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Biomedical subjects

W R Fleischmann

Publications and source records attributed to W R Fleischmann.

At least 73 records · Page 4Linked to original sources
PubMed1981

The activity of interferon on ultraviolet light-induced squamous cell carcinomas in mice.

The activity of interferons was tested in ultraviolet light-induced skin tumors in mice. After the tumors were well established, they were injected and measured daily for 19 days. Mouse virus type (IF-alpha + IF-beta) and immune (IF-gamma) interferons were injected intralesionally into three groups of test animals and compared with a fourth group which received mock interferon (control). When used separately, virus type and immune interferons did not affect tumor growth; however, we observed regression in tumor size when the two interferons were used in combination.

Animals↗
PubMed1980

Potentiation of antitumor effect of virus-induced interferon by mouse immune interferon preparations.

In inbred DBA/2 mice, the antitumor activities of separate and combined preparations of mouse immune interferon and mouse virus-induced interferon on the development of P388 tumors were studied. Immune interferon alone (25 U/day) did not affect tumor development. Virus-induced interferon alone (25,000 U/day) delayed tumor development and increased survival time. The mouse immune interferon preparations significantly enhanced or potentiated the antitumor effects of mouse virus-induced interferon when the interferons were used in combined therapy.

Animals↗
PubMed1979

Potentiation of interferon activity by mixed preparations of fibroblast and immune interferon.

Mixed preparations of fibroblast and immune interferons interacted with cells synergistically to cause the development of a much greater level of protection than expected on the basis of their separate activities. This increased level of protection was 5- to 20-fold greater than expected on the basis of a simple additive effect of the interferons. The potentiating factor copurified with both fibroblast interferon and immune interferon as they were partially purified. The potentiation was not an artifact of a more rapid development of immune interferon-induced antiviral resistance in the presence of fibroblast interferon. The results were consistent with the hypothesis that fibroblast and immune interferons mutually potentiate each other, thus supporting the supposition that they have different modes of action.

Animals↗
PubMed1979

Induction of an inhibitor of interferon action in a mouse lymphokine preparation.

An inhibitor of interferon action was identified in mouse lymphokine preparations. The inhibito was first detected in the supernatant fluid of mouse spleen cells at 72 h after stimulation by staphylococcal enterotoxin A. Inhibitor was not detected in supernatant fluids from unstimulated cultures. This inhibitor blocks the antiviral activity of both immune and fibroblast interferons. The inhibitor was purified 1,000-fold by two-step column chromatography. The partially purified inhibitor blocked the antiviral activity of up to 400 U of interferon. The immunosuppressive effect of interferon was also blocked by the inhibitor, suggesting that the inhibitor may modulate the immunoregulatory function of interferon.

Animals↗
PubMed1977

Priming of interferon action.

Pretreatment of L cell cultures with low levels of mouse interferon caused a more rapid development of and a greater degree of protection with subsequent exposure to higher levels of mouse interferon than that observed for control cultures. Such priming was a specific event which required cellular RNA synthesis. Priming by mouse fibroblast interferon, mouse immune interferon, and human leukocyte interferon was directly related to the plaque reduction titer of each of the interferons on L cells.

Animals↗
PubMedDate not supplied

Effect of hyperthermia on the antitumor actions of interferons.

Hyperthermia treatment has been shown to enhance the in vitro antiproliferative effects of IFN-alpha, IFN-beta, and IFN-gamma, with IFN-gamma being more strongly enhanced than IFN-alpha. The comparative effects of hyperthermia on the in vivo antitumor activities of IFN-alpha and IFN-gamma were evaluated in the murine system using both subcutaneous and intraperitoneal B16 melanoma tumor model systems. Heat-induced whole body hyperthermia, resulting in a 2 degree C rise in body temperature, was administered by incubating the mice for 8 hours in a dry incubator at 37.1 degrees C. Whole body hyperthermia was found to enhance the antitumor activity of IFN-alpha by approximately 1.0 fold and 1.2 fold for the subcutaneous and intraperitoneal tumor models, respectively. This represented an additive effect of hyperthermia and IFN-alpha. Hyperthermia was found to enhance the antitumor activity of IFN-gamma by approximately 2.9 fold and 2.2 fold for the subcutaneous and intraperitoneal tumor models, respectively. This represented a synergistic effect of hyperthermia and IFN-gamma. The results of this in vivo study confirm and extend the in vitro observation that hyperthermia more strongly enhances the antitumor action of IFN-gamma than IFN-alpha. These results may have clinical importance because they suggest that hyperthermia may be used in combination with IFN-gamma to provide a synergistically enhanced antitumor action.

