNF or rHuIFN-gamma were given intraperitoneally at the time of tumour cell injection most mice survived, whereas control mice died in 4-8 weeks. Once the disease was established (seven days or more after injection) either agent alone was ineffective. In the combined results of three experiments with one xenograft, with a total of 21 mice in each group, cumulative survival at 154 days was 0% for control mice and 5% and 15% for mice treated with 1 microgram/day rHuTNF or 5 X 10(4) U/day rHuIFN-gamma, respectively, when therapy was started seven days after tumour cell injection. Combining the two agents led to a cumulative survival of 85%. This combination cured 40% of mice by 21 days after tumour cell injection. With a further two ovarian cancer xenografts, the combination of rHuTNF and rHuIFN-gamma produced a significant survival advantage.

Animals↗
PubMed1987

DNA fragmentation and cytotoxicity caused by tumor necrosis factor is enhanced by interferon-gamma.

Recombinant human tumor necrosis factor (rhuTNF) induced DNA fragmentation in sensitive cell lines. This fragmentation was similar to that caused by lymphotoxin-containing cytotoxic T cell culture supernatants. The percentage of DNA cleaved correlated with the degree of cell growth inhibition shown by individual cell lines. DNA fragmentation was first seen after 12 h treatment, and increased slowly with time. The presence of 100 microM ZnSO4 inhibited the rhuTNF-induced DNA cleavage in MCF-7 cells. Recombinant interferon-gamma (rhuIFN-gamma) did not induce DNA cleavage, although it reduced the growth of all the cell lines used in this study. However, it interacted with rhuTNF to produce a doubling in the percentage of DNA fragmentation, and increased cytotoxicity in rhuTNF-sensitive cell lines. Pretreatment with rhuIFN-gamma for 1 h prior to rhuTNF treatment also enhanced DNA fragmentation and cell killing.

Cells, Cultured↗
PubMed1987

The effect of recombinant human tumour necrosis factor on growth and macromolecular synthesis of human epithelial cells.

We have studied the effect of recombinant human tumour necrosis factor (rHuTNF) on growth and macromolecular synthesis in a range of normal and transformed epithelial cell types. Tumour necrosis factor did not affect the growth of normal human mammary epithelial cells, but its growth-inhibitory action on the SV40-transformed human mammary epithelial cell line HBL-100 increased with passage number in association with a progression of malignant phenotype. However, of two lines derived from nude mouse tumours of HBL-100 lines, one, HBLT-12, did not respond to rHuTNF, and the other, HBLT-11 showed some growth stimulation by high dose rHuTNF. Macromolecular synthesis in HBLT-11 was not affected by rHuTNF. The breast cancer cell lines MCF-7 and BT20 were sensitive to the cytotoxic effects of rHuTNF. In MCF-7 a gradual decrease in RNA and DNA synthesis occurred over 48 h, ending with an accumulation of cells in S and G2 phase of the cell cycle and cell death. The addition of alpha- or gamma-interferon increased, but did not accelerate the cytotoxicity of rHuTNF.

Breast Neoplasms↗
PubMed1987

Interferon gamma regulates HLA-D expression on solid tumors in vivo.

In vivo administration of recombinant human interferon-gamma, rIFN-gamma, to nude mice bearing human tumor xenografts resulted in a strong induction of HLA-DR expression on the tumor cells in 2 of 3 lines tested. The induction was dose-dependent and declined rapidly after cessation of therapy. IFN-gamma also switched on DQ and DP products when the xenograft cells were treated in vitro. The in vivo alteration of tumor surface properties by rIFN-gamma may have therapeutic implications.

Animals↗
PubMed1987

A trial of human alpha interferon as an adjuvant agent in breast cancer after loco-regional recurrence.

Thirty-two women who had developed loco-regional recurrence of breast carcinoma were entered into a controlled trial of adjuvant alpha-interferon. All patients had histological confirmation of recurrence, local treatment with radiotherapy and negative staging investigations. They were then randomized to either observation alone, or treatment with human alpha interferon 3 x 10(6) units subcutaneously daily for 1 year. There were no differences detected in the rate of local or distant relapse. With this lack of clinically significant efficacy and a high incidence of side effects, it is concluded that alpha interferon is of doubtful value in the adjuvant treatment of breast cancer.

Adjuvants, Immunologic↗
PubMed1986

Effects of mouse interferon on human tumour xenografts in the nude mouse host.

Murine interferon (IFN) inhibited the growth of 3/3 human tumour xenografts growing in nude mice. This inhibition was independent of the sensitivity of the xenograft to human IFN. In contrast to human IFN, the murine IFN did not directly affect the human tumour cells in vitro as measured by levels of the IFN-induced enzyme 2-5A synthetase or elevation of HLA expression. In preliminary investigations into the role of the host in the murine IFN-mediated tumour inhibition, we found equal activities of this IFN in nude and in beige (NK-deficient) nude mice. Moreover, murine IFN did not elevate levels of NK-cell activity in either of these mouse strains. We conclude that murine IFN mediates this tumour inhibition via an effect on the tumour-bearing host that may or may not involve immune mechanisms.

Animals↗
PubMed1986

The effect of interferon on experimental metastases in immunocompetent and immunodeficient mice.

