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Biomedical subjects

N R Bachur

Publications and source records attributed to N R Bachur.

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

Phytohemagglutinin isolectin subunit composition.

The subunit compositions of individual phytohemagglutinin isolectins from red kidney bean Phaseolus vulgaris were examined by isoelectric focusing and sodium dodecyl sulfate electrophoresis on polyacrylamide gels. Isoelectric focusing reveals heterogeneous but unique and non-overlapping protein band patterns for each of the homotetrameric isolectins, E4 and L4. Isoelectric focusing of the intermediate isolectins which contain both subunits (E3L1, E2L2, and E1L3) show all the protein bands common to isolectins E4 or L4 in proportions relative to their suggested subunit compositions. Polyacrylamide gel electrophoresis in a continuous sodium dodecyl sulfate buffer system gives a single protein band for all of the isolectins. In contrast, a discontinuous sodium dodecyl sulfate buffer procedure resolves isolectins E4 and L4 into single major protein bands of apparent molecular weights 31 700 (+/-600) and 29 900 (+/-200), respectively. Each of the intermediate isolectins contained both protein bands and their relative proportion, as determined by absorbance scanning, confirms the phytohemagglutinin isolectin subunit compositions as E4, E3L1, E2L2, E1L3, and L4.

Electrophoresis, Polyacrylamide Gel↗
PubMed1981

Cyclophosphamide and dimethylsulfoxide in the treatment of squamous carcinoma of the lung. Therapeutic efficacy, toxicity, and pharmacokinetics.

To determine whether dimethylsulfoxide (DMSO) can potentiate antitumor activity of cyclophosphamide (CYC) in patients with squamous cell carcinoma of the lung, 14 patients were treated with 5 l of a 5% or 6% DMSO solution PO over 3 days and 1,500 mg CYC/m2 IV as a 60-min infusion on the third day of treatment. Serial blood, CSF, and urine samples were collected to assess the pharmacokinetics of CYC. Courses were repeated every 3-4 weeks. No antitumor responses were observed. Toxicity was mainly hematologic and similar to that of CYC alone. There was one death from infection during granulocytopenia. Nonhematologic toxicity was moderate to severe and included nausea (14 patients) and vomiting (five patients). The plasma pharmacokinetics of CYC in this study are similar to previously reported results for CYC alone, but the 24-h urinary excretion of CYC in our study is much lower than previously reported. Further studies in tumors more responsive to CYC may be warranted.

Adult↗
PubMed1981

Daunorubicin reduction mediated by aldehyde and ketone reductases.

1. The cancer chemotherapeutic antibiotic, daunorubicin, is metabolized in rabbit liver by two distinct cytoplasmic reductases, with pH optima at 6.0 and 8.5. 2. A comparison of inhibition and activation of these two enzymes provides evidence of biochemical and kinetic differences, and suggests that the enzymes belong to different classes of carbonyl reductases; the pH 8.5 optimum reductase activity is classified as an aldehyde reductase, whereas the pH 6.0 optimum reductase is a ketone reductase.

4-Chloromercuribenzenesulfonate↗
PubMed1981

Growth inhibition by thymidine of leukemic HL-60 and normal human myeloid progenitor cells.

We compared the relative susceptibility of HL-60, a human acute progranulocytic leukemia cell line, and the normal human myeloid progenitor cell, the colony-forming unit in culture, to growth inhibition by thymidine. Normal human myeloid colony formation was more sensitive to thymidine than was HL-60 colony formation, the former being inhibited by greater than or equal to 0.5 mM thymidine and the latter by greater than or equal to 5.0 mM. Colony inhibition by thymidine was irreversible in both cases after a seven-day incubation of the colony-forming unit in culture in liquid medium enriched with thymidine and subsequent replating in thymidine-free soft agar. Thymidine-induced inhibition of HL-60 cloning could be partially prevented by deoxycytidine, whereas normal myeloid cloning could not, suggesting that high-concentration thymidine may affect processes necessary for cloning in addition to deoxyribonucleotide synthesis. HL-60 growth in liquid suspension culture could be suppressed transiently by 1.0 mM thymidine, suppressed totally by greater than or equal to 5.0 mM thymidine, and rescued completely by concomitant addition of deoxycytidine. The development of resistance to 1.0 mM thymidine could not be accounted for by reduction in thymidine pool size or by reduction in thymidine kinase activity. Replating of HL-60 cells growing in the presence of 1.0 mM thymidine in liquid medium in thymidine-free soft agar produced significant colony inhibition, also suggesting that thymidine affects more than just deoxyribonucleotide synthesis or that the clonogenic HL-60 cell presents a distinct subpopulation with more sensitive deoxyribonucleotide-synthetic control mechanisms.

