Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Quinidine, which has antiarrhythmic activity, greatly enhanced the cytotoxicity of vincristine (VCR) in tumor cells and especially in VCR-resistant sublines of P388 leukemia (P388/VCR) and human myelogenous leukemia. A nontoxic concentration of quinidine increased VCR cytotoxicity in these resistant tumor cells about 50 to 80 times, and the drug in combination with VCR could completely reverse VCR resistance of these cell lines. Quinidine also enhanced the cytotoxicity of Adriamycin, especially in the Adriamycin-resistant subline of P388 leukemia; this enhancement (8-fold) was less than that of VCR toxicity in the VCR-resistant tumor line. When administered daily for 10 days with VCR, quinidine at doses of 50 to 125 mg/kg significantly enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. Some other antiarrhythmic agents also showed similar effects in vitro, but these effects were considerably lower than that of quinidine. Quinidine increased the cellular levels of VCR and daunomycin in VCR-resistant sublines of mouse and human tumors and the ADM-resistant mouse tumor line in vitro, respectively. Quinidine also enhanced the cellular accumulation of VCR in P388/VCR cells in vivo. Thus, the therapeutic effect observed in P388/VCR-bearing mice might be due to the enhanced accumulation of VCR in P388/VCR cells by quinidine. The increase of cellular accumulation of VCR was partly explained by inhibition of efflux of VCR and daunomycin from the resistant tumor cells. The mechanism of this phenomenon is discussed in relation to previous findings on calcium channel blockers.
 ...
PMID:Effects of quinidine and related compounds on cytotoxicity and cellular accumulation of vincristine and adriamycin in drug-resistant tumor cells. 646 92

Paclitaxel, a novel diterpenoid compound, has been used by dissolving in Cremophor EL (polyoxyethylene castor oil) due to its poor aqueous solubility. Cremophor EL was shown to reverse multidrug resistant phenotypes of various cell lines as well as to reverse cross-resistance to paclitaxel of a multidrug resistant cell line in vitro. Thus, a study was carried out to determine the modifying activity of Cremophor EL on the antitumor activity of paclitaxel against P388 leukemia, adriamycin-resistant subline (P388/ADM) and vincristine-resistant subline (P388/VCR) in vivo. Dimethyl sulfoxide (DMSO) was used as a counterpart solvent. The results showed that, although no significant antitumor activity was observed by paclitaxel in both solvents against P388/ADM, a significantly higher antitumor activity was induced by paclitaxel dissolved in Cremophor EL-based solvent compared with DMSO-based solvent against P388/VCR. However, more significant difference in the antitumor activity of paclitaxel against P388 parental line was observed between two solvents and both resistant sublines showed an obvious cross-resistance to paclitaxel. Therefore, it appeared that cross-resistance reversing activity of Cremophor EL is not so high as to be detectable at in vivo level.
 ...
PMID:[Study for modifying activity of solvents on antitumor activity of paclitaxel]. 790 93

Overexpression of the human multidrug resistance gene (MDR1) on acute myelogenous leukemia (AML) correlates with poor prognosis. We evaluated several methods for mRNA estimation to standardize simple and reliable techniques for identifying MDR1 positive leukemia among untreated AMLs in large scale studies. Northern blot detection of MDR1 mRNA suffered from low signal-to-noise ratio under the conventional conditions, that was improved mainly by removing unincorporated radioactivity. The amount of MDR1 transcripts on positive cells was estimated less than 10% of that of constitutive mRNA species. A modified method seemed useful in estimating the total amount of the MDR1 mRNA in a whole leukemic cell population, and suitable to study stock samples or for large prospective clinical trials. RT-PCR was more sensitive in detecting MDR1 mRNA than Northern blot analysis, and the very feature made it virtually impossible to exclude contamination with normal hematopoietic cells. This procedure showed that FAB M3 leukemias were essentially MDR1 negative, and there existed frequently myelodysplastic syndrome subpopulation which had excessive MDR1 transcripts. In situ hybridization of the mRNA with a FITC-labeled phosphorothioate oligonucleotide probe was visualized using flowcytometry or con-focus lightmicroscopy, enabled us to recognize the difference between multidrug resistant K562/ADM and its wild type.
 ...
PMID:Methods for detection of MDR1 mRNA expression on acute myelogenous leukemia cells. 796 78