Animals↗
PubMedDate not supplied

Resistance to the antiproliferative activity of IFN-alpha: further characterization and demonstration of antagonistic effects of IFN-gamma.

Mouse B16 melanoma cells have been shown to rapidly develop resistance to the antiproliferative effects of MuIFN-alpha or MuIFN-beta when exposed to these interferons. In cloning studies, the maximal antiproliferative effects of MuIFN-alpha were seen with 2-4 days treatment. This resistance has been further characterized. The level of resistance which develops in B16 melanoma cells is dependent upon the concentration of MuIFN-alpha to which the cells are exposed. In addition, B16 melanoma cells which are resistant to the antiproliferative effects of MuIFN-alpha have greatly elevated levels of the interferon-induced enzyme 2',5'-oligoadenylate (2-5A) synthetase. Since it has previously been shown that B16 melanoma cells do not develop resistance to the antiproliferative effects of MuIFN-gamma, several experiments studied the influence of MuIFN-gamma on the development of resistance to MuIFN-alpha. Combinations of IFN-gamma and IFN-alpha have previously been shown to result in a synergistic enhancement of the antiproliferative effects. Kinetic studies show that the response of the cells to the MuIFN-gamma antiproliferative effect appears to be dominant over the development of resistance since no resistance develops in response to combination treatment. Not only is MuIFN-gamma able to prevent development of resistance when it is present continuously, but also when it is used for the sequential treatment of the cells before their exposure to MuIFN-alpha. A 2-day pretreatment with MuIFN-gamma is sufficient to prevent the development of resistance during later exposure of the cells to MuIFN-alpha alone for up to 6 additional days.(ABSTRACT TRUNCATED AT 250 WORDS)

2',5'-Oligoadenylate Synthetase↗
PubMedDate not supplied

Effects of phenytoin on the production of interferons: differential effects on type I and type II interferons.

The relative effects of treatment with an anticonvulsant, phenytoin, on the production of interferons were determined for both the murine and human systems. Phenytoin treatment was found to have differential effects on the in vitro production of Type I and Type II interferons. Phenytoin had either no effect (HuIFN-alpha) or an enhancing effect (MuIFN-alpha/beta) on the in vitro production of Type I interferons. In contrast, phenytoin pretreatment had an inhibitory effect on the in vitro production of Type II interferons (IFN-gamma) for both the murine and human systems. Phenytoin appeared to exert its inhibitory effect directly on the IFN-gamma-producing cell and was active even when added as late as 6 h after IFN-gamma induction. This inhibition was not related to a toxic effect of the phenytoin and occurred at phenytoin concentrations which were pharmacologically relevant (10-20 micrograms/ml). The effects of phenytoin on the in vivo production of MuIFN-gamma were also examined. In parallel to the in vitro observations, phenytoin treatment of mice significantly reduced the in vivo induction of MuIFN-gamma. The results raise the possibility that phenytoin therapy in humans may significantly affect the production of HuIFN-gamma.

Animals↗
PubMedDate not supplied

Regulation of MuIFN-alpha/beta and MuIFN-gamma-induced antiviral states: differential effects with different challenge viruses and lack of correlation with 2'5' oligoadenylate synthetase levels.

The MuIFN-alpha/beta and MuIFN-gamma induced antiviral states which are directed against mengovirus have been shown previously to be differentially regulated. Following interferon removal, the MuIFN-alpha/beta-induced antiviral state decays rapidly, while the MuIFN-gamma-induced antiviral state increases dramatically. To determine whether these observations with mengovirus represent part of a general phenomenon, these studies have been extended using vesicular stomatitis virus and vaccinia virus, which represent two distinctly different groups of viruses. The antiviral states induced by MuIFN-gamma against all three viruses increased dramatically following interferon removal. The antiviral state induced by MuIFN-alpha/beta against vesicular stomatitis virus was stable following interferon removal, while the antiviral states induced by MuIFN-alpha/beta against mengovirus and vaccinia virus decayed rapidly. Also, levels of 2'5' oligoadenylate synthetase were determined at various times following interferon removal. MuIFN-alpha/beta was found to be a relatively strong inducer of 2'5' oligoadenylate synthetase, while MuIFN-gamma was a relatively weak inducer. Further, while the changes in 2'5' oligoadenylate synthetase levels paralleled the changes in the levels of the antiviral states induced by MuIFN-alpha/beta and MuIFN-gamma against mengovirus and vaccinia virus, the changes in 2'5' oligoadenylate synthetase levels did not parallel the changes in the antiviral state induced by MuIFN-alpha/beta against vesicular stomatitis virus. The results suggested that the 2'5' oligoadenylate synthetase levels did not correlate with the level of antiviral state.

