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J F Weiss

Publications and source records attributed to J F Weiss.

At least 37 records · Page 2Linked to original sources
PubMed1988

Long-term effects of radioprotector WR-2721 on locomotor activity and body weight of mice following exposure to ionizing radiation.

The effects of 13 Gy gamma-radiation alone and in combination with 200 mg/kg of the radioprotector S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on locomotor activity and body weight were examined in CD2F1 mice over a 10-month period. The results confirmed that WR-2721 is an excellent radioprotector against lethality. All mice receiving 13 Gy without WR-2721 died in 5-7 days. For mice that received WR-2721 alone or WR-2721 + radiation, survival at 30 days was 100% and 70%, respectively. Body weights of mice receiving WR-2721 without radiation were comparable to control animals. Body weights of animals given WR-2721 + radiation fell on days 1-5 and then increased until day 11, but remained below control values throughout the experiment. Animals in the radiation-only group did not exhibit any significant reductions in behavior until day 2 post-irradiation. Mice administered WR-2721 alone showed significantly reduced locomotor activity levels on day 0 then completely recovered within 24 h and exhibited normal body weights. Animals given WR-2721 before irradiation showed greater reductions in locomotor activity on day 0 than either the WR-2721 or radiation-only groups and recovered to control level by day 3. Beginning on day 5, they showed significant reductions in activity. Mice pretreated with WR-2721 that survived a normally lethal dose of radiation showed a 20-40% reduction in locomotor performance that recovered in 2-5 months.

Amifostine↗
PubMed1988

Opposite effects of WR-2721 and WR-1065 on radiation-induced hypothermia: possible correlation with oxygen uptake.

Ionizing radiation induces hypothermia in guinea pigs. While systemic injection of the radioprotectant S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) did not block hyperthermia induced by exposure to 10 Gy of gamma radiation, central administration did attenuate it. The dephosphorylated metabolite of WR-2721, N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065), accentuated radiation-induced hypothermia by both routes of administration. In brain homogenates, oxygen uptake was inhibited by WR-2721 but elevated by WR-1065. These results suggest that the antagonism of radiation-induced hypothermia found only after central administration of WR-2721 is due to its direct actions and not to its dephosphorylated metabolite and that this effect may be correlated with the inhibition by WR-2721 of oxygen uptake.

Amifostine↗
PubMed1987

Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice.

The effects of the radioprotector S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on locomotor activity were evaluated in CD2F1 male mice. Separate groups of animals (N = 10/group) received an IP injection of vehicle, 25, 50, 100, 200, or 400 mg/kg of WR-2721 immediately before testing. Horizontal and vertical activity were measured using a Digiscan automated animal activity monitor. The latency to onset and duration of action of each dose of the radioprotector were recorded. For both behavioral measures, a significant reduction was observed in activity at doses of 200 and 400 mg/kg. A dose of 200 mg/kg had a 12- to 14-min latency to onset and significantly reduced behavioral activity for 3 hr. Mice injected with 400 mg/kg exhibited locomotor deficits within 8-10 min and were affected for up to 9 hr. The ED50 for horizontal and vertical activities at 1 hr postinjection were determined to be 271 and 105 mg/kg, respectively. The results demonstrate that significant reductions in locomotor activity are exhibited at doses of 200 mg/kg or more and that vertical activity was more sensitive to the disruptive effects of WR-2721 than was horizontal activity.

Amifostine↗
PubMed1987

Selenium pretreatment enhances the radioprotective effect and reduces the lethal toxicity of WR-2721.

Although WR-2721, S-2-(3-aminopropylamino)ethylphosphorothioic acid, is an effective radioprotector, its use is limited by its toxicity. Combining WR-2721 with other agents might decrease its toxicity and/or increase its effectiveness. The effect of selenium (Se) pretreatment on the acute toxicity and radioprotective effect of WR-2721 was studied in male CD2F1 mice. Injection of 1.6 mg/kg Se 24 hr before WR-2721 (800-1200 mg/kg, IP) decreased the lethality of WR-2721 significantly. Lower doses of Se were also effective, but simultaneous administration was not effective. Se injection alone (1.6 mg/kg) 24 hr before cobalt-60 irradiation increased the survival (dose reduction factor, DRF = 1.1) significantly. A synergistic effect on post-irradiation survival was observed when Se was injected 24 hr before WR-2721 (200-600 mg/kg IP 1/2 before irradiation). For example, after exposure to 22 Gy (1 Gy/min), 30-day survival was 100% when mice were treated with both Se and 600 mg/kg WR-2721, and was 13% with WR-2721 alone. The DRF after 400 mg/kg WR-2721 was 2.6 with Se compared to 2.2 without Se pretreatment. Alkaline phosphatase activity in bone marrow cells and serum was significantly depressed after treatment with 1.6 mg/kg Se, suggesting that a retardation of conversion of WR-2721 to its active free sulfhydryl form through the action of alkaline phosphatase might be partly responsible for the effects of Se. Other possible mechanisms related to the antioxidant properties of Se are under investigation.

