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M P Hacker

Publications and source records attributed to M P Hacker.

72 records · Page 4Linked to original sources
PubMed1982

Anticholinesterase activity of the unsymmetric bisquaternary 6-aminoquinoline salt NSC-176319.

The anticholinesterase activity of the unsymmetric bisquaternary 6-aminoquinoline salt NSC-176319 (QB) was studied in vitro. QB proved to be a noncompetitive inhibitor of both acetylcholinesterase (or true cholinesterase) and butyrylcholinesterase (or pseudocholinesterase) having a KI = 0.5 X 10(-6) M for acetylcholinesterase and 1.5 X 10(-6) M for butyrylcholinesterase. Further, QB inhibited esterase activity of murine plasma in a noncompetitive manner (KI = 4.2 X 10(-6) M). The inhibition was instantaneous in onset and did not diminish with prolonged incubation of the drug and enzyme. All mice treated intravenously with 2 mg QB/kg died within 5 min. Prior to death, mice developed severe parasympathomimetic effects and convulsions. Although the parasympathomimetic effects were diminished by atropine sulfate pretreatment, death could only be prevented by barbiturate anesthesia.

Animals↗
PubMed1982

Synthesis and antitumor activity of new platinum complexes.

A new type of antitumor platinum complex has been prepared and examined for antitumor activity against L1210 leukemia both in vitro and in vivo. The coordination environment of platinum in these complexes consists of three anionic chloride ions and a positively charged amine. The positive charge is introduced by monoprotonation or monoalkylation of a diamine. Platinum(IV) derivatives have been prepared for several of the complexes, and a water-soluble sulfate derivative has been prepared for one of them. Several of these complexes exhibit significant in vitro activity, and trichloro(3-aminoquinuclidinium)platinum(II) (QTP) exhibits significant in vivo activity as well. An increase in life span of approximately 40% has been observed using QTP. QTP is toxic at doses slightly in excess of effective doses.

Animals↗
PubMed1982

Effect of disulfiram (tetraethylthiuram disulfide) amd diethyldithiocarbamate on the bladder toxicity and antitumor activity of cyclophosphamide in mice.

Cyclophosphamide is the most commonly prescribed alkylating agent in clinical medicine. The usefulness of cyclophosphamide is often limited, however, by its propensity to cause hemorrhagic cystitis especially in children or patients receiving concomitant radiotherapy. Administration i.p. of cyclophosphamide at doses of 100 mg/kg or more to mice produced a significant increase in urinary bladder weight within 48 hr of treatment. The present studies demonstrate that disulfiram prevented cyclophosphamide-induced bladder damage when administered p.o. within 1 hr of cyclophosphamide treatment. Diethyldithiocarbamate, a sulfhydryl-containing metabolite of disulfiram, had identical uroprotective activity. Unlike disulfiram, diethyldithiocarbamate was effective only when administered 2 to 4 hr after cyclophosphamide. Disulfiram augmented slightly the antitumor activity of cyclophosphamide against L1210 murine leukemia in vivo when administered 30 min prior to cyclophosphamide. In contrast, diethyldithiocarbamate had no effect on the antitumor activity of cyclophosphamide when administered 4 hr after cyclophosphamide.

Animals↗
PubMed1982

Specific in vivo and in vitro antibody response to tetanus toxoid immunization.

Booster immunization of normal individuals with soluble tetanus toxoid (TT) produced significant levels of plasma anti-tetanus IgG and IgM detectable by an enzyme linked immunosorbent assay (ELISA). Similar changes in circulating anti-TT antibody were found in mice following primary immunization. There was. however, no correlation observed between circulating anti-TT antibody response and the proliferative response of peripheral blood mononuclear cells exposed to soluble TT in the immunized individuals. The capacity of the peripheral blood mononuclear cells to produce specific anti-TT antibody in vitro was evaluated using a new microculture antibody synthesis enzyme-linked assay (MASELA). It was observed that the production of specific antibody in vitro correlated with the circulating anti-TT antibody level and not with the proliferative response. Peripheral blood mononuclear cells from these recently secondary immunized individuals produced greater specific anti-TT antibody when cultured in TT coated plastic wells than did controls. The potential utility of this technique in assessing response to immunization and basic immune competence is discussed.