2',5'-Oligoadenylate Synthetase↗
PubMedDate not supplied

Differential antiproliferative activities of IFNs alpha, beta and gamma: kinetics of establishment of their antiproliferative effects and the rapid development of resistance to IFNs alpha and beta.

Interferons have been recognized to have potent in vitro antiproliferative activities in mouse and human systems. To further investigate the kinetics of development of interferons' antiproliferative activities, mouse B-16 melanoma cells were treated with MuIFN-alpha, MuIFN-beta or MuIFN-gamma for various initial periods of time during an 8 day cloning assay. With MuIFN-alpha and MuIFN-beta treatments, maximal expression of antiproliferative activity was attained with 2 to 4 days of interferon treatment. In contrast, with MuIFN-gamma treatment, expression of antiproliferative activity increased with progressively longer periods of time of MuIFN-gamma treatment. These results suggested that B-16 melanoma cells were initially sensitive to all three of the interferons but rapidly became resistant to MuIFN-alpha and MuIFN-beta after 2 to 4 days of treatment. This suggestion was confirmed by cell growth kinetics experiments. The cells which were resistant to the antiproliferative activity of the MuIFN-alpha remained sensitive to the antiviral activity of MuIFN-alpha, suggesting that MuIFN-alpha and MuIFN-beta regulate their antiviral and antiproliferative responses via different mechanisms. The cells which were resistant to the antiproliferative activities of MuIFN-alpha and MuIFN-beta remained sensitive to MuIFN-gamma, suggesting that they were not generally resistant to antiproliferative effects. The cells which were resistant to the antiproliferative activities of the interferons gradually lost their resistance with a half-life of 11 days when they were cultured in the absence of interferons. The differential antiproliferative actions of alpha, beta and gamma interferons observed with murine B-16 melanoma were confirmed in the human system with G-361 melanoma cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Effects of hyperthermia on the in vitro antiproliferative activities of HuIFN-alpha, HuIFN-beta, and rHuIFN-gamma employed separately and in combination.

The relative enhancing effects of hyperthermia on the three types of interferon were evaluated in cloning studies for three human cell lines: G-361 malignant melanoma cells, WISH ammion cells, and AGS stomach adenocarcinoma cells. Hyperthermia enhanced the antiproliferative activity of rHuIFN-gamma against each of the three cell lines and the levels of enhancement by hyperthermia were seen to increase with increasing concentrations of rHuIFN-gamma. The maximum observed levels of enhancement of rHuIFN-gamma activity by hyperthermia varied from cell line to cell line. However, when the relative sensitivities of the cell lines to rHuIFN-gamma were taken into account, the levels of enhancement of rHuIFN-gamma antiproliferative activity by hyperthermia were seen to be similar for each of the cell lines, indicating that hyperthermia consistently enhanced rHuIFN-gamma antiproliferative activity. Hyperthermia did not consistently enhance the antiproliferative activities of HuIFN-alpha and HuIFN-beta. Further studies indicated that hyperthermia enhanced by approximately 6-fold the antiproliferative effects of combinations of rHuIFN-gamma with HuIFN-alpha and HuIFN-beta. The results support the possibility that a combination treatment protocol of hyperthermia and interferon administration (particularly HuIFN-gamma or combinations of HuIFN-gamma with HuIFN-alpha or HuIFN-beta) may provide an enhanced antitumor effect in man.

Adenocarcinoma↗
PubMedDate not supplied

Potentiation of interferon action.

Potentiation of interferon action was described as a non-additive, synergistic enhancement of interferon activity by combined preparations of immune and virus-type interferons. The potentiated antiviral activity was demonstrated for a variety of virus types as well as for the human and mouse in vitro systems. Potentiation by combined immune and fibroblast interferons was also demonstrated for the antitumor and direct anticellular effects of interferon. Use of partially purified immune and fibroblast interferons demonstrated that potentiation appeared to be a property of the interferon molecules themselves.

Animals↗