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E Solary

Publications and source records attributed to E Solary.

At least 109 records · Page 6Linked to original sources
PubMed1994

[Value of rhodamine 123 in the detection of minor amounts of multidrug resistant cells].

The neoplasias resistance to chemotherapy is mainly due to multidrug resistance phenomenon (MDR) mediated by an ATP-dependent efflux pump called P-glycoprotein. This function can be reversed by many multidrug reversing agents so numerous chemotherapy regimens have been initiated in malignancies. To make sure the success of these protocols it is necessary to detect as soon and as certain as possible the presence of resistant cells among malignant population. We have chosen to evaluate functional test using rhodamine 123 in this aim in view. We have made various mixtures of resistant ans sensitive cells of three cell lines. Rhodamine 123 allows to detect 1% of resistant cells among sensitive cells. Influence of dead cells on the interpretation is discussed.

Antimetabolites, Antineoplastic↗
PubMed1994

Apoptosis of human leukemic HL-60 cells induced to differentiate by phorbol ester treatment.

In the human leukemic HL-60 cell line, we have reported previously that monocytic/macrophage-like differentiation induced by TPA (12-O-tetradecanoylphorbol-13-acetate) was associated with a decreased sensitivity to various apoptosis-inducing stimuli (Solary, Bertrand, Pommier, Blood 1993; 81:1359-1368). In the present study, we studied further the effects of TPA alone on the induction of apoptosis in HL-60 cells. Based on morphology by electron microscopy, identification of internucleosomal DNA cleavage by gel electrophoresis and quantitation of DNA fragmentation by a filter binding assay, we observed that neither morphologic changes nor DNA damage were identified in TPA-differentiated HL-60 cells as long as they kept the adherent phenotype characteristic of this differentiation pathway. However, adherent TPA-treated HL-60 cells that secondarily detached from the flask demonstrated internucleosomal DNA fragmentation associated with morphologic changes characteristic of apoptosis. Similarly, HL-60 cells that never became adherent after TPA treatment underwent rapid apoptosis. Granulocytic differentiation by retinoic acid (RA) treatment also induced apoptosis although more slowly. Interestingly, in both TPA- and RA-treated cells, apoptotic bodies appeared to be phagocytosed by differentiated cells from the same lineage. Internucleosomal DNA fragmentation was also identified in HL-60 cells induced to differentiate by sodium butyrate and dimethylsulfoxide treatment, suggesting that apoptosis could be the common mode of death of terminally differentiated HL-60 cells.

Apoptosis↗
PubMed1994

Comparative effects of quinine and cinchonine in reversing multidrug resistance on human leukemic cell line K562/ADM.

We have previously suggested that quinine and cinchonine could be good candidates for clinical circumvention of multidrug resistance (MDR) in hematological malignancies because of their tolerance and their retained efficacy in serum. In the present study, we have used the well-characterized multidrug resistant human leukemic cell line K562/ADM to compare the effect in vitro of quinine and cinchonine on doxorubicin, mitoxantrone, and vincristine uptake and cytotoxicity. In serum-free medium, quinine induced a dose-dependent increase of doxorubicin uptake reaching about 200% at 40 microM, while it had a slight and no effect on mitoxantrone and vincristine uptake respectively. In the same conditions, cinchonine induced a rapid and significant increase in the accumulation of the three drugs, reaching a plateau phase between 5 and 10 microM. Quinine and cinchonine induced both potentiation of doxorubicin, vincristine and mitoxantrone cytotoxicity in K562/ADM cells. However, quinine reached a plateau phase at 10 microM, while cinchonine had a maximal effect at 5 microM and was significantly more potent at low concentrations. When diluted in plasma, cinchonine was less bound to proteins than quinine. The free fraction of alkaloids was 37-55% for cinchonine and 20-30% for quinine. Cinchonine-induced enhancement of vincristine cellular accumulation was little modified by plasma proteins. When incubated in whole blood, the fraction of cinchonine trapped in red blood cells was rapidly and completely exchangeable with plasma. We conclude that cinchonine is a stronger inhibitor of MDR than quinine.