Alkaline Phosphatase↗
PubMed1986

Inhibition of glutathione peroxidase and glutathione transferase in mouse liver by misonidazole.

The mechanisms of toxicity and sensitization by the radiosensitizer misonidazole [1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol] are not well understood. We report here on the inhibition of total glutathione peroxidase (GSHPx), selenium-dependent glutathione peroxidase (selenium-GSHPx) and glutathione transferase (GSHTx) activities by misonidazole. Mouse liver cytosol GSHPx and selenium-GSHPx were inhibited in vitro with 0.5 mM misonidazole. On administration of the drug intraperitoneally (800 mg/kg) to mice, it was found that GSHPx, selenium-GSHPx, and GSHTx were inhibited in homogenate, cytosol, and microsomal fractions of mouse liver. GSHPx was depressed in all fractions up to 60-70% of control values, with maximum depression occurring in the cytosol and homogenate fractions in less than 2 hr. Recovery of activity was slower in the microsomes. In general, the pattern of depression of selenium-GSHPx was parallel to that of GSHPx except in microsomes, where GSHPx is minimal. Quantitatively, selenium-GSHPx was least affected. GSHTx was inhibited 70-80% of control values in cytosol and homogenate with recovery by 24 hr, whereas a second period of depression occurred at 24 hr in the microsomes. The inhibition of peroxide-metabolizing enzymes may lead to elevation of intracellular peroxide levels, contributing to the radiosensitizing effect and/or toxicity of misonidazole.

Animals↗
PubMed1986

A novel interaction of diethyldithiocarbamate with the glutathione/glutathione peroxidase system.

Diethyldithiocarbamate (DDC) exhibits a variety of pharmacologic activities, including both radioprotective and sensitizing properties. Since the glutathione/glutathione peroxidase system may be a significant factor in determining radiation sensitivity, the potential mechanisms of action of DDC in relation to this system were examined in vitro. The interaction of DDC with reduced glutathione (GSH) was tested using a simple system based on the reduction of cytochrome c. When DDC (0.005 mM) was incubated with GSH (0.5 mM), the reduction of cytochrome c was eightfold greater than that expected from an additive effect of DDC and GSH. GSH could be replaced by oxidized glutathione and glutathione reductase. Cytochrome c reduced by DDC was oxidized by mitochondria. The interaction of DDC with both the hexosemonophosphate shunt pathway and the mitochondrial respiratory chain suggests the possibility of linking these two pathways through DDC. Oxidation of DDC by peroxide and reversal by GSH indicated that the drug can engage in a cyclic reaction with peroxide and GSH. This was confirmed when DDC was used in the assay system for glutathione peroxidase (GSHPx) without GSHPx. DDC at a concentration of 0.25 mM was more active than 0.01 unit of pure GSHPx in eliminating peroxide, and much more active than the other sulfhydryl compounds tested. These studies indicate that DDC can supplement GSHPx activity or substitute for it in detoxifying peroxides, and suggests a unique role in the chemical modification of radiation sensitivity.

Animals↗
PubMed1985

Behavioral toxicity and efficacy of WR-2721 as a radioprotectant.