Cell Differentiation↗
PubMed1981

Effects of deoxynucleosides on cultured human leukemia cell growth and deoxynucleotide pools.

We investigated the mechanism of cell growth inhibition caused by the deoxyribonucleosides thymidine (dThd), deoxyguanosine (dGuo), deoxyadenosine (dAdo), and deoxycytidine (dCyd). Growth of the cultured human leukemic cells HL-60 and K-562 was measured by cloning in soft agar. Of the deoxyribonucleosides, dGuo was the most potent cell growth inhibitor; however, the potency of added dAdo was probably attenuated by the presence of adenosine deaminase in the tissue culture growth medium. The concentrations of nucleoside causing 50% inhibition of HL-60 cloning were: dCyd, greater than 10,000 microM; dAdo, 500 microM; dThd, 5,000 microM; and dGuo, 80 microM. For K-562 cloning, the concentrations causing 50% inhibition of cloning were dCyd, greater 10,000 microM; dAdo, 1,600 microM; dThd, 880 microM;' and dGuo, 100 microM. Measurement of deoxycytidine 5'-triphosphate (dCTP) pool size in HL-60 cells following incubation with 750 microM deoxyribonucleosides revealed that dGuo caused the greatest reduction of dCTP pools, both in early (passage 10)- and late (passage 71)-passage-derived HL-60 cell cultures (35 and 19% of control, respectively), compared to dThd (61 and 26% of control, respectively) and dAdo (39% of control of HL-60 passage 10). In K-562 cells, reductions in dCTP pool size caused by dAdo, dThd, and dGuo were 68, 46, and 35% of control, respectively. Incorporation of [3H]dCyd into DNA of HL-60 and K-562 cells was enhanced by dThd and dGuo, but the degree of enhancement was greater for dThd than for dGuo. Despite its effect in reducing HL-60 dCTP pool size, dAdo failed to enhance [3H]dCyd incorporation in either HL-60 or K-562 cells. Addition of dCyd to the cultures could only partially rescue the inhibition of HL-60 cloning caused by dThd or dGuo, suggesting that inhibition of cytidine 5'-diphosphate reduction by ribonucleotide reductase is not the only mechanism whereby these nucleosides inhibit leukemic cell cloning. These data suggest that, in addition to inhibiting de novo dCTP production via ribonucleotide reductase, these nucleosides may affect other processes in the salvage pathway such as cellular uptake and phosphorylation or the DNA polymerase reaction itself.

Adenosine Deaminase↗
PubMed1980

Cis-Dichlorodiammine platinum and adriamycin therapy for advanced gynecological and genitourinary neoplasms.

Cis-Dichlorodiammine platinum (DDP) 75 mg/m2 on days 1 and 8 and Adriamycin (ADR) 60 mg/m2 on day 1 were used in 31 patients with advanced gynecological and genitourinary neoplasms. The DDP was given by 6 hours intravenous infusion with 2 liters of 5% Dextrose and 0.5 normal saline using Mannitol and/or furosemide diuresis. Courses were repeated every 21 to 28 days. Responses were seen in 7 of 8 patients with germinal cell neoplasms (5 complete, 2 partial) with a median duration of eight months. A partial response was obtained in 3 of 7 patients with bladder carcinoma with a median duration of three months. There were four partial responses obtained in 9 patients with ovarian carcinoma with a median duration of five months. Toxicities included nausea and vomiting in all 31 patients, nephrotoxicity (serum creatinine > 2 g/100 ml) in patients, tinnitus and/or high frequency hearing loss in 10 patients, and neurotoxicity (peripheral neuropathy, normal pressure hydrocephalus, papilledema) in 8 patients. Severe leukopenia (WBC < 2000/cu mm) and thrombocytopenia (< 100,000/cu mm) occurred in 25% and 45% of evaluable courses, respectively and necessitated dosage reduction in all and delay of therapy in some patients. Peak plasma Pt levels were 2.61 +/- .18 microgram/cc on day 1 and 3.52 +/- .39 microgram/cc on day 8 with a longer terminal half-life on day 8 (252 hours) compared to day 1 (156 hours). Peak plasma ADR levels ranged from .53 to 1.67 N moles/cc with an average terminal half-life of 22.8 hours. This agrees with values of ADR when given alone. This dose and schedule of DDP-ADR is active against advanced gynecological and genitourinary neoplasms, but the amount of toxicity seen indicates that modifications will have to be made.

