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Biomedical subjects

R N Taub

Publications and source records attributed to R N Taub.

At least 37 records · Page 2Linked to original sources
PubMed1985

Isolation and characterization of an anthracycline-resistant human leukemic cell line.

An anthracycline-resistant subline of HL-60 promyelocytic leukemia cells (HL-60/AR) has been isolated in vitro by subculturing in progressively higher concentrations of Adriamycin. The resistant cells are capable of sustaining continuous growth in 10(-6) M Adriamycin which is more than 50 times the 50% inhibitory dose for the parent line. HL-60/AR expressed variable degrees of cross-resistance to daunorubicin, dihydroxyanthracenedione, vincristine, vinblastine, and actinomycin D, but it remained sensitive to methotrexate and 1-beta-D-arabinofuranosylcytosine. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of glycoproteins of HL-60/AR revealed two prominent glycoproteins with molecular weights of 160,000 +/- 10,000 and 110,000 +/- 10,000 which were not detected in the sensitive cells. Cellular uptake and retention of daunorubicin was studied in the resistant and sensitive cells utilizing digitized video fluorescence microscopy. The sensitive cells accumulated more drug and showed at least 2-fold greater levels of brightness than the resistant cells. Studies of total intracellular accumulation, utilizing 10(-6) M [14C]-daunorubicin as a marker, showed a 1-h accumulation of 98 +/- 20 pmol/10(6) cells in HL-60/AR versus 255 +/- 25 pmol/10(6) cells in HL-60. Exposure to nontoxic concentrations of the calcium channel blocker Verapamil (10(-5) M) led to enhanced accumulation (175 +/- 8 pmol/10(6) cells) and retention of the drug in HL-60/AR, resulting in increased cytotoxicity in HL-60/AR. These anthracycline-resistant leukemic cells may serve as a valuable experimental model in studying the phenomenon of multiple drug resistance as well as strategies to circumvent it in human myeloid leukemia.

Antibiotics, Antineoplastic↗
PubMed1984

Assessment of potential exposure to antineoplastic agents in the health care setting.

In response to reports of measurable air levels of antineoplastic agents in hospitals and preliminary evidence of exposure to personnel handling these agents, a survey was designed and conducted to document the current handling practices of injectable antineoplastic drugs by hospital and health care workers at two major teaching hospitals and three affiliated community hospitals. The survey included assessment of drug preparation, administration, and disposal. A sample of nurses, pharmacists, physicians, and other staff who routinely come in contact with these drugs was interviewed for validation of the observed results. Typical working conditions encountered and the potential numbers of people at risk and their job titles are presented here. Drug preparation facilities and methods were not uniform even within a single institution, including local preparation in the pharmacy under controlled or uncontrolled conditions, as well as individual drug preparation and administration on the hospital floors. Handling practices for drug preparation were not consistent from practitioner to practitioner. In some cases, where laboratory coats and disposable gloves were provided, it was not a routine practice to wear them. Based on such analysis of risk factors, recommendations for improved practices are given.

Antineoplastic Agents↗
PubMed1984

Immunotherapy for chronic myelogenous leukemia: survival not affected by treatment in the stable phase.

Thirty-one consecutive patients with chronic myelogenous leukemia were treated in the chronic phase with immunotherapy in addition to chemotherapy. Immunotherapy consisted of Bacillus Calmette-Guérin and allogeneic myeloblasts given by vaccination, and chemotherapy comprised busulfan p.o. in most patients. No randomly allocated control group was designated, but patient characteristics appear to be typical of those of other published groups. Twenty-eight of 31 patients were followed from diagnosis to death, and the three remaining patients were followed for over 5 years. The median survival of the patients in our group was 37 months. There was a constant rate of decline in survival with time, with a mean annual death rate of 30% per year. Twenty-five of the 31 patients terminated in blast crisis. One of 21 patients achieved complete remission in blast crisis of myeloid or indeterminate type, and three of four patients achieved complete remission for blast crisis of lymphoid type. The median survival, the rate of decline in survival, and the remission rate in blast crisis do not appear to differ from those of comparable groups of patients treated with chemotherapy alone.

Adult↗
PubMed1984

Aberrant sialylation of granulocyte membranes in chronic myelogenous leukemia.