S-2-(3-Aminopropylamino)ethylphosphorothioic acid (WR-2721) is a promising protectant for radiation-induced lethality. However, treatment with WR-2721 also produces nausea, vomiting, diarrhea, and hypotension, which implies severe functional consequences. Three studies were conducted to assess the effects of WR-2721 on rat motor performance and weight and to assess the ability of WR-2721 to mitigate the early performance decrement (PD) produced by ionizing radiation. In the first study, rats trained on the accelerod motor performance task were give 200, 300, or 400 mg/kg WR-2721 intraperitoneally (ip). The highest dose used referenced the maximum tolerated dose in the rat, which is two-thirds the median lethal dose (590 mg/kg). The subjects were tested immediately after treatment, at 30-min intervals for 3 h, and again at 24 h. All groups (N = 6/group) demonstrated a significant decrease in accelerod performance compared to control levels across the eight test trials, which ranged from 24 to 44% in the 200 and 400 mg/kg dose groups, respectively. Performance returned to baseline levels at 24 h. Some deaths occurred at all dose levels. In the second study, motor performance was measured after exposure to radiation alone or a drug/radiation combination (N = 8/group). WR-2721 was administered 30 min before exposure to 130 Gy of gamma radiation from a 60Co source at a dose rate of 20 Gy/min. Rats were tested on the accelerod immediately after WR-2721 treatment and at 10, 15, 30, 60, and 120 min and 24 h following radiation. Performance was significantly depressed compared to control throughout the 24 h following radiation exposure, with and without WR-2721. The decrement produced by WR-2721 and radiation alone appeared to add up to the combined drug/radiation decrement found over the 15- to 120-min test periods. In the third study assessing the effects of WR-2721 on weight, untrained rats treated with 200 or 400 mg/kg WR-2721 exhibited significant weight loss that lasted up to 3 days. Weight returned to pretreatment levels in 15 days, and no deaths occurred. In summary, the data suggest that in the rat (1) WR-2721 is behaviorally toxic at doses relevant to radioprotection, (2) WR-2721 treatment along with the stress of motor performance may combine to lower the level at which lethalities occur, (3) WR-2721 does not protect for radiation-induced PD, and (4) WR-2721 combined with radiation disrupts performance more severely than either radiation or WR-2721 alone.

Amifostine↗
PubMed1984

In vitro prostaglandin release from guinea pig parenchymal lung tissues is not stimulated by thymic peptides.

Prostaglandins (PGs) have been demonstrated to both enhance and inhibit immune responses. As several chemically distinct serum and thymic polypeptide preparations have been shown to stimulate immunologic reactivity in several cell populations, animal models, or clinical patient trials, we have investigated the capacity of these hormone-like products from the thymus and blood to modulate PGs generation/release in normal parenchymal lung tissues of the guinea pig. Several concentrations of thymosin fraction 5, serum thymic factor, tuftsin or thymopentin, as well as histamine or A23187 (as positive controls) were exogenously applied to parenchymal lung fragments in vitro, and supernatants analyzed for PG content by radioimmunoassay. No alteration in PG levels (enhancement or suppression) from basal (spontaneous) release was found. These findings suggest that during a 30-min incubation, all four polypeptide immunomodulators were ineffective in eliciting an immediate response in the arachidonic acid cascade via the cyclooxygenase pathway.

Animals↗
PubMed1984

Suppression of delayed-type hypersensitivity to oxazolone in whole-body-irradiated mice and protection by WR-2721.

The effect of whole-body irradiation on cellular immunity, as measured in vivo by delayed-type hypersensitivity (DTH) to oxazolone (4- ethoxymethylene -2-phenyl- oxazol -5-one), was determined in CD2F1 mice. DTH, determined by changes in ear swelling after challenge with oxazolone, was significantly depressed in irradiated mice (500-900 rad of 60Co) in a dose-dependent fashion when animals were irradiated after sensitization and before challenge with oxazolone. Administration of WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] 30 min before irradiation (2 days after sensitization) resulted in protection against suppression of DTH, which was dependent on drug and radiation dose. An effective dose of WR-2721 (200 mg/kg body wt) provided an approximate dose-modifying factor of 1.3. The data suggest that WR-2721 interacts with cells involved in that DTH response (lymphocytes and/or macrophages) and that WR-2721 may be useful in protecting against radiation-induced decrements in cell-mediated immunity.

Amifostine↗
PubMed1982

Effect of azimexon (BM 12.531) on mouse granulocyte-macrophage and monocyte-macrophage progenitor cells.

Treatment of mice with 25 mg/kg azimexon (BM 12.531) resulted in an increase ln granulocyte-macrophage colony-forming cells (GM-CFC) in spleen and bone marrow after a transient depression in the cell populations. Bone marrow monocyte-macrophage colony-forming cells (MM-CFC) increased at 7 days after treatment, and splenic MM CFC were least affected by azimexon treatment. The increase in granulocytic and monocytic colony-forming cells may play a role in the previously reported protection by azimexon against radiation and drug-induced toxicity.

Animals↗
PubMed1981

Effects of smoking and age on serum levels of immune-reactive proteins altered in cancer patients.