Antineoplastic Agents↗
PubMed1993

Dual inhibition of topoisomerase II and tubulin polymerization by azatoxin, a novel cytotoxic agent.

Azatoxin (NSC 640737) is a synthetic molecule that was rationally designed as a topoisomerase II inhibitor (Leteurtre et al., Cancer Res 52: 4478-4483, 1992). The present study was undertaken in order to investigate the molecular pharmacology and the cytotoxic activity of azatoxin in human tumor cells. Alkaline elution experiments performed in HL-60 cells demonstrated that: (1) azatoxin induces DNA-protein cross-links and protein-linked DNA single- and double-strand breaks characteristics of topoisomerase II inhibition in HL-60 cells; and (2) the potency of azatoxin is comparable to that of etoposide (VP-16). Testing of azatoxin in 45 human cell lines in the National Cancer Institute (NCI) in vitro Drug Screening Program indicated that azatoxin was potent (mean IC50 = 0.13 microM), but that its cell line sensitivity profile was correlated with that of tubule inhibitors rather than that of topoisomerase II inhibitors. These data led us to investigate the anti-tubulin activity of azatoxin. We found that azatoxin inhibited tubulin polymerization in vitro and was a mitotic inhibitor at 1 microM and above in the human colon cancer cell line KM20L2. In these cells topoisomerase II inhibition, as detected by the induction of protein-linked DNA strand breaks, required azatoxin concentrations of at least 10 microM. In summary, azatoxin is a potent cytotoxic agent that inhibited both tubulin and topoisomerase II. At lower azatoxin concentrations the former activity prevailed whereas at higher concentrations topoisomerase II inhibition became prominent.

Cell Death↗
PubMed1993

Differential induction of apoptosis in undifferentiated and differentiated HL-60 cells by DNA topoisomerase I and II inhibitors.

The effects of monocytic/macrophage and granulocytic differentiation induced by phorbol myristate acetate (TPA) and all-trans retinoic acid, respectively, were tested on the induction of apoptosis in human promyelocytic leukemia HL-60 cells treated with topoisomerase I and II inhibitors. Using a filter-binding assay, we observed a strong inhibition of DNA fragmentation induced by 3- and 24-hour continuous exposure to camptothecin, VP-16, VM-26, and m-AMSA in TPA-differentiated cells. The inhibition of the typical internucleosomal DNA fragmentation was confirmed by agarose gel electrophoresis. By contrast, drug-induced DNA fragmentation was not inhibited in retinoic acid-differentiated cells, and apoptosis occurred in these cells after 4 to 5 days in the absence of drug treatment. The TPA inhibitory effect was maximal after 24 hours of treatment and was correlated with differentiation, because phorbol dibutyrate ester was active, whereas 4-alpha-TPA, a nontumor promoter that does not induce differentiation, was not active. Using alkaline elution, we observed that TPA and retinoic acid differentiation were associated with changes in topoisomerase-mediated DNA breaks that were not correlated with their differential effects on drug-induced DNA fragmentation. Moreover, TPA also inhibited DNA fragmentation induced by vinblastine, cycloheximide, calphostin C, and x-rays. Using a cell-free system, we observed that DNA fragmentation was not inhibited in nuclei from TPA-differentiated cells. Rather, inhibition of apoptosis seemed to take place in the cytoplasm. We conclude that phenotypic changes associated with TPA-induced differentiation include inactivation of a cytoplasmic activity that can induce DNA fragmentation associated with apoptosis.

Amsacrine↗
PubMed1993

Apoptosis and its modulation in human promyelocytic HL-60 cells treated with DNA topoisomerase I and II inhibitors.