The 7-substituted 6H-pyrazolo[4,5,1-de]acridin-6-ones with (aminoalkyl)amino and/or (hydroxyalkyl)amino groups in the side chains were synthesized by bromination using N-bromosuccinimide and the subsequent reaction with amines from the 7-substituted 5-bromo-2-methyl-6H-pyrazolo-[4,5,1-de]acridin-6-one. The substitution reaction of the amines with alkyl bromide (the C2 position) and aryl bromide (the C5 position) was accomplished by choosing the proper reaction conditions. These compounds show DNA intercalating ability in ethidium fluorescence assay and antiproliferative activity against Hela S3 cells. Impressive antitumor activity in vivo against murine P388 leukemia and murine sarcoma 180 solid tumor in mice was demonstrated for the 7-hydroxy analogs. In addition, some of these showed excellent antitumor activity against adriamycin-resistant murine P388 leukemia (P388/ADM) in mice.
 ...
PMID:6H-pyrazolo[4,5,1-de]acridin-6-ones as a novel class of antitumor agents. Synthesis and biological activity. 815 13

Twenty-one patients with advanced-stage, intermediate- and high-grade non-Hodgkin's lymphomas were treated with alternating CHOP-MEVP chemotherapy. CHOP therapy consisted of CPA 650 mg/m2, ADM 45 mg/m2, VCR 1.4 mg/m2 and Pred 40 mg/m2 (po). MEVP therapy consisted of MIT 10 mg/m2 (iv) VDS 2 mg/m2 (iv) on day 1, etoposide 200 mg/m2 (po) on days 1-3, and Pred 40 mg/m2 (po) on days 1-5. Three courses of CHOP therapy and MEVP therapy were alternatively administered every three weeks. CR was achieved in 15 (71.4%) of 21 patients. Survival rate and relapse-free rate at 2 years for all 21 patients were 61.9% and 30.9%, respectively. Toxicity was generally tolerable except for CMV interstitial pneumonitis in a patient with IBL-like T-cell lymphoma and secondary leukemia in a patient with T-cell lymphoma. Chemotherapy of higher dose intensity is required to improve the relapse-free survival rate in these subsets of lymphoma.
 ...
PMID:[Alternating CHOP-MEVP chemotherapy for advanced-stage, intermediate- and high-grade non-Hodgkin's lymphomas]. 823 84

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.
Leukemia 1994 Jan
PMID:Comparative effects of quinine and cinchonine in reversing multidrug resistance on human leukemic cell line K562/ADM. 828 82

The efficacy of MS-209, a quinoline derivative synthesized as a new multidrug resistance (MDR)-reversing agent, was studied on blast cells from 33 acute myelogenous leukaemia (AML) patients and on the human myelogenous leukaemia K562 cell line resistant to adriamycin (K562/ADM). By the addition of MS-209, the intracellular daunorubicin (DNR) contents which had been found to be low in P-gp-positive AML blasts and in K562/ADM were significantly enhanced to the level of P-gp-negative blasts and that of sensitive K562. The intracellular rhodamine (Rh123) contents also increased in P-gp-positive blasts and K562/ADM cells with MS-209. A leukaemic blast colony assay also demonstrated the effect of MS-209, i.e. a high D10 value for DNR of P-gp-positive blasts was reduced to the D10 level similar to that observed in P-gp-negative blasts by the addition of MS-209. The greater DNR sensitivity reversing effect of MS-209 was observed in blasts with higher P-gp positivity. These findings suggest the potential usefulness of MS-209 in overcoming MDR in AML patients, especially those with high P-gp expression. This study clarified the relationship between the clinical outcome of the patients and the P-gp positivity, intracellular DNR content and DNR drug sensitivity of leukaemic progenitors.
 ...
PMID:Recovery of drug sensitivity by MS-209, a new multidrug resistance-reversing agent, on acute myelogenous leukaemic blasts and K562 cells resistant to adriamycin cell line. 915 Jul 13

