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

Acute promyelocytic leukemia (APL) cells express a considerable level of CD33, which is a target of gemtuzumab ozogamicin (GO), and a significantly lower level of P-glycoprotein (P-gp). In this study, we examined whether GO was effective on all-trans retinoic acid (ATRA)- or arsenic trioxide (ATO)-resistant APL cells. Cells used were an APL cell line in which P-gp was undetectable (NB4), ATRA-resistant NB4 (NB4/RA), NB4 and NB4/RA that had been transfected with MDR-1 cDNA (NB4/MDR and NB4/RA/MDR, respectively), ATO-resistant NB4 (NB4/As) and blast cells from eight patients with clinically ATRA-resistant APL including two patients with ATRA- and ATO-resistant APL. The efficacy of GO was analyzed by (3)H-thymidine incorporation, the dye exclusion test and cell cycle distribution. GO suppressed the growth of NB4, NB4/RA and NB4/As cells in a dose-dependent manner. GO increased the percentage of hypodiploid cells significantly in NB4, NB4/RA and NB4/As cells, and by a limited degree in NB4/MDR and NB4/RA/MDR cells. Similar results were obtained using blast cells from the patients with APL. GO is effective against ATRA- or ATO-resistant APL cells that do not express P-gp, and the mechanism of resistance to GO is not related to the mechanism of resistance to ATRA or ATO in APL cells. Leukemia (2005) 19, 1306-1311. doi:10.1038/sj.leu.2403807; published online 26 May 2005.
Leukemia 2005 Aug
PMID:Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. 1592 Apr 95

The aim of the present study was to determine in vitro antileukaemic activity of extracts obtained from selected berry plant leaves (Fragaria x ananassa Duch. cv Elsanta, raspberry Rubus ideus L. cv Polana and blueberry Vaccinium corymbosum L. cv Bluecrop) against promyelocytic HL60 cell line and its multidrug resistant sublines exhibiting two different MDR phenotypes: HL60/VINC (overexpressing P-glycoprotein) and HL60/DOX (overexpressing MRP1 protein). It was found that the blueberry extract was the most efficient against sensitive HL60 cell line (about 2-fold more active than strawberry and raspberry extracts) but presented much lower activity towards resistant cells. In contrast, strawberry and raspberry extracts exhibited the high cytotoxic activity against sensitive leukaemia HL60 cell line as well as its MDR sublines. The values of resistance factor (RF) found for these extracts were very low lying in the range 0.32/2.0.
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PMID:In vitro antileukaemic activity of extracts from berry plant leaves against sensitive and multidrug resistant HL60 cells. 1603 42

Flavonoids and their in vivo metabolites are neuroprotective, cardioprotective and chemopreventive agents acting as hydrogen-donating antioxidants or modulators functioning at protein kinase and lipid signaling pathways. In presented study treatments of human leukemia cells HL60 and their MDR-1 resistant subline HL60/VCR by flavonoids apigenin (API), luteolin (LUT), quercetin (QU) and anticancer drug doxorubicin (DOX) are reported. Of all flavonoids used only QU treatments led in both cell lines to DNA fragmentation, cleavage of poly (ADP- ribose) polymerase (PARP), up-regulation of proapoptotic Bax and posttranslational modification (phosphorylation) of antiapoptotic Bcl-2. Cytochrome c and p21WAF1/CIP1 levels remained unchanged in these cells. Furthermore, treatments of both cell lines by QU and in its combined application with DOX increased phosphorylation of ERK, while Akt-1 and phosphorylated Akt-1 levels were not changed. All these events resulted in effective induction of apoptosis associated with down-regulation of P-glycoprotein in resistant cells. Presented results suggest that in human leukemia cells QU is a potent regulator of the cell apoptotic program associated with the modulation of several signaling molecules.
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PMID:Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants. 1605 41

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.
Leukemia 2005 Dec
PMID:Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000. 1613 67

Researches on MDR (multidrug resistance) of tumor presently focus on seeking chemosensitizers with more targets, high efficiency and low toxicity from traditional Chinese medicine. This paper reviews the research progress in the reversion of MDR of leukemia, hepatocarcinoma, breast carcinoma and oral epithelioid neoplasia by TDM compound, its extracts, its groups of active ingredients or its active ingredients.
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PMID:[Research progress in the reversion of traditional Chinese medicine on multidrug resistance of tumor]. 1624 13

1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enylfuran-2-caroxylate (SH-7), a new naphthoquinone compound, derived from shikonin, exhibited obvious inhibitory actions on topoisomerase II (Topo II) and topoisomerase I (Topo I), which were stronger than its mother compound shikonin. Notably, the SH-7's inhibitory potency on Topo II was much stronger than that on Topo I. In addition, SH-7 significantly stabilized Topo II-DNA cleavable complex and elevated the expression of phosphorylated-H2AX. The in vitro cell-based investigation demonstrated that SH-7 displayed wide cytotoxicity in diversified cancer cell lines with the mean IC(50) value of 7.75 microM. One important finding is SH-7 displayed significant cytotoxicity in the 3 MDR cell lines, with an average IC(50) value nearly equivalent to that of the corresponding parental cell lines. The average resistance factor (RF) of SH-7 was 1.74, which was much lower than those of reference drugs VP-16 (RF 145.92), ADR (RF 105.97) and VCR (RF 197.39). Further studies illustrated that SH-7 had the marked apoptosis-inducing function on leukemia HL-60 cells, which was validated to be of mitochondria-dependence. The in vivo experiments showed that SH-7 had inhibitory effects on S-180 sarcoma implanted to mice, SMMC-7721, BEL-7402 human hepatocellular carcinoma and PC-3 human prostate cancer implanted to nude mice. Taken together, these results suggest that SH-7 induces DSBs as a Topo II inhibitor, which was crucial to activate the apoptotic process, and subsequently accounts for its both in vitro and in vivo antitumor activities. The well-defined Topo II inhibitory activity, antitumor effects particularly with its obvious anti-MDR action, better solubility and less toxicity make SH-7 as a potential antitumor drug candidate for further research and development.
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PMID:SH-7, a new synthesized shikonin derivative, exerting its potent antitumor activities as a topoisomerase inhibitor. 1657 Feb 88