Electron microscopy studies demonstrate unequivocally that the observed oligonucleosome-sized secondary DNA fragmentation in human promyelocytic HL-60 cells treated with the topoisomerase inhibitors camptothecin and teniposide is correlated with the morphological changes in cell structure typical of programmed cell death (apoptosis). Since apoptosis has been associated with potential involvement of intracellular signaling linked to the Ca2+/calmodulin and protein kinase C transduction pathways, we also investigated the effects of signaling modulators on camptothecin- and teniposide-induced secondary DNA fragmentation in HL-60 cells. Neither calcium chelators, calcium/calmodulin inhibitors (calmidazolium or cyclosporine A), protein kinase C stimulation by TPA, protein phosphatase inhibition by okadaic acid, protein kinase inhibition by staurosporine, calphostin C, genistein or H7, nor cell cycle alterations by caffeine had any detectable effect. Interestingly, most of these intracellular signaling modulators were able to induce DNA fragmentation in HL-60 cells by themselves. These results may suggest that even though modulation of these signaling pathways was unable to prevent topoisomerase inhibitor-induced apoptosis, their sole deregulations could induce apoptosis in HL-60 cells. In contrast, aphidicolin blocked camptothecin-induced secondary DNA fragmentation, indicating that replication-induced DNA damage is required for camptothecin- but not teniposide-induced secondary DNA fragmentation. Zinc, 3-aminobenzamide, and spermine also modulated both camptothecin- and teniposide-induced secondary DNA fragmentation without significant alteration of topoisomerase-mediated primary DNA strand breaks. Hence, poly(ADP-ribosyl)ation and chromatin structure may be important in modulating oligonucleosome-sized DNA fragmentation associated with apoptosis in HL-60 cells treated with topoisomerase inhibitors.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Efficacy and tolerance of an amphotericin B lipid (Intralipid) emulsion in the treatment of candidaemia in neutropenic patients.

The efficacy and tolerance of a new amphotericin B lipid emulsion (AmB-IL) in which amphotericin B was diluted in a lipid solution for parenteral nutrition (Intralipid) was assessed in fourteen episodes of candidaemia occurring in neutropenic patients. The strains isolated were Candida krusei (nine cases), Candida albicans (three cases), Candida parapsilosis (one case) and Candida lusitaniae (one case). An AmB-IL was administered at a mean dosage of 1.18 mg/kg/day (range 0.73-1.55) for 22 days (range 6-62). Flucytosine was added to AmB-IL in 12 patients (mean duration 10.6 days). Chills were noted in only 3/306 infusions of AmB-IL. A mild increase of serum creatinine level from 9.3 +/- 3 mg/L (baseline) to 10.9 +/- 3 mg/L (after completion of AmB-IL) and mild decrease of creatinine clearance from 83 +/- 28 mL/min to 56 +/- 21 mL/min were observed. These changes did not correlate with either daily or total dose of AmB-IL or length of therapy. Seven patients were cured and six improved (patients who subsequently died due to nonfungal cause) with AmB-IL. One patient died due to C. krusei pneumonia. In conclusion AmB-IL is a well-tolerated method of amphotericin B administration. It could facilitate the use of amphotericin B without impairing its efficacy for the treatment of candidaemia in neutropenic patients.

Adult↗
PubMed1992

Radioimmunoassay for the measurement of serum IL-6 and its correlation with tumour cell mass parameters in multiple myeloma.