Peripheral blood granulocytes from patients with chronic myelogenous leukemia (CML) were studied for accessibility of membrane sialic acid and galactose residues to sodium borohydride-3H radiolabeling after oxidation with sodium metaperiodate (PI/B3H4) or with galactose oxidase (GO/B3H4). Granulocytes from untreated patients with chronic myelogenous leukemia showed increased radiolabeling with PI/B3H4, and decreased labeling with GO/B3H4 when compared to normal granulocytes. Granulocytes from leukemic patients receiving chemotherapy showed normal labeling patterns. Gel electrophoresis of membrane extracts showed that the changes in PI/B3H4 and GO/B3H4 reactivity of CML cells were distributed over all membrane protein bands. Our data suggest that CML granulocyte membrane proteins are aberrantly sialylated, with decreased accessibility of galactose residues, and that these changes may be reversed by clinical drug treatment.

Cell Membrane↗
PubMed1983

Phase II trial of the dopaminergic inhibitor pimozide in previously treated melanoma patients.

Pimozide, a potent neuroleptic which inhibits the release of pituitary releasing factors and is an effective dopamine antagonist, was administered to 30 patients with previously treated metastatic melanoma. Six patients were inevaluable because of poor drug tolerance (two), disease progression within 1 week and death within 2 weeks (three), and death from other causes (one). Among the 24 evaluable patients, two had complete response, two had partial response, and two had disease stabilization. Responses were observed in soft tissue, lymph nodes, liver, and lung. Toxic effects consisted of extrapyramidal manifestations in nine patients and malaise in seven. Pimozide has activity in patients with previously treated metastatic melanoma (17% response rate in evaluable patients) and merits consideration of further study in combination regimens.

Adult↗
PubMed1983

Differences in daunomycin retention in sensitive and resistant P388 leukemic cells as determined by digitized video fluorescence microscopy.

Cellular uptake and binding of daunomycin were studied using the digitized video fluorescence microscopy technique, in a sensitive and a resistant subline of P388 leukemic ascites tumor cells. When a 60-min time course of uptake was monitored, the sensitive cells had a 4-fold greater uptake than did the resistant cells. When the cells were perfused with drug-free medium, identical exchangeable levels of the drug were lost from both sublines. The difference in drug uptake could be accounted for entirely on the basis of differences in a slowly exchanging drug fraction which probably represents bound intracellular drug. In glucose-free medium, uptake of daunomycin was accelerated by metabolic inhibition to a greater extent in resistant than in sensitive cells. Furthermore, there was minimal decrease in the fluorescence when both sublines were perfused with drug-free medium. The addition of glucose to this medium induced a significant decrease in fluorescence in resistant but not in sensitive cells. These data raise the possibility that decreased drug uptake in resistant cells associated with decreased slowly exchanging drug fraction may be associated with an inherent defect in drug binding which is reversed by inhibition of energy metabolism. Parallel in vitro and in vivo studies revealed the presence of uptake heterogeneity; both sensitive and resistant cells contained subpopulations (20 to 30%) that have less or more fluorescence than the predominant pattern. This observation demonstrates the possible use of the digitized video fluorescence microscopy for recognizing subsets of cells with different drug susceptibility and to monitor the emergence of anthracycline-resistant cell populations.

Animals↗
PubMed1982

Effects of dopamine agonists and antagonists on murine melanoma: correlation with dopamine binding activity.