The aim of this study was to examine the role of reductive activation of mitoxantrone (MX) by human liver NADPH cytochrome P450 reductase (CPR) in increasing its ability to inhibit the growth of human promyelocytic sensitive leukaemia HL60 cell line as well as its MDR sublines exhibiting two different phenotypes of MDR related to the overexpression of P-glycoprotein (HL60/VINC) or MRP1 (HL60/DOX). Our assays showed that the reduction of MX by exogenously added CPR in the presence of low NADPH concentration had no effect in increasing its ability to inhibit the growth of sensitive and MDR tumour cells. In contrast, an important increase in antiproliferative activity of MX after its reductive activation by CPR at high NADPH concentration was observed against HL60/VINC as well as HL60/DOX cells.
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PMID:Bioreductive activation of mitoxantrone by NADPH cytochrome P450 reductase. Implications for increasing its ability to inhibit the growth of sensitive and multidrug resistant leukaemia HL60 cells. 1657 18

This study was aimed to detect the gene expression profile changes between human acute leukemia cell line HL-60 and VCR-resistance HL-60, and to investigate the underlying mechanisms of MDR by using genechip technology. In experiments, mRNA were harvested using TrizoL reagent from these two cell lines, through RT-PCR, the biotinylated nucleotide were incorporated into the cRNA during the in vitro transcription reaction. The high quality RNA was hybridized to the gene expression array--human genome U133A developed by Affymetrix. It was scanned by G2500A GeneArray Scanner and the acquired image was analysed by a series of softwares. The results showed that 5,507 genes were differentially expressed between human acute leukemia cell line HL-60 and VCR-resistant HL-60. Compared with HL-60, 3,100 genes were up-regulated and 2,407 genes were down-regulated in VCR-resistant cell line. These genes were involved in different cell activities such as growth regulation and signal transduction. Among the genes with remarkable differential expression between the two cell lines, 435 were up-regulated and 605 were down-regulated. It is concluded that many different kinds of genes are involved in the mechanism of MDR and there is an intricate molecular network that controls the sensitivity of leukemia cells to the chemotherapeutic agents. Genechip is an efficient tool for parallel gene expression analysis.
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PMID:[Difference of gene expression profiles between HL-60/VCR and HL-60 cells detected by human genome genechip]. 1680 Sep 28

We have established an arsenic trioxide (As2O3)-resistant cell line (K562/AS-3) derived from the human leukemia cell line K562. K562/AS-3 was sequentially cultured with increasing concentrations of As2O3 up to 3.5 microM and then cloned by the limiting dilution method. K562/AS-3 was found to be about 7-fold more resistant to As2O3 than the parent cells (IC50=12.9 microM for K562/AS-3 and 1.8 microM for K562), and also showed cross resistance to VP-16 and vincristine. The multidrug resistance-associated protein (MRP1) gene was found to be overexpressed, but the MDR gene was not detected. MRP1 function was evaluated by measuring calcein acetoxymethyl ester (calcein-AM) efflux, and by verifying its inhibition by MK571, a potent MRP inhibitor. In addition, an increase of the total intracellular glutathione content was found in K562/AS-3. The resistance of K562/AS-3 to As2O3 was reversed by the addition of MK571, but not by verapamil. K562/AS-3 may be useful for studying the mechanism of the anticancer effect of As2O3 and how to overcome As2O3-resistance.
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PMID:Establishment of an arsenic trioxide-resistant human leukemia cell line that shows multidrug resistance. 1726 98

The leukemic stem cells in patients with chronic myeloid leukemia (CML) are well known to be clinically resistant to conventional chemotherapy and may also be relatively resistant to BCR-ABL-targeted drugs. Here we show that the lesser effect of imatinib mesylate (IM) on the 3-week output of cells produced in vitro from lin(-)CD34(+)CD38(-) CML (stem) cells compared with cultures initiated with the CD38(+) subset of lin(-)CD34(+) cells is markedly enhanced (>10-fold) when conditions of reduced growth factor stimulation are used. Quantitative analysis of genes expressed in these different CML subsets revealed a differentiation-associated decrease in IL-3 and G-CSF transcripts, a much more profound decrease in expression of BCR-ABL than predicted by changes in BCR expression, decreasing expression of ABCB1/MDR and ABCG2 and increasing expression of OCT1. p210(BCR-ABL) and kinase activity were also higher in the lin(-)CD34(+)CD38(-) cells and formal evidence that increasing BCR-ABL expression decreases IM sensitivity was obtained from experiments with a cell line model. Nevertheless, within the entire CD34(+) subset of CML cells, BCR-ABL expression was not strongly affected by changes in cell cycle status. Taken together, these results provide the first evidence of multiple mechanisms of innate IM resistance in primitive and quiescent CML cells.
Leukemia 2007 May
PMID:Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. 1733 Jan 1


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