In patients with solid malignancies, such as those associated with chronic smoking, levels of immunosuppressive acute-phase proteins (haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin) are increased and correlate directly with extent of tumor and inversely with immune reactivity. Other serum proteins with immunorestorative properties (alpha 2HS-glycoprotein, prealbumin) are decreased and correlate directly with immune reactivity. Serum levels of these glycoproteins and albumin were measured in normal volunteers (132 cigarette smoking and 140 nonsmoking) to determine the effects of smoking history, age, and sex on protein levels. The alpha 1-acid glycoprotein increased, whereas albumin decreased with age in both groups, and haptoglobin increased with age in smokers. The alpha 1-acid glycoprotein, haptoglobin, and albumin levels also correlated with the extent of smoking (pack-years). In a comparison of age- and sex-matched smokers and nonsmokers, alpha 1-antitrypsin uniquely and significantly increased (P less than 0.001) in smokers but was not related to age or extent of smoking. The diagnostic and immunological implications of smoking and age-related changes in serum protein levels are discussed.

Adult↗
PubMed1980

Serum glycoproteins in cancer patients: first report of correlations with in vitro and in vivo parameters of cellular immunity.

Serum levels of proteins previously shown to be elevated [acute-phase proteins (APP)-haptoglobin, alpha 1-acid glycoprotein, alpha 1-antitrypsin] or depressed (alpha 2 HS-glycoprotein, prealbumin, albumin) in cancer patients were correlated with tumor extent, in vitro lymphocyte reactivity (LR) to phytohemagglutinin (PHA), and quantitative delayed hypersensivity (DH) to dinitrochlorobenzene (DNCB) in 147 preoperative patients with operable solid malignancies either confined to the primary site or with regional spread only. Compared to 58 normal controls, levels of the APP were significantly elevated, alpha 2 HS-glycoprotein and prealbumin depressed, and albumin levels unchanged in patients with either local or regional tumors. In patients with normal DH to DNCB, the APP were higher and prealbumin was lower than in controls; in patients with impaired DH to DNCB, haptoglobin and alpha 1-acid glycoprotein were higher and alpha 2 HS-glycoprotein and prealbumin lower than in patients with normal DH to DNCB. Albumin levels did not differ from normals in any of the groups. Serum protein levels appeared to be more related to the immune status of the patient than to tumor extent. The levels of the three APP correlated directly with each other but inversely with alpha 2 HS-glycoprotein and prealbumin; levels of alpha 2 HS-glycoprotein and prealbumin correlated directly with each other. Levels of haptoglobin and alpha 1-acid glycoprotein correlated inversely with LR to PHA; however, levels of alpha 2 HS-glycoprotein correlated directly with LR to PHA, and uniquely the levels of alpha 2 HS-glycoprotein and LR to PHA both showed similar changes for each of the four quantitative levels of DH to DNCB measured in the cancer patients. The data show that the proteins studied, except for albumin, correlate inversely (APP) or directly (alpha 2 HS-glycoprotein and prealbumin) with in vitro and in vivo parameters of cellular immunity. The results provide a rationale for attempts to improve depressed cellular immunity by lowering circulating levels of APP, as is being attempted in ongoing trials using plasmapheresis, and assessing the effect of exogenous alpha 2 HS-glycoprotein or prealbumin in patients with low levels of these glycoproteins and depressed cellular immunity. The correlations between serum glycoprotein levels and in vitro and in vivo parameters of cellular immunity lend rationale to investigations of the interactions of serum glycoproteins and blood cells having immunologic function that determine the level of cellular immunity expressed in vivo.

Adult↗
PubMed1980

Levamisole inhibition of microsomal lipid peroxidation as related to its sulfhydryl metabolite dl-2-oxo-3-(2-mercaptoethyl)-5-phenylimadazolidine.

Levamisole was previously shown to protect rat liver microsomes from lipid peroxidation induced by ADP-Fe and either NADPH, ascorbate, or X irradiation. The present experiments provide information about the mechanism of protection. Incubation of levamisole with a microsomal system containing ADP-Fe and NADPH resulted in protection of sulfhydryl groups, whereas reaction of levamisole with ascorbate (nonenzymatic system) indicated generation of a sulfhydryl metabolite. Production of a sulfhydryl metabolite of levamisole, dl-2-oxo-3-(2-mercaptoethyl)-5-phenylimidazolidine (OMPI), in either the enzymatic or nonenzymatic system was demonstrated by gas chromatography-mass spectrometry. While levamisole acts as an antioxidant at concentrations of 1.0 and 2.0 mM, OMPI had an enigmatic effect on microsomal lipid peroxidation induced enzymatically or nonenzymatically. OMPI exhibited a biphasic effect: at concentrations below 25 microM a prooxidant effect was observed, and at concentrations exceeding 50 microM an antioxidant effect was observed. The data suggest that the inhibition of microsomal lipid peroxidation by levamisole is due to the generation of a sulfhydryl metabolite and that the active intermediate is probably OMPI.

Animals↗