Interleukin-6 (IL-6) was demonstrated to be a strong autocrine or paracrine plasmocytoma cell growth factor in humans. Using a bioassay, high serum IL-6 (S-IL-6) levels were correlated with disease severity in plasma cell dyscrasias. Since other cytokines could interfere with the bioassays, we developed a specific radioimmunoassay to study S-IL-6 levels in 102 patients with monoclonal gammopathy (MG). S-IL-6 level was studied by a double antibody radioimmunoassay using a rabbit polyclonal anti-IL-6 antibody and a human recombinant IL-6 as the standard. The lowest value of the standard significantly different from zero was found to be 78 pg/ml. Within-run and between-run precisions were characterized by a mean coefficient of variation of 3.72 and 5.5%, respectively. The mean analytical recovery was found to be 113% and the immunochemical identity of IL-6 standard and S-IL-6 was shown by dilution tests. IL-6 was detected in all tested sera. Sera from 66 healthy volunteers and 43 patients with acute leukemia or malignant lymphoma were tested as controls. In healthy subjects, S-IL-6 values were 294 +/- 86 pg/ml. MG were classified as multiple myeloma (MM), macroglobulinemia, and MG of undetermined significance (MGUS). The distribution of S-IL-6 levels in patients with MG was significantly higher than in healthy subjects but lower than in patients with acute leukemia or Hodgkin's lymphoma. Results obtained in 55 patients with MM were related to other biological parameters. S-IL-6 levels correlated with bone-marrow plasmacytosis (P less than .0005), serum-lactate dehydrogenase (S-LDH; P less than .005), serum beta 2 microglobulin (S -beta 2m; P less than .01), and serum calcium (S-Ca; P less than .025) and inversely correlated with haemoglobin (P less than .025). Our results indicate that 1) radioimmunoassay is suitable for the measurement of human IL-6 in serum; 2) high S-IL-6 levels are observed in a small number of patients with MG; and 3) S-IL-6 level correlates with tumour cell mass in patients with overt MM.

Bone Marrow↗
PubMed1992

Clinical evaluation of a new lipid-based delivery system for intravenous administration of amphotericin B.

In a retrospective study a new lipid-based delivery system for administration of amphotericin B was evaluated in 26 treatment courses in 22 patients. Amphotericin B was given by infusion diluted in either the lipid solution (1 mg/kg/d; 13 courses) or dextrose (0.92 mg/kg/d; 13 courses). No differences were noted in the serum pharmacokinetics. Fever or rigors were observed in 6 of 13 courses in the conventional amphotericin B group versus none in the lipid amphotericin B group (p = 0.007). Four of 13 courses of treatment were discontinued due to adverse effects in the conventional amphotericin B group compared to none in the other group (p = 0.048). In the lipid amphotericin B group the decrease in creatinine clearance was significantly lower on the fourth day of treatment (p = 0.04) and significantly fewer patients had a decrease of more than 25% in creatinine clearance on the sixth day (4/12 vs 9/11 p = 0.02). These preliminary findings suggest that this lipid amphotericin B formulation is well tolerated with few nephrotoxic effects.

Adult↗
PubMed1992

Radiolabeling of DNA can induce its fragmentation in HL-60 human promyelocytic leukemic cells.

Incorporation of radiolabeled thymidine is commonly used to investigate DNA damage. Using a filter-binding assay, we observed that the addition of various doses of [methyl-3H]thymidine (0.2 and 2 microCi/ml) or [2-14C]thymidine (0.02 and 0.2 microCi/ml) in the culture medium for 2 days, a standard method for cell-labeling, induces DNA fragmentation in HL-60 human promyelocytic cells. This effect was dose- and time-dependent and the DNA fragments were not protein-linked since the levels of DNA fragmentation were identical in the presence and in the absence of proteinase K (0.5 mg/ml). Radiolabeled thymidine-induced DNA fragmentation was associated with an inhibition of cell growth, but cells remained able to exclude trypan blue, suggesting that plasma membrane integrity was conserved, except at very high doses of [methyl-3H]thymidine (2 microCi/ml). By agarose-gel electrophoresis, the DNA-fragmentation was demonstrated to be internucleosomal with a typical ladder pattern. Addition of unlabeled thymidine to the culture medium prevented DNA fragmentation in a dose-dependent manner, indicating that radiolabeled thymidine incorporation in DNA was directly responsible for DNA fragmentation. We conclude that radiolabeling of DNA using thymidine incorporation can induce DNA fragmentation in some cell lines such as HL-60. This observation must be taken into account in methods using radiolabeling to study DNA damage in these cells.

Apoptosis↗
PubMed1992

New case of t(3;17)(q26;q22) as an additional change in a Philadelphia-positive chronic myelogenous leukemia in acceleration.