Adolescent↗
PubMed1980

Diurnal variation of circulating human myeloid progenitor cells.

We investigated whether human circulating myeloid progenitor cells (CFU(c)) exhibit diurnal variation. Peripheral venous blood samples were drawn every 3 h from each of the nine healthy male volunteers. Blood mononuclear cells were harvested by the Ficoll-Hypaque method. CFU(c) content of blood was determined by the soft agar cloning assay. Human placental conditioned medium (HPCM) was used as colony stimulating factor. We found a 24 h cyclic variation of colonies/10(5) mononuclear cells plated with a maximum at 9 a.m. (P < 0.01). Analysis of the colonies by in situ staining indicated that this variation could be attributed almost entirely to colonies composed of eosinophilic cells (representative of CFU(eos)). Neutrophil/macrophage colonies (representative of CFU(G,M)) exhibited a trend toward a 9 a.m. maximum, but this variation was not statistically significant. We conclude that time of blood collection should be standardized in experiments measuring human peripheral blood CFU(c).

Cells, Cultured↗
PubMed1979

Phaseolus vulgaris isolectin binding to human erythrocytes.

The Phaseolus vulgaris isolectins L4,L3E1, L2E2, L1E3, and E4 were isolated by affinity and ion exchange chromatography. Pure isolectins were radiolabeled by the chloramine-T method with Na125IO4 and their binding to human erythrocytes was studied. A normal erythrocyte has approximately 8 times 10(5) receptor sites for each isolectin; however, the association constants (Ka) of binding increased from 1.1 times 10(7) M-1 to 3.8 times 10(8) M-1, with increasing number of E subunits per tetrameric isolectin molecule. Isolectin to erythrocyte binding reached equilibrium rapidly and was reversed by fetuin. All isolectins competed with 125I-E4 for erythrocyte binding sites, with a constant (KI) similar to the Ka calculated for each respective radiolabeled isolectin. When isolectin binding at 0 degrees C, 4 degrees C, or 8 degrees C was compared to that at 25 degrees C, there was no reduction in the number of binding sites per cell, but the Ka of E4 was reduced to 3 times 10(7) M-1. Fixed erythrocytes displayed similar isolectin binding characteristics.

Binding Sites↗
PubMed1979

Mathematical model for adriamycin (doxorubicin) pharmacokinetics.

Adriamycin (doxorubicin), an active antineoplastic drug, is rapidly distributed across cell membranes and is concentrated within cells. Binding to protein and to tissue readily occurs. The drug is metabolized to both fluorescent and nonfluorescent compounds, the liver being the main organ of biotransformation and elimination. A multicompartment, open model that accounts for these processes has been derived. The model assumes an initial volume of distribution of 60% of body weight and includes two peripheral adriamycin compartments and a subsystem for adriamycinol, a major metabolite. Plasma and urine concentrations of adriamycin and adriamycinol were determined for four patients treated with adriamycin (60 mg/m2), and these concentrations were used to calculate rate constants for the model. Concentrations were measured by fluorescence assay after thin-layer chromatographic separation of parent compound and metabolites. Differential equations were solved by the SAAM computer program. Evaluation of adriamcinol pharmacokinetics suggests that the previously reported high concentrations of adriamycinol immediately after IV infusion of adriamycin are an artifact of the fluorescence method and that observed plasma concentrations of adriamycinol are the sum of adriamycinol concentrations and approximately 10% of the adriamycin concentrations. Corrected peak plasma concentrations of adriamycinol occur 2--12 h after infusion of adriamycin.

Doxorubicin↗
PubMed1979

NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals.

With NADPH as the electron donor, rat liver NADPH cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4) catalyzes the single-electron reduction of several quinone antibiotics to a semiquinone or free radical state. The benzanthraquinones adriamycin, daunorubicin, carminomycin, 7-O-methylnogalarol, and aclacinomycin A and the N-heterocyclic quinones streptonigrin and mitomycin C are activated to free radical intermediates which can transfer their single electron to molecular oxygen to form superoxide. The overall Km range for this electron transfer is 0.4 to 42.1 X 10(-4) M. We postulate that the formation of the "site-specific free radical/ intermediate is central to the cytotoxic action of these antibiotics.

Animals↗