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)

Transport and accumulation of copper benzochlorin iminium salt (CDS1), a cationic photosensitizing agent, were examined using the P388/ADR murine leukemia, which exhibits the MDR (multidrug resistance) phenotype, and the wild-type parent cell line, P388. The recent availability of radioactive CDS1 permitted kinetic studies at drug levels in the submicromolar range. Exclusion of CDS1 by P388/ADR cells could be demonstrated, indicating that this agent is a substrate for the outward transport system associated with MDR. These results have implications with regard to the efficacy of cationic photosensitizers against this common neoplastic phenotype. The CDS1 was readily accumulated by P388 cells and by P388/ADR cells when the outward transport system was inhibited. Under these conditions, CDS1 was tightly bound and could not be washed out even when the outward transport system was reactivated.
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PMID:Impaired accumulation of a cationic photosensitizing agent by a cell line exhibiting multidrug resistance. 807 77

In our efforts to identify clinically effective drugs for reversing multidrug resistance (MDR) mediated by P-glycoprotein, we tested terfenadine for anti-MDR activity because it appeared to sensitize a patient to doxorubicin and because it met structural requirements defined for this activity. Terfenadine sensitized MCF-7/ADR human breast cancer cells and L1210/VMDRC.06 murine leukemia cells to doxorubicin. At concentrations < or = 10 microM, terfenadine decreased the IC50 to doxorubicin by up to 25-fold against MCF-7/ADR cells and completely restored sensitivity to L1210/VMDRC.06 cells. The drug had no effect on the sensitive, parental cell lines and enhanced activity of other drugs affected by the MDR phenotype. Terfenadine was as potent as trans-flupenthixol, one of the most active modulators of MDR. The mechanism of action of terfenadine appeared to be due to inhibition of the function of P-glycoprotein since it augmented the accumulation of doxorubicin and inhibited the efflux of rhodamine 123 from MDR lines but had no effect on drug accumulation or efflux in sensitive cells. Terfenadine displaced azidopine from P-glycoprotein, but at concentrations higher than expected based on its overall potency. Since terfenadine is clinically available, has numerous structural derivatives available for study, and has a relatively low toxicity profile, this drug and drugs of its class should be evaluated for future clinical trials.
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PMID:Terfenadine (Seldane): a new drug for restoring sensitivity to multidrug resistant cancer cells. 809 15

Because of the fact that tumor cell sensitivity to cytotoxic agents may play a major role in cancer treatment, and several anthracyclines are widely used for first-line treatment of leukemia, lymphoma and other tumors, and since the overexpression of the mdr-1 gene-coded 170 Kd glycoprotein (P170) decreases cell sensitivity to anthracyclines, we investigated the relationship between P170 overexpression and the cytotoxicity of two classic anthracyclines (Daunorubicin or DNR and Doxorubicin or DX) and two lipophilic anthracycline derivatives (Idarubicin or IDA and Iododoxorubicin or IDX). For these purposes, we used multidrug resistant (MDR) and non-MDR tumor and leukemia cell lines and the MTT-microcultured tetrazolium colorimetric assay. We showed that mdr-1 gene overexpression was strongly associated with the development of a high level of resistance to DNR and DX, but not to the derivatives IDA and IDX. These data suggest that more lipophilic anthracycline derivatives may also be active in MDR cell systems.
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PMID:A comparative analysis of the sensitivity of multidrug resistant (MDR) and non-MDR cells to different anthracycline derivatives. 809 29