The biosynthetic pathway melanin is present in many melanomas. Previous investigations have suggested that pharmacologic levels of intermediates in this pathway (L-dopa, dopamine, and their analogues) may inhibit macromolecular synthesis in some tissue culture melanoma cell lines and prolong survival in tumor-bearing mice. Recently, a potent antidopamine drug (pimozide) has been developed. This study was designed to investigate the effects of these drugs on murine melanomas and to correlate effects on macromolecular synthesis with competitive dopamine binding activity (receptors) and melanin synthesis. Three murine melanomas (F1, F10, B16) were studied. The amelanotic B16 cell line showed no inhibition by dopa, dopamine, or pimozide when assayed for 14C-leu or 3H-TdR incorporation. Using a competitive binding assay, only low levels of dopamine binding were present. The very melanotic F1 cell line showed no inhibition by dopa or dopamine, but pimozide inhibited 14C-leu and 3H-TdR incorporation in a dose-response fashion; 50% inhibition was noted at 10(-9) M concentration with no loss in cell viability as tested by trypan blue exclusion or cell counting. Competitive dopamine binding was present (19 pmoles per g of wet tissue) with a Kd of 0.2 nM, figures approximating those seen in normal dog caudate nucleus controls. The F10 line, with melanin production between the B16 and F1, was intermediate in terms of inhibition of 14C-leu and 3H-TdR incorporation and dopamine binding. Purified melanin did not bind and, thus, does not appear to explain these binding results. These data suggest that pimozide, a drug which is a potent dopamine antagonist, may inhibit 14C-leu and 3H-TdR incorporation in murine melanoma cells and that competitive dopamine binding (receptor) appears to correlate with this inhibition. This drug and the dopamine binding assay may be useful in the study of human melanoma.

Animals↗
PubMed1982

Immunotherapy for remission maintenance in acute myeloblastic leukemia.

Forty-eight patients with acute myeloblastic leukemia in remission were treated with immunotherapy in addition to remission-maintenance chemotherapy. The first 16 patients were treated with weekly BCG and a leukemia cell vaccine (group 1). The next 32 patients were randomly allocated to receive BCG and a leukemia cell vaccine given once monthly (group 2) or BCG given monthly with no leukemia cell vaccine (group 3). There was no significant difference in remission duration or survival between the randomly allocated groups (2 and 3). Comparisons with group 1 are limited by the non-random allocation to this group, but selection bias was unlikely and clinical features were similar in the three patient groups. No significant difference in remission duration or survival was seen amongst the three groups studied. There was no advantage in the addition of leukemia cell vaccine (groups 1 and 2) to BCG alone (group 3) and no advantage to weekly (group 1) versus monthly immunotherapy (groups 2 and 3). Only 7 of the 48 patients achieved a second remission, and 4 of these were short-term partial remissions.

Adult↗
PubMed1982

Characterization of compounds shed from the surface of human leukemic myeloblasts in vitro.

Human leukemic myeloblasts shed glycoproteins from the cell surface during short-term in vitro culture. Shed surface glycoproteins yield a characteristic profile when studied by gel chromatography, isoelectric focusing, immune precipitation, and polyacrylamide gel electrophoresis. Isolation of immunologically active material yields a compound to approximately 75,000--80,000 daltons, with an isoelectric point of 7.6 to 7.9. Various morphological subtypes of acute myelogenous leukemia shed these compounds, but they are most easily obtained from the more differentiated M2 and M4 types as compared to the undifferentiated M1 type. The shed compounds appear to be quantitatively and qualitatively different from compounds shed by other leukemic cells or nonleukemic cells.

Cells, Cultured↗
PubMed1982

Digitized video fluorescence microscopy studies of adriamycin interaction with single P388 leukemic cells.

We have evaluated a new fluorescent method, the digitized video fluorescence microscopy technique, for the analysis of Adriamycin drug levels in single-cell suspension. This method uses a Leitz microscope equipped with an HBO 50 watt mercury source; the vertical body of the microscope is attached to an intensified silicone intensifier video camera with its output coupled to a video cassette recorder and to an Apple II microcomputer equipped with a video image digitizer. Using this technique, we were able to corroborate previous findings of decreased uptake and increased efflux in resistant as compared to sensitive P388 leukemic cells. This instrument may have wide applications in the study of anthracycline cell interaction or of any other drug with fluorescent properties.

Adsorption↗
PubMed1981

Acute myeloblastic leukemia-associated antigens: detection and clinical importance.

Antigenic compounds from the surface of leukemic myeloblasts are shed in vitro on short-term culture. Blast cells radiolabeled by lactoperoxidase iodination release soluble compounds that react immunologically with alloantisera to leukemia-associated antigens. Partially characterized soluble antigens were used to raise heteroantisera in monkeys that are selectively reactive with leukemic myeloblasts and unreactive with nonleukemic cells. Monkey heteroantisera were used to further characterize soluble leukemia antigens. Sera from patients with acute myeloblastic leukemia inhibit the reactivity of the heteroantisera, suggesting that soluble leukemic antigen is released in vivo as well.

Antibodies, Neoplasm↗