Hepatitis C after needlestick injuries.
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Centers for Disease Control and Prevention, U.S.↗
Biomedical subjects
N O Hill
Publications and source records attributed to N O Hill.
Human cytokines, tumor necrosis factor, and interferons: gene cloning, animal studies, and clinical trials.
Presented is a comprehensive program designed to isolate human cytokine genes and investigate their relative induction, and to analyze cytokine activities in cell culture, animal tumor models, and human clinical trials. Human cytokine cDNAs have been isolated from a cDNA library made from normal human peripheral blood leukocytes (PBLs) treated with Sendai virus and the relative induction of tumor necrosis factor (TNF), alpha and gamma interferons (IFN-alpha, IFN-gamma), and interleukin-1 beta IL-1 beta) genes has been analyzed. In the Sendai virus-induced PBL system, IL-1 beta mRNA was shown to be approximately twofold higher than TNF or IFN-alpha mRNA whereas IFN-gamma mRNA was 50-100-fold lower than TNF or IFN-alpha mRNA. The cytotoxic activity of TNF was analyzed on several cell lines and IFN-alpha and IFN-gamma were shown to potentiate TNF cytotoxicity about 2-200-fold depending on cell lines. The LD50 for recombinant TNF in BALB/c mice was determined to be 6 X 10(7) U/kg and the therapeutic dose of recombinant TNF in sarcoma 180 bearing BALB/c mice was 3 X 10(5) U/kg, indicating a wide therapetic index. Phase I clinical trials of recombinant TNF given I.V. indicated a tolerated dose of 150,000 U/kg with biphasic half-life (T-1/2) of 2 and 31 min following TNF injection. Phase II trials of TNF and trials of TNF combined with IFN-alpha are in progress. These studies indicate that cytokines such as TNF and IFN-alpha are subject to similar induction systems, potentiate each other's activities, and can be tolerated at specific doses for potential therapeutic use.
Animals↗
Antiproliferative assay of human leucocyte interferon.
An in vitro microtitration system of the antiproliferative effect of human leucocyte interferon (IFN-alpha(Le)) was investigated. The preliminary experiments suggested that the antiproliferative effect of IFN-alpha(Le) was increased by prolonging the incubation period, by reducing the target cell concentration, and might be prescribed by the total IFN amounts in the challenge medium. By employing a system consisted of 1.5 X 10(4) Daudi cells in 0.2 ml of medium containing IFN dilutions and an incubation period of 3 days at 37 degrees C, the antiproliferative effects of twenty-one lots of partially purified IFN-alpha(Le) (PIF-alpha(Le)) preparations were titrated. The interassay variations in the antiproliferative titers of three PIF-alpha(Le) established in the present system were found to be in the same range as those in the antiviral titers estimated by a standard macroplaque reduction assay. The each titration curve was parallel, and the antiproliferative titers, assessed by the reciprocals of the IFN dilutions which suppress the cell growth in 50%, were significantly (p less than 0.01) correlated to the antiviral international units of them.
Antiviral Agents↗
Comparison of the antitumor effects of human natural and recombinant interferons (alpha and beta) on human cancer cell lines.
The antitumor effects of 5 different subtypes of human type I interferons (IFN-alpha(Le), rIFN-alpha A, rIFN-alpha D, IFN-beta, and rIFN-beta) were studied on 3 human cancer cell lines (Daudi lymphoma, PLC/PRF/' hepatoma, and G361 melanoma). IFN-alpha(Le) was the most potent against Daudi cells. The effects of IFNs were cytostatic. On the other hand, 500 IU/ml of IFN-alpha(Le), IFN-beta and 5000 IU/ml of rIFN-beta showed cytocidal effect against PLC/PRF/5 cells. The G361 cells were the least sensitive to the IFNs tested. This is the first report on the antitumor effect of rIFN-beta isolated from insect cells. The effect of this rIFN-beta was similar to that of IFN-beta.
Antineoplastic Agents↗
Antitumor effect of human necrosis factor on human hepatoma cells PLC/PRF/5.
The antitumor activity of natural human tumor necrosis factor (TNF) on a human hepatoma cell line PLC/PRF/5 was studied in vitro. TNF produced by the LuKII human lymphoblastoid cell line showed a cytostatic effect on the hepatoma cells, whereas the growth of non-tumorigenic Chang liver cells was little affected. The combined effects of TNF and interferon-gamma (IFN-gamma) were additive on the PLC/PRF/5 cells as shown by statistical analyses. The same combination showed synergistic effects on a human breast cancer cell line BT-20, which was highly sensitive to TNF. These data may provide some informations concerning the use of TNF in the treatment of hepatoma.
Animals↗
Antiviral and antiproliferative activities of human leukocyte interferon potentiated by cimetidine in vitro.