The effects of eight isoquinolinesulphonamide compounds on resistance to vinblastine in adriamycin-resistant mouse leukaemia cells (P388/ADR) which overexpress the relative molecular weight (M(r)) 140 kDa P-glycoprotein in the plasma membrane were investigated. N-[2-(Methylamino)ethyl]-5-isoquinolinesulphonamide (H-8) and N-(2-aminoethyl)-5-isoquinolinesulphonamide (H-9) did not reverse vinblastine resistance. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino] ethyl]-5-isoquinolinesulphonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl] amino]ethyl]-5-isoquinolinesulphonamide (H-87) caused accumulation of intracellular vinblastine and inhibition of vinblastine efflux from the cells and reversed the resistance. Addition of an aminoethyl group to the nitrogen atom of the sulphonamide group (W-66) or a formyl group at the terminal amino group (H-85) of H-86 reduced those activities. Conversion of the chlorophenyl group of H-87 to pyridinyl (H-31) or furanyl (H-34) markedly decreased activities against the drug resistance. The activity against vinblastine accumulation closely correlated with the apparent partition coefficient of compounds. These compounds dose-dependently inhibited photoaffinity labelling of a photosensitive analogue of vinblastine, N-(p-azido-(3-[125I)salicyl)-N'-beta-aminoethyl-vindesine ([125I]NASV), and there was a good correlation between inhibition of [125I]NASV-photolabelling and hydrophobicity. Although these isoquinolinesulphonamides inhibited protein kinase A with different magnitudes, this activity did not correlate with the effect on the drug resistance. These results indicate that isoquinolinesulphonamide compounds with a hydrophobic group interact with antitumour drugs on P-glycoprotein and reverse multidrug resistance without involvement of their activity on protein kinase A.
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PMID:Effects of isoquinolinesulphonamide compounds on multidrug-resistant P388 cells. 809 66

The effect of growth stimulation on the sensitivity of normal and leukemic human bone marrow progenitors to idarubicin and doxorubicin was studied. Clonogenic assays from colony-forming units of the granulocyte-macrophage lineage (CFU-GM) and leukemic clonogenic cells (CFU-L) were applied using human placenta conditioned medium (HPCM) as source of growth factors. Before seeding cells in clonogenic assay they were exposed to the anthracyclines for 2 h without preincubation, or following a 48 h preincubation period in the presence of HPCM. Drug concentrations used ranged from 0.001-0.1 microgram/ml for idarubicin and from 0.1-1.5 microgram/ml for doxorubicin. In addition, a limited number of bone marrow samples were exposed to the cytostatically active metabolite of idarubicin; idarubicinol (Idol; range 0.001-0.1 microgram/ml). Proliferation of CFU-GM and CFU-L during 48 h was measured by iododeoxyuridine (IdUrd) incorporation. Spontaneous proliferation of CFU-GM increased from 38 to 88% after 48 h stimulation by HPCM. The mean number of proliferating CFU-L increased from 40 to 77% when stimulated with HPCM. Doxorubicin inhibited colony formation of CFU-GM and CFU-L to 50% (IC50CFU-GM, IC50CFU-I) at mean concentrations of 0.355 microgram/ml and 0.103 microgram/ml when applied before preincubation with HPCM, and 0.108 microgram/ml and 0.055 microgram/ml when applied after preincubation. Idarubicin appeared the most potent drug in all experiments regardless of the preincubation procedure or sample origin, with average IC50CFU-GM and IC50CFU-L of 0.008 microgram/ml and 0.006 microgram/ml, respectively, when applied before preincubation with HPCM, and 0.006 microgram/ml and 0.005 microgram/ml when applied after preincubation with HPCM. Idarubicinol showed intermediate potency with average IC50CFU-GM of 0.022 microgram/ml and 0.023 microgram/ml when applied before and after preincubation with HPCM, respectively. In order to assess the effect of growth stimulation on drug sensitivity, samples were evaluated pair-wise (sensitivity of the same sample before vs. after preincubation with HPCM) and were submitted to the Wilcoxon test for matched pairs. Statistically significant enhancement of cytotoxicity was demonstrated for Doxorubicin vs. CFU-GM (p < or = 0.021) and a strong trend versus CFU-L (p = 0.06). The data further demonstrate that proliferation-dependency of doxorubicin toxicity is more pronounced for CFU-GM than for CFU-L. These data also show that idarubicin and idarubicinol toxicity is proliferation-independent. Idarubicin is relatively more potent than doxorubicin in suppressing the growth potential of low or nonproliferating progenitors.(ABSTRACT TRUNCATED AT 400 WORDS)
Leukemia 1994 Mar
PMID:Toxicity of idarubicin and doxorubicin towards normal and leukemic human bone marrow progenitors in relation to their proliferative state. 812 43

