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  • 1
    Electronic Resource
    Electronic Resource
    1-β-D-Arabinofuranosylcytosine-, mitoxantrone-, and paclitaxel-induced apoptosis in HL-60 cells: improved method for detection of internucleosomal DNA fragmentation (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 365-371 
    Details
    ISSN: 1432-0843
    Keywords: Key words: Apoptosis – DNA fragmentation – HL-60 cells – Ara-C – Mitoxantrone – Taxol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. We investigated the ability of different doses and durations of exposure to the chemotherapeutic drugs 1-β-D-arabinofuranosylcytosine (Ara-C), mitoxantrone (MTN), and paclitaxel (taxol, TXL) to induce internucleosomal DNA fragmentation and apoptosis in human acute myeloid leukemia (AML) HL-60 cells in suspension culture. At clinically achievable concentrations, all three drugs have been shown to induce apoptosis in HL-60 cells. An improved method was developed for the isolation of pure genomic DNA and the detection of drug-induced internucleosomal DNA fragmentation in 〈1.0 μg of DNA sample by agarose gel electrophoresis. Morphologic evidence for apoptosis was determined by light microscopy following Wright staining, and cell viability was assessed by trypan blue dye exclusion. Internucleosomal DNA fragmentation was observed following exposure to 1.0 μM Ara-C for 4 h, which increased with 10 and 50 μM Ara-C. Incubation with 100 μM Ara-C produced internucleosomal DNA fragmentation starting at 3 h, which increased with longer periods of exposure to Ara-C. Utilizing a schedule of 1-h exposure followed by 3-h suspension in drug-free medium, 0.25 μM MTN was found to initiate DNA fragmentation, which increased with exposure to 1.0 and 5.0 μM MTN. However, identical treatment with higher concentrations of MTN resulted in random DNA degradation. Alternatively, continuous exposure to 1.0 μM MTN for 3 h was necessary to initiate internucleosomal DNA fragmentation. This increased with exposure intervals of up to 6 h. Exposure to TXL concentrations as low as 0.01 μM for 24 h caused internucleosomal DNA fragmentation, which increased with dose escalation (0.05, 0.1, 0.5, and 1.0 μM) of TXL. Although continuous exposure to 1.0 μM TXL for a period as short as 8 h produced internucleosomal DNA fragmentation, this increased significantly with longer exposure intervals. In general there appears to be a threshold concentration and duration of exposure below which none of these three drugs activates endonucleolytic internucleosomal DNA fragmentation and apoptosis. This threshold is lower for the DNA-interactive drugs MTN and Ara-C but higher for the non-DNA-interactive drug TXL. Higher doses or prolonged treatments with the drugs produce random DNA fragmentation associated with necrotic cell death. These in vitro results may further improve our understanding of the antileukemic cytotoxic effects of these drugs, which may enable a more rational design of drug regimens for optimal treatment of AML.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685559
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  • 2
    Electronic Resource
    Electronic Resource
    1-β-d-arabinofuranosylcytosine-, mitoxantrone-, and paclitaxel-induced apoptosis in HL-60 cells: improved method for detection of internucleosomal DNA fragmentation (1994)
    Springer
    Cancer chemotherapy and pharmacology 34 (1994), S. 365-371 
    Details
    ISSN: 1432-0843
    Keywords: Apoptosis ; DNA fragmentation ; HL-60 cells ; Ara-C ; Mitoxantrone ; Taxol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We investigated the ability of different doses and durations of exposure to the chemotherapeutic drugs 1-β-d-arabinofuranosylcytosine (Ara-C), mitoxantrone (MTN), and paclitaxel (taxol, TXL) to induce internucleosomal DNA fragmentation and apoptosis in human acute myeloid leukemia (AML) HL-60 cells in suspension culture. At clinically achievable concentrations, all three drugs have been shown to induced apoptosis in HL-60 cells. An improved method was developed for the isolation of pure genomic DNA and the detection of drug-induced intergenomic DNA and the detection of drug-induced internucleosomal DNA fragmentation in 〈1.0 μg of DNA sample by agarose gel electrophoresis. Morphologic evidence for apoptosis was determined by light microscopy following Wright staining, and cell viability was assessed by trypan blue dye exclusion. Internucleosomal DNA fragmentation was observed following exposure to 1.0 μM Ara-C for 4 h, which increased with 10 and 50 μM Ara-C. Incubation with 100 μM Ara-C produced internucleosomal DNA fragmentation starting at 3 h, which increased with longer periods of exposure to Ara-C. Utilizing a schedule of 1-h exposure followed by 3-h suspension in drug-free medium, 0.25 μM MTN was found to initiate DNA fragmentation, which increased with exposure to 1.0 and 5.0 μM MTN. However, identical treatment with higher concentrations of MTN resulted in random DNA degradation. Alternatively, continuous exposure to 1.0 μM MTN for 3 h was necessary to initiate internucleosomal DNA fragmentation. This increased with exposure intervals of up to 6 