Adult↗
PubMed1982

The prevention of cyclophosphamide-induced cystitis in mice by disulfiram.

Cyclophosphamide administered intraperitoneally to mice at a dose of 100 mg/kg caused a dose related increase in urinary bladder weight within 48 hours of treatment. Disulfiram effectively prevented cyclophosphamide-induced increase in bladder weight when disulfiram was administered by either the oral or intraperitoneal route. Disulfiram (125 mg/kg) was most effective when given within one hour of cyclophosphamide treatment. These results suggest that disulfiram, unlike other putative protectants, is effective when administered orally.

Animals↗
PubMed1981

Combination of dihydroxyanthraquinone and radiation on L1210 murine leukemia.

A new synthetic anthraquinone, dihydroxyanthraquinone (DHAQ), was tested as a single agent and in combination with whole-body x-irradiation in mice bearing L1210 leukemia in the ascites form. DHAQ alone had significant antitumor activity as evidenced by prolonged mean survival times; radiation was ineffective. The combination of the two modalities produced a therapeutic benefits greater than that produced by either agent alone: mean survival times were increased and a number of cures (animals alive at 30 days) produced. These results suggest the potential of using DHAQ and radiation in a combined modality therapeutic approach.

Animals↗
PubMed1981

Amelioration of adriamycin and daunorubicin myocardial toxicity by adenosine.

Primary cultures of rat myocardial cells were used to investigate the dose and time-dependent cellular enzyme release induced by either Adriamycin or daunorubicin, Concentrations of either anthracycline (1.8 or 18 microM) produced significant release of creatine phosphokinase and lactic dehydrogenase from myocardial cells within 24 hr of exposure without a detectable decrease in cell viability. Preincubation of the myocardial cells with varying concentrations of adenosine (10 microM to 1 mM) for 24 hr prior to the addition of anthracycline decreased or prevented drug-induced enzyme release. Other putative myocardial protectants, i.e., N-acetyl-L-cysteine, alpha-tocopherol, or carnitine, were ineffective in preventing anthracycline-induced enzyme release. Although adenosine was an effective myocardial protectant, it had no significant effect on cellular uptake of daunorubicin, nor did adenosine adversely affect the oncolytic activity of daunorubicin against L1210 leukemia cells in vitro. Anthramycin, another oncolytic agent having reported cardiotoxic effects, was also tested in the in vitro system. With this drug, however, no enzyme release was detected at less than lethal doses nor did adenosine have any protective potential against the toxicity of anthramycin. Finally, Adriamycin caused no significant lactic dehydrogenase release when incubated at 1.8 or 18 microM with H9c2 cells, a cell line having primarily skeletal muscle characteristics. This result suggests a specific toxicity of anthracyclines for myocardial but not skeletal muscle cells.

Adenosine↗
PubMed1980

Effect of osmotic diuresis on gentamicin-induced nephrotoxicity in rats.

The effect of isosorbide diuresis on gentamicin excretion and tissue accumulation as well as gentamicin-induced histopathologic changes in renal tissue were examine in rats. Gentamicin (30, 60, 120, 160 mg/kg) was administered s.c. for 10 consecutive days with or without isosorbide pretreatment. Osmotic diuresis with isosorbide did not significantly reduce the dose-dependent extent of gentamicin accumulation in renal tissues in comparison to nondiuresed rats. Although the urinary concentration of gentamicin was reduced in the diuresed animals, total gentamicin excretion remained unaffected. In addition, diuresis altered neither the renal excretion of the proximal tubular cell marker enzyme, N-acetyl-B-glucosaminidase, nor the severity of pathologic damage as determined by light microscopic examination of renal tissues. It appears that osmotically-induced diuresis alone is insufficient to prevent or significantly reduce gentamicin nephrotoxicity in rats. This is in contrast to other forms of diuretic therapy, such as furosemide, which have been shown to effectively reduce renal accumulation and resultant renal toxicity of aminoglycoside administration.