The antitumor drug 3-nitrobenzothiazolo [3,2-a] quinolinium chloride (NBQ) stimulates the in vivo lens regeneration in the adult newt Notophthalmus viridescens and induces a differentiated state in HL-60 leukemia cells. Because the cytotoxic drug doxorubicin (Adriamycin) induces differentiation of HL-60 cells in vitro we decided to compare the effect(s) of doxorubicin with NBQ on lens regeneration in vivo. Both drugs were injected intraperitoneally at six different schedules. Morphological criteria of the different regeneration stages were used in the analysis of the regenerates. NBQ stimulated lens regeneration independently of the time intervals and the stage of regeneration at which the drug was administered. There was an increase in the mean number of mitoses suggesting that NBQ stimulated cell proliferation. Doxorubicin administered for five days did not modify the regenerative process. On the other hand, doxorubicin given for periods of nine or more days after lentectomy, strongly inhibited the formation of a new lens. Thus, the inhibitory effect of doxorubicin is dependent on the continuous long term contact with the tissue. Although NBQ and doxorubicin are both DNA intercalators, they induced the effects on lens regeneration through different mechanisms.
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PMID:Effects of 3-nitrobenzothiazolo[3,2-a]quinolinium chloride (NBQ) and doxorubicin on lens regeneration in the adult newt: a morphological study. 818 78

Co-administration of doxorubicin and verapamil in Alzet mini-osmotic pumps increased the survival of B6D2F1 mice bearing the multidrug-resistant P388/ADR leukemia. A range of doxorubicin and verapamil combinations was studied to define dose-dependent efficacy and toxicity. High doses of doxorubicin (10 mg/kg/day) and verapamil (150 mg/kg/day) could be administered alone without any effect on survival. However, combining high doses of these two agents resulted in host toxicity. Doxorubicin doses of 1 to 10 mg/kg/day in combination with verapamil at 25-100 mg/kg/day were found to improve survival compared with either agent alone. Combination therapy also improved the survival of mice bearing the drug-sensitive P388/0 leukemia when compared to anthracycline treatment alone. The efficacy of the mini-osmotic pump delivery protocol was compared with other regimens delivering the same total cumulative dose of doxorubicin via repeated i.p. injections.
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PMID:Modulation of doxorubicin efficacy in P388 leukemia following co-administration of verapamil in mini-osmotic pumps. 819 70

Reduced accumulation of multiple drugs is a characteristic of cells overexpressing P-glycoprotein. This phenotype is referred to as multidrug-resistance (MDR). A protocol based on reduced accumulation of fluorescent dyes is proposed for discriminating MDR cells in cell populations. The combination of three fluorescent dyes, Hoechst 33342, rhodamine 123 and Nile red, with different intracellular targets, has been designed to characterize cells with different levels of resistance, using image cytometry. The fluorescence intensity of each dye was quantified in living cells. The protocol was applied to human leukemia cell lines, (K562, K562/ADR, CCRF-CEM, CEM/VLB100, CEM/VM-1). The effect of verapamil on dye accumulation is emphasized.
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PMID:Detection of human leukemia cells with multidrug-resistance phenotype using multilabeling with fluorescent dyes. 823 35

Previous studies using cloned lines of Adriamycin-sensitive and -resistant P388 murine leukemia cells have suggested that a reduction in DNA topoisomerase II alpha (topo II alpha) enzyme activity and protein levels in drug-resistant cell lines (A. M. Deffie, J. K. Batra, and G. J. Goldenberg, Cancer Res., 49: 58-62, 1989) may be due to an allelic mutation in the topo II alpha gene (A. M. Deffie, D. J. Bosman, and G. J. Goldenberg, Cancer Res., 49: 6879-6882, 1989). The drug-resistant cell lines P388/ADR/3 and P388/ADR/7 express a shortened topo II alpha mRNA transcript in addition to the native transcript present in the drug-sensitive P388/4 cell line. Using complementary DNA probes derived from the coding sequence and 3' untranslated region of the native mouse topo II alpha transcript, we have determined that the shorter 4.5-kilobase topo II alpha transcript expressed in the drug-resistant cell lines contains only 3.5-kilobases of topo II sequence from the 5'-terminus onwards. Using a 3'-rapid amplification of cDNA ends strategy, we have cloned cDNAs representing the 3'