h. Exposure to TXL concentrations as low as 0.01 μM for 24 h caused internucleosomal DNA fragmentation, which increased with dose escalation (0.05, 0.1, 0.5, and 1.0 μM) of TXL. Although continuous exposure to 1.0 μM TXL for a period as short as 8 h produced internucleosomal DNA fragmentation, this increased significantly with longer exposure intervals. In general there appears to be a threshold concentration and duration of exposure below which non of these three drugs activates endonucleolytic internucleosomal DNA fragmentation and apoptosis. This threshold is lower for the DNA-interactive drugs MTN and Ara-C but higher for the non-DNA-interactive drug TXL. Higher doses or prolonged treatments with the drugs produce random DNA fragmentation associated with necrotic cell death. These in vitro results may further improve our understanding of the antileukemic cytotoxic effects of these drugs, which may enable a more rational design of drug regimens for optimal treatment of AML.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00685559
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    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Comparative in vitro cytotoxic effects of taxol and its major human metabolite 6α-hydroxytaxol (1995)
    Springer
    Cancer chemotherapy and pharmacology 36 (1995), S. 129-135 
    Details
    ISSN: 1432-0843
    Keywords: Taxol ; 6α-Hydroxytaxol ; HL-60 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Taxol is metabolized by the liver microsomal cytochrome P450 enzyme system into its principal metabolite 6α-hydroxytaxol (6HT). In the present in vitro studies 6HT was compared to taxol with respect to its effects on tubulin depolymerization, mitotic arrest, clonogenic survival and apoptosis in HL-60 cells. 6HT was generated by incubating taxol with human liver microsomes in a NADPH-generating system. HL-60 cells were incubated for 24 h with either taxol or 6HT, washed and placed in drug-free suspension or cultured for colony growth in agarose. For the suspension and colony culture growth of the cells, the IC50 concentrations of 6HT were 500±46 and 350±37 nM, while those of taxol were 3.2±0.2 and 2.8±0.5 nM, respectively. Immediately after a 24-h exposure of HL-60 cells to 50 nM taxol, electrophoresis of genomic DNA from HL-60 cells revealed an internucleosomal DNA fragmentation ‘ladder’. In addition, 39% of the cells were arrested in mitosis and 16% showed the morphologic features of apoptosis. In contrast, an identical treatment with 6HT resulted in the mitotic arrest of only 2.8% of the cells, with 4.0% displaying apoptosis (P〈0.01); internucleosomal DNA fragmentation was not observed. 6HT was also significantly less effective than taxol in inhibiting the temperature-induced depolymerization of microtubules in a cell-free system. However, at equipotent concentrations, the effect of 6HT on tubulin depolymerization, mitotic arrest or apoptosis was similar to that of taxol. In addition, at concentrations of taxol or 6HT at or below their IC50, there was little tubulin depolymerization, mitotic arrest or apoptosis. The results presented here show that the biotransformation of taxol to 6HT substantially detoxifies taxol.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689197
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  • 4
    Electronic Resource
    Electronic Resource
    Membrane glycoprotein changes associated with anthracycline resistance in HL-60 cells (1991)
    Springer
    Cancer chemotherapy and pharmacology 28 (1991), S. 93-101 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The glycoproteins on the surface of HL-60/S wild-type, drug-sensitive human leukemia cells and HL-60/AR anthracycline-resistant cells which do not overexpress the P-glycoprotein, were characterized by labeling with [35S]-methionine, NaB[3H4], phosphorus 32, or sodium iodide I 125. HL-60/S and HL-60/AR cell lysates and membrane fractions tagged with [35S]-methionine or phosphorus 32 showed no significant differences in their protein patterns as analyzed by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) and by autoradiography. HL-60/S cells labeled with NaB[3H4] yielded glycoproteins that were smeared predominantly in the molecular-weight range of 210,000 and 160,000 Da, with pI values ranging between pH 4 and pH 4.4. In contrast, NaB[3H4]-labeled HL-60/AR cells showed 7–8 discrete glycoproteins within a molecular-weight range of 170,000 and 140,000 Da, with pI values also ranging between pH 4 and pH 4.4. In addition, [3H]-glucosamine incorporation into HL-60/S and HL-60/AR cells revealed that the latter showed lower uptake of [3H]-glucosamine than did the former. Following treatment with tunicamycin, [3H]-glucosamine uptake in HL-60/S cells decreased, whereas that in HL-60/AR cells remained unchanged. Surface-membrane radioiodination of HL-60/S and HL-60/AR cells showed two distinct protein electrophoretic patterns, with differences being observed in both the high-(220–95 kDa) and low-molecular-weight ranges (21 kDa). Flow cytometric analysis of HL-60/S and HL-60/AR cells using myeloid and lymphoid antigen-specific antibodies demonstrated no antigenic differences between HL-60/S