A new case of t(3;17)(q26;q22) was observed in a Philadelphia-positive (Ph+) chronic myelogenous leukemia in acceleration 1 month before occurrence of the blastic phase. Abnormal megakaryocytopoiesis and thrombopenia were noted, but blast cells did not express platelet markers. The same translocation was previously reported in three myeloproliferative disorders in acceleration or in the process of becoming acute. Translocations or inversions of chromosome 3 with breakpoint involving the band 3q26 were specifically associated with megakaryoblastic acute phase or abnormal megakaryocytopoiesis. This report confirms that the t(3;17)(q26;q22) is a specific nonrandom chromosomal abnormality associated with the acute nonlymphoblastic phase of myeloproliferative disorders and megakaryocytopoiesis dysfunction.

Bone Marrow↗
PubMed1992

High concentrations of intrathecal interleukin-6 in human bacterial and nonbacterial meningitis.

Interleukin-6 (IL-6) is multipotent cytokine that acts in a network of factors directing the inflammatory reaction of purulent bacterial meningitis (PBM). However, little is known about the role of IL-6 in aseptic or "viral" meningitis (AM). IL-6 was assayed by RIA in cerebrospinal fluid (CSF) and serum samples obtained from patients with AM (n = 65), PBM (n = 8), and lymphocytic bacterial meningitis (LBM, n = 11). Of patients with AM, 89% had detectable IL-6 in CSF, with high IL-6 titers (median, 2160 pg/mL; 95% confidence interval [CI], 1320-2540 pg/mL) compared with 100% in patients with PBM (median, 6575 pg/mL; 95% CI, 450-32,000 pg/mL) and 90.9% in patients with LBM (median, 875 pg/mL; 95% CI, 150-2180 pg/mL). There was a highly symmetrical correlation between IL-6 and the percentage of polymorphonuclear cells in CSF of patients with PBM (r = .97, P = .01) and AM (r = .49, P = .002). In conclusion, this study shows evidence that IL-6 is released into the meningeal space in aseptic meningitis and is correlated with the local acute inflammatory response.

Humans↗
PubMed1992

Correlation of MDR1/P-170 expression with daunorubicin uptake and sensitivity of leukemic progenitors in acute myeloid leukemia.

Prior studies have shown that multidrug resistance gene products may be detected in acute myeloid leukemia (AML) cells, and are associated with poor response to therapy. We studied whether P-170 expression was associated with in vitro daunorubicin (DNR) accumulation and sensitivity of leukemic clonogenic cells (CFU-L) to DNR in 16 newly diagnosed AML samples. P-170 expression was assessed by indirect immunofluorescence using the monoclonal antibody MRK16. DNR cellular content was measured by flow cytometry after short incubation with increasing concentrations of DNR, and was not correlated with P-170 expression, although there was a trend for higher values in P-170-negative samples. The sensitivity of CFU-L was studied in a semisolid culture assay by calculating the dose of DNR inhibiting the growth of 90% of CFU-L (D90). The D90 was significantly higher in P-170-positive than in P-170-negative samples (mean = 1.68 +/- 0.42 microgram/ml versus 0.97 +/- 0.35 micrograms/ml respectively, p less than 0.005). Eight of 9 cases achieving complete remission (CR) after intensive chemotherapy were P-170-negative, whereas 7 of 7 nonresponders were P-170-positive (p less than 10(-5)). D90 was significantly lower for patients achieving CR than for those who did not achieve CR (1.12 +/- 0.55 micrograms/ml versus 1.59 +/- 0.37 micrograms/ml, p = 0.04). It is concluded that P-170 expression is correlated with in vitro resistance of clonogenic cells to DNR and may be one mechanism of resistance to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Feasibility of using quinine, a potential multidrug resistance-reversing agent, in combination with mitoxantrone and cytarabine for the treatment of acute leukemia.