The influence of cimetidine on antiviral activity of leukocyte interferon (IFN-alpha (Le] was studied in plaque-reduction assays using Utrecht (U) amnion cells challenged with vesicular stomatitis virus (VSV) and in CPE inhibition assays using A549 cells challenged with encephalomyocarditis (EMC) virus and WISH cells challenged with VSV. The IFN-alpha (Le)-induced antiviral activity was slightly enhanced in cells treated with cimetidine, whereas cimetidine treatment alone did not show any antiviral effect. The observed titer (OT) was significantly higher (p less than 0.05) in cells treated with cimetidine together with IFN-alpha (Le) compared with the control without cimetidine. The effect of cimetidine on IFN-alpha (Le)-induced cell growth inhibition was studied on Daudi (a Burkitt's lymphoma cell line) and on G361 (a melanoma cell line) cells. The growth of these cells was slightly suppressed by cimetidine alone. When cells were treated with IFN-alpha (Le)/cimetidine, the cell growth inhibition rates were significantly higher (p less than 0.02) than the rates obtained with IFN-alpha (Le) or cimetidine alone. These results indicate that cimetidine can enhance the antiviral as well as the antiproliferative activities of IFN-alpha (Le) in "in vitro" studies.
Cell Division↗
Effects of cimetidine on various biological activities of human leucocyte interferon and on interferon production in lymphocytes.
In vitro effects of cimetidine on the antiviral, the antiproliferative and the natural killer (NK) cell stimulating activities of human leucocyte interferon (IFN-alpha (Le], and on the Sendai virus induced interferon production in lymphocytes were investigated. The antiviral activity of IFN-alpha (Le) was dosedependently enhanced by cimetidine, which alone did not demonstrate any antiviral action. The observed titer of the same IFN preparation titrated with 60 micrograms/ml of cimetidine was significantly higher (p less than 0.05) than that without cimetidine. Cimetidine slightly but dosedependently inhibited the growth of Daudi or G-361 cells. The combination effects of these two agents were revealed to be statistically additive or synergistic. The NK cell activity of peripheral blood lymphocytes (PBL) was suppressed after a 16 hr pretreatment with cimetidine. Furthermore, the interferon production in normal lymphocyte cultures was suppressed dosedependently by cimetidine. On the other hand, the augmentation of the NK cell activity by interferon was further potentiated by cimetidine.
Cell Division↗
Third international symposium on transfer factor.
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Animals↗
The usefulness of transfer factor in asthma associated with frequent infections.
Fifteen patients underwent controlled trial with transfer factor for repeated infections and severe asthma. Marked decrease in respiratory infections and striking improvement in asthma resulted. The authors suggest that transfer factor may reconstitute immune function, thus representing a unique approach to severe asthma associated with frequent infections.
Adolescent↗
Systemic lupus erythematosus in twin sisters following ten years of hyperglobulinemic purpura (Waldenström).
Uniovular twin sisters have been diagnosed 10 years ago as having hyperglobulinemic purpura (Waldenström) at age 12. The diagnosis was documented by purpura of the lower extremities, increased gamma-globulin after serum electrophoresis, and increased 7S component upon ultracentrifugation. In addition, there was an elevated ESR, a positive rheumatoid arthritis latex test, and their LE prep. was negative at that time. At a later date, however, both of them developed polyarthritis. After 9 years for the one and 10 years for the other, their LE prep. became strongly and constantly positive, while their gamma-globulin remained within abnormal limits.
Blood Proteins↗
Improvement in delayed hypersensitivity in Hodgkin's disease with transfer factor: lymphapheresis and cellular immune reactions or normal donors.
Passive transfer of delayed hypersensitivity was achieved, with normal transfer factor, in patients with Hodgkin's disease in remission. The cellular immune responses of the recipients improved. It is suggested that, in addition to specific effect the transfer factor (or factors) has a nonspecific effect causing improvement in the state of delayed hypersensitivity of the recipient in general. The average number of E-rosette T lymphocytes was 46.3% after the transfer factor treatment in Hodgkin's disease. The control patients with Hodgkin's disease, not receiving transfer factor, had a value of 37.8%. Removal of 4.9 X 10(9) to 1.08 X 10(10) lymphocytes did not diminish the delayed hypersensitivity of the donor. Side effects attributable to transfer factor were not seen.
Cell Count↗
Production of interferon for clinical trials.
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Humans↗
Clinical studies of Platinum Coordination compounds in the treatment of various malignant diseases.
Following the prior work of Rosenberg et al, Rosenberg and VanCamp, and Speer et al, we started clinical trials with cis-dichlorodiammineplatinum(II) in April 1971. Marked tumor regression was noted in several malignant diseases in these initial clinical studies which were reported at the Chemotherapy Congress in Prague, August 1971. At the present time over 178 patients have been treated wihhis durg for a variety of malignant conditions. Approximately half of these patients received the platinum compound alone and the other half received it in combination with four other chemotherapeutic agents...
Aged↗
Platinum analogs of clinical interest.
Eight platinum analogs including complexes containing two isomeric forms of 1,2-diaminocyclohexane have received preliminary clinical trials. Dosage and limiting toxicity have been identified for racemic malonato-1,2-diaminocyclohexaneplatinum(II) (PHM) and its trans(-)-1,2-diaminocyclohexane isomer (neo-PHM). Dosage and toxicity for racemic sulfato-1,2-diaminocyclohexaneplatinum(II) have been identified and preliminary dosage data for the trans(-)-1,2-diaminocyclohexane isomer are presented. Of the four remaining compounds, three have been abandoned due to toxicity or lack of promise as antitumor agents and the fourth is not being pursued actively at the present time. Further trials of PHM, and especially the neo-PHM isomer, in combination with standard agents seem indicated and are underway. The search for platinum analogs of clinical interest may yet identify analogs significantly superior in effectiveness and safety to cis-dichlorodiammineplatinum(II).
Bone Marrow↗