and HL-60/AR cells. HL-60/S cells incubated in the presence of tunicamycin, an inhibitor ofN-linked glycosylation, or the protein kinase C agonist phorbol 12-myristate 13-acetate (PMA) developed a glycoprotein pattern similar to that observed in HL-60/AR cells. In addition, tunicamycin treatment of HL-60/S cells decreased daunorubicin (DNR) retention and altered its intracellular distribution as compared with that in HL-60/AR cells. These data indicate that HL-60/AR cells do not possess either de novo or amplified high-molecular-weight surface-membrane proteins; instead, existing proteins are hypoglycosylated. These results also show that HL-60/AR cells exhibit the multidrug-resistant phenotype in association with altered membrane glycoproteins of both high (220–95 kDa) and low molecular weight (21 kDa), but without overexpression of the P-glycoprotein. Furthermore, in HL-60/S cells, the multidrug-resistant phenotype is partially inducible by inhibition ofN-linked glycosylation of cell-surfac proteins.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00689695
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  • 5
    Electronic Resource
    Electronic Resource
    Effect of deoxycytidine on the in vitro response of human leukemia cells to inhibitors of de novo pyrimidine biosynthesis (1987)
    Springer
    Cancer chemotherapy and pharmacology 19 (1987), S. 226-232 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of high concentrations of exogenous dCyd on the growth inhibitory properties of several inhibitors of de novo pyrimidine biosynthesis (dThd, 3-DAU, PALA, PF) was examined in three cultured human leukemic cell lines (HL-60, K-562, KG-1), and a dCyd kinasedeficient, Ara-C-resistant variant (HL-60/Ara-C). In the presence of dCyd concentrations (10-3 M), far exceeding normal human plasma levels (0.5 to 4.0×106 M), substantial but partial reversal of pyrimidine antagonist-mediated growth inhibition and restoration of intracellular dCTP levels was noted in all cell types except HL-60/Ara-C. When high concentrations of dCyd (10-3 M) were combined with low levels of uridine or cytidine (10-5 M), full restoration of growth was observed in sensitive cell lines. When exposed to supraphysiologic concentrations of dCyd, HL-60/Ara-C cells were more sensitive to the growth inhibitory effects of pyrimidine antagonists than parent HL-60 cells; this phenomenon was maximal at 10-4 M dCyd and was not observed in the presence of dCyd concentrations of 10-6 M or lower. These studies suggest that in the presence of low concentrations of uridine or cytidine, perturbations in intracellular dCTP pools may play a critical role in determining the in vitro antiproliferative response of human leukemic myeloid cells to diverse inhibitors of de novo pyrimidine biosynthesis. They also raise the possibility that modulation of exogenous dCyd concentrations may improve the therapeutic efficacy of pyrimidine antagonists toward certain salvage pathway-deficient, drug-resistant leukemic cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00252977
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  • 6
    Electronic Resource
    Electronic Resource
    Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells (1997)
    Springer
    Breast cancer research and treatment 42 (1997), S. 73-81 
    Details
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; Bcl-2 ; Bax ; estradiol ; taxol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Recent studies have demonstrated that following estrogen ablation, estrogen responsive breast cancer cells undergo apoptosis. In addition, estrogen receptor (ER) expression has been strongly correlated with the expression of the bcl-2 gene product, p26Bcl-2 protein, which is known to inhibit apoptosis. In the present studies, we investigated whether estrogen affects the intracellular levels of p26Bcl-2 and thereby modulates taxol-induced apoptosis of estrogen responsive human breast cancer MCF-7 cells. Transfer of MCF-7 cells to a culture-medium without estrogens reduced their intracellular p26Bcl-2 levels by 50%. Inclusion of 0.1 μM estradiol in the medium produced approximately a four-fold increase in p26Bcl-2, but not p29Bcl-xL or p21Bax levels; the expression of the c-myc and mdr-1 genes remained unchanged. Estradiol-induced four-fold increase in the ratio of the p26Bcl-2 to p21Bax levels caused a significant decline in the lethal, kilobase size DNA fragments of apoptosis, which had resulted when MCF-7 cells were cultured in a medium without estrogen. In addition, in MCF-7 cells, estradiol-induced increase in the intracellular p26Bcl-2 to p21Bax ratios was associated with a significant reduction in the large-sized DNA fragmentation induced by treatment with taxol. The increased ratios also protected MCF-7 cells against taxol-mediated cytotoxicity as assessed by the MTT assay. These results suggest that by modulating p26Bcl-2 levels, estrogens may affect the antitumor activity of taxol and potentially of other anti-breast cancer drugs against estrogen responsive human breast cancer cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005777219997
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