PURPOSE: We demonstrated previously that sera from quinine-treated patients reversed the multidrug resistance (MDR) of a human leukemic cell line. We now report a phase I and II clinical study that examined the toxicity of the combination of quinine with mitoxantrone and cytarabine (Ara-C). PATIENTS AND METHODS: Fifteen adult patients with relapsed or refractory acute leukemia were treated with quinine formiate (30 mg/kg/d in continuous intravenous (IV) infusion from day 1 through day 5 or 6) associated with Ara-C (1 g/m2 in 3-hour IV infusion twice a day for 5 days) and five increasing doses of mitoxantrone (from 8 mg/m2/d for 4 days to 12 mg/m2/d for 5 days). RESULTS: The main toxicity was severe myelosuppression: the mean times to leukocyte recovery (> 500/microL), granulocytes recovery (> 500/microL), and platelet count recovery (> 50,000/microL) were 23 days (range, 17 to 29 days), 30.6 days (range, 17 to 48 days), and 35.4 days (range, 14 to 75 days), respectively. The nonhematopoietic toxicity of this regimen was acceptable. Nausea and vomiting were common, but severe mucositis was observed in only two patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia and a clinically well-tolerated bradycardia. Tinnitus and vertigo were observed in 10 cases (67%), and mild hearing loss and transient increase of serum bilirubin were observed in six patients (40%). Total quinine serum levels reached a steady-state concentration between 6.4 and 18 mg/L in 24 hours. Complete remission (CR) was achieved in eight of 14 (57%) assessable patients, and partial response (PR) was achieved in two additional patients (14%). P-glycoprotein expression was detected on blast cells from five of 13 studied patients before treatment. A response was observed in all P-glycoprotein-positive cases. CONCLUSION: Quinine can be used safely as a potential reversing agent of MDR for the treatment of clinically resistant acute leukemias.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Bone marrow necrosis and human parvovirus associated infection preceding an Ph1+ acute lymphoblastic leukemia.

A case of bone marrow necrosis associated with a serologically documented recent Parvovirus B 19 infection which preceded the development of PH1+ acute lymphoblastic leukemia is reported. No conclusions can be drawn on the basis of a single case but the question of the role of human Parvovirus B19 in the pathogenesis of bone marrow necrosis is discussed. It is suggested that the virus may act as a co-factor for the induction of bone marrow necrosis, in some cases.

Adult↗
PubMed1992

Surface markers in adult acute myeloblastic leukemia: correlation of CD19+, CD34+ and CD14+/DR--phenotypes with shorter survival. Groupe d'Etude Immunologique des Leucémies (GEIL).

The immunophenotype of blast cells was investigated in a multicentric study of 154 adult acute myeloblastic leukemias (AMLs). A panel of 27 monoclonal antibodies (MoAbs) was tested in indirect immunofluorescence. Expression of CD14 (UCHM1), CD19 (SB4), CD36 (OKM5), and HLA-DR were associated with higher mean leucocyte counts. CD14 expression correlated with low hemoglobin level and the absence of CD33 (MY9) with low platelet counts. Extramedullary disease was associated with CD16 (Leu11b) and HLA-DR antigen positivity. The study of relationships between surface markers and FAB criteria confirmed the predominant expression of CD14 in the M5 sub-group (p less than 0.000001) and the association of CD19 and CD36 with monocytic M4/M5 subgroups (respectively p less than 0.00002 and p less than 0.000001). All patients received an induction therapy including an anthracycline and cytarabine. The median follow-up was 13 months. The achievement of complete remission (CR) was inversely correlated with CD34 (B13C5) and CD19 expression: CR was obtained in 31 of 59 (53%) CD34-positive AML versus 64 of 75 (85%) CD34-negative cases (p less than 0.0001) and 11 of 24 (46%) CD19-positive versus 95 of 122 (78%) CD19-negative cases (p less than 0.01). In univariate analysis, a longer survival was associated with CD33 expression and the combined phenotypes CD36+/CD19- and CD16+/CD14-. Conversely, the CD18(IOT18)+/CDw65(VIM2)- phenotype was related to shorter survival. The expression of CD19, of CD34, and of the combined phenotype CD14+/DR--correlated with shorter survival as demonstrated both in univariate and multivariate analysis (p less than 0.03 in each case in multivariate analysis).

Antigens, CD↗