A recombinant human hybrid alpha interferon (rIFN-alpha A/D) with antiviral, immunomodulating and cell-growth-inhibitory activity on murine cells strongly inhibited the development of experimental pulmonary metastases of the Colo 26 adenocarcinoma in BALB/c mice. Twenty-one days after i.v. injection of 5 X 10(4) cells, 8/8 control mice had greater than 200 lung tumour nodules whereas 1/6 mice receiving 500 ng rIFN-alpha A/D had one lung tumour nodule and the other 5 mice were tumour-free. Equally strong inhibition was seen in immunodeficient BALB/c nu/nu (athymic) and beige nu/nu (athymic and NK-deficient) mice. Scheduling experiments in vivo showed that the most important time of IFN treatment was from the day of tumour cell injection to day 5, although statistically significant reductions in lung tumour nodule number and lung weight were seen even when IFN treatment was started 7 days after cell injection. rIFN-alpha A/D was cytostatic to Colo 26 in vitro, causing 50% or more inhibition of cell growth or colony number at IFN levels that could be achieved in the sera of IFN-treated mice. Although rIFN-alpha A/D stimulated NK-cell activity in BALB/c mice, Colo 26 cells were resistant in vitro to such cells whether from control or IFN treated mice.

Adenocarcinoma↗
PubMed1986

Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons.

We have studied the activity of recombinant human tumor necrosis factor (rHuTNF) on six different human tumor xenografts derived from primary breast and bowel tumors and maintained by passage in nude mice. When 5 micrograms rHuTNF was given daily intratumorally to mice with established (approximately, 0.5 cm) tumors, total tumor regression was observed by 3-4 weeks in three of six xenograft lines. In a further two lines tumor stasis or significant slowing of growth was seen. This antitumor action was not accompanied by any consistent macroscopic change in the tumor such as necrosis, but histological examination revealed tumor cell degeneration and a large peritumoral infiltration of host inflammatory cells after 4-7 days therapy. In contrast to these data, little effect was seen when the same dose of rHuTNF was administered i.p. to nude mice bearing these tumors. In only two of six lines was any significant slowing of tumor growth seen. A 5-fold increase in the i.p. dose resulted in improved activity on only one of two xenograft lines tested. Efficacy of the i.p. rHuTNF dose could, however, be enhanced by simultaneous administration of human interferon, alpha or gamma. No obvious signs of toxicity were observed at all rHuTNF doses administered and weights of control and treated mice at the end of the experiments were comparable.

Animals↗
PubMed1986

Interferons: from molecular biology to man. Part 1. Genetics and molecular biology of the interferon system.

In 1986, 29 years after the original papers on 'the interferon', Alick Isaacs' optimism and enthusiasm for this discovery has been more than justified and the scope of interferon research ranges from genetics and molecular biology to clinical trials in man. In this series of three articles I hope to explain the importance of interferons to these, and other, areas of science. Part 1 describes the genetics of the interferon system, how the genes are controlled, and the properties of their products. It will also outline some of the molecular changes that occur in the cell after the interaction of interferons with a specific cell-surface receptor. Part 2 describes how the interferon-induced changes in cellular RNA and protein synthesis can cause profound changes in cell behaviour, and Part 3 relates such functional changes in the cell to the interferon system in the whole animal and discusses the therapeutic potential of interferons given as antiviral or anticancer therapy.

Animals↗
PubMed1986

Interferons: from molecular biology to man. Part 3. Interferons and disease.

The previous two articles described how the interferons (IFNs) bring about a number of specific molecular changes in the cell which result in functional alterations. IFN-treated cells enter an antiviral state which renders them resistant to a broad spectrum of viruses. They show enhanced differentiated behaviour, significant alterations in cell membrane proteins and slower progress through the cell cycle. This third (and final) article discusses the relevance of the IFN system to the whole animal, both as part of the natural defence against disease and as part of a new series of therapeutic agents collectively called biological response modifiers.

Animals↗
PubMed1986

Augmentation of cytotoxicity of chemotherapy by human alpha-interferons in human non-small cell lung cancer xenografts.

Three human non-small lung cancer xenograft lines were used to study the activity of combinations of cytotoxic drugs with human alpha-interferons (IFNs). Statistically significant potentiation of cis-platinum (CDDP) and cyclophosphamide (CY) given weekly in a low dose was seen when human lymphoblastoid interferon (IFN-alpha nl) (2 X 10(5) mu/mouse/day) was administered simultaneously. The median tumor doubling times for CDDP in the three tumors (35, 22, and 29 days) increased to 52, 51, and 41 days when IFN-alpha nl was added. A similar though less marked effect was seen with CY (median doubling time increased from 21.5, 19.5, and 27 days to 32, 27, and 35 days with the addition of IFN-alpha nl). IFN-alpha nl alone at this dosage was shown to have some cytotoxic activity. Similar potentiation of CDDP and ifosfamide was seen in two tumors when human recombinant alpha-2 interferon was added at a lower dose (2 X 10(4) mu/mouse/day). Median doubling times for CDDP increased from 17 and 14 days to 27 and 18.5 days with the addition of human recombinant alpha-2 interferon, whereas for ifosfamide they increased from 11.5 and 14 days to 15 and 16 days. Human recombinant alpha-2 interferon in this dose had no effect as a single agent.

Animals↗