Acetylglucosaminidase↗
PubMed1977

Partial purification of human lymphocyte-activating factor (LAF) by ultrafiltration and electrophoretic techniques.

Lymphocyte-activating factor (LAF) has been produced by culturing human peripheral blood leukocytes in the presence of lipopolysaccharide and autologous human serum. The major LAF activity, identifiable by Sephadex chromatography (m.w. 13,000) was separated from most serum proteins in the culture medium by ultrafiltration with a hollow fiber device. Sucrose gradient isoelectric focusing of the concentrated ultrafiltrate yielded a single peak of LAF activity with an average isoelectric point of pH 6.8. Semi-preparative polyacrylamide gel electrophoresis of the isoelectric focusing sample resulted in separation of the LAF activity from detectable amounts of serum proteins. The recovered LAF activity was estimated to be purified more than 16,000-fold and is judged to be active in submicrogram amounts.

Animals↗
PubMedDate not supplied

Chronobiologic fluctuation of cyclophosphamide induced urinary bladder damage in mice.

Cyclophosphamide is the most widely used alkylating agent in clinical medicine. The usefulness of this drug is often limited by its propensity to produce hemorrhagic cystitis. To be active cyclophosphamide must be metabolized by the mixed function oxidase system. It has been previously demonstrated that the oncolytic activity and host lethality of cyclophosphamide are dependent upon circadian fluctuations. When cyclophosphamide is administered i.p. to male mice there is a dose dependent increase in urinary bladder weight. Histopathologic examination of these bladders revealed hemorrhage, edema, inflammation and stretching of the epithelial lining. When administered i.p. at 4-h intervals throughout a 24-h time period, cyclophosphamide produced maximum bladder damage when administered at 0500 and 1700 and little or no damage to the bladder when administered at 0100 or 1300. These studies suggest that cyclophosphamide induced cystitis, a toxicity resulting from the metabolic production of acrolein, may also be dependent upon chronobiologic fluctuations.

Animals↗
PubMedDate not supplied

Pharmacologic and toxicologic evaluation of thioproline: a proposed nontoxic inducer of reverse transformation.

The ability of thioproline to act as a nontoxic inducer of reverse transformation was examined. Thioproline was unable to effect reproducibly morphologic changes characteristic of the reversed transformed state of HeLa, WI-38VA13, C1300 neuroblastoma, and CHO-K1 cell lines. Reversal of transformed cells with dibutyryl cyclic AMP was, however, readily demonstrated in both the CHO-K1 and C1300 cell lines. Thioproline produced severe, life-threatening CNS toxicity in both mice and rats at levels far below those previously reported to be without any toxic effects. We conclude that not only is thioproline incapable of producing a reversal of the transformed state in HeLa and other cell lines in vitro, it is also a compound that must be described as a strongly CNS toxic agent.

Animals↗
PubMedDate not supplied

Modulation of methotrexate resistance by genistein in murine leukemia L1210 cells.

We have previously shown that methotrexate (MTX) transport is impaired in murine L1210 cells selected for cisplatin (DDP) resistance (L1210/DDP) and that the decreased MTX uptake may be due to an altered 66 kDa membrane protein. We have further hypothesized that tyrosine phosphorylation is necessary for the function of this protein. To determine the importance of tyrosine phosphorylation we studied the effect of genistein, a tyrosine kinase inhibitor, on methotrexate sensitivity, uptake and tyrosine phosphorylation of the 66 kDa protein in L1210/0 cells. After 5 h of treatment with 50 microM genistein, methotrexate uptake was decreased by nearly 50% and the cells were protected from methotrexate cytotoxicity. Immunoblotting of whole cell lysates with a phosphotyrosine monoclonal antibody demonstrated that genistein treatment decreased phosphorylation of the 66 kDa membrane protein. We concluded that phosphorylation of a 66 kDa protein may be critical for methotrexate transport and that genistein protects L1210/0 cells from methotrexate toxicity.

Animals↗