We compared test methods based on specific mechanisms of daunorubicin (DNR) resistance to more global procedures. Assessment of P-glycoprotein (P-gp) expression and function by means of immunocytochemistry, DNR accumulation, and modulation of resistance and accumulation by the P-gp inhibitor cyclosporin A (CsA) were selected as parameters for multidrug resistance (MDR). On the other hand, we used the MTT assay and measured apoptosis and proliferative activity (S- and G2M-phases of the cell cycle) by flow cytometry. Validation of test methods was achieved for four leukemic cell lines (HL-60, KG-1a, K562/WT, K562/ADM). This battery of tests was then applied to mononuclear cells (MNC) from 18 leukemic patients. Low proficiency of MNC to undergo apoptosis and low proliferative activity rather than P-gp-mediated MDR correlated with DNR resistance as measured by the MTT assay. Bell-shaped dose-response curves for apoptosis, however, which reflect a switch from the apoptotic to the necrotic death mode with increasing cellular damage tend to limit practicability in clinical testing, because appropriate dose range and time points need to be explored. Thus, measurement of apoptosis by flow cytometry may be less convenient than the MTT assay for determination of chemosensitivity, if clinical samples with unknown patterns of responsiveness are to be tested. Spontaneous apoptosis in untreated MNC following 24 h incubation in vitro correlated significantly with DNR sensitivity in the MTT assay. A lack of essential viability factors (eg growth factors or cytokines) in vitro which are known to prevent apoptosis may contribute to DNR sensitivity.
Leukemia 1997 Jul
PMID:Apoptosis and resistance to daunorubicin in human leukemic cells. 920 9

Using a doxorubicin-resistant subline (K562/ADM) of human leukaemia K562 cells (Tsuruo et al, 1986), the effect of immunoliposomes that targeted a cellular transferrin receptor (TFR) was examined by neutralization of doxorubicin (DOX) resistance. OKT9-CIL, prepared by conjugation of DOX-encapsulated liposome with an anti-TFR monoclonal antibody, OKT9 (Aisenberg and Wilkes, 1980), showed similar binding to both K562 and K562/ADM. Although an 80-fold higher sensitivity to free DOX on cell growth inhibition in K562 than in K562/ADM was found, the difference was clearly diminished after OKT9-CIL treatment through the increased sensitivity of K562/ADM. The cellular DOX level 30 min after the exposure of free DOX was 45-fold lower in K562/ADM than in K562, whereas nearly equivalent DOX levels were detected in K562 and K562/ADM after OKT9-CIL treatment. In addition, DOX in K562/ADM in the free DOX treatment was efficiently excreted by 54% within 120 min of incubation, whereas almost all DOX supplied by OKT9-CIL remained uncleared. Fluorescence microscopic observation showed that OKT9-CIL was internalized into juxtanuclear vesicles in K562/ADM cells. These results suggest that OKT9-CIL has a potency to accumulate DOX, resulting in augmentation of DOX cytotoxicity in DOX-resistant tumour cells.
 ...
PMID:Modulation of doxorubicin resistance in a doxorubicin-resistant human leukaemia cell by an immunoliposome targeting transferring receptor. 921 37

To overcome the problem of multidrug resistance, we investigated the effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells. Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS-treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed with sense or random control oligonucleotides. The expression of mdr1 mRNA in K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the random control. Intracellular rhodamine retention and [3H]daunorubicin also increased after antisense treatment. Chemosensitivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucleotides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia.
 ...
PMID:Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene (mdr1) antisense oligonucleotides. 955 71


<< Previous 1 2 3 4 5 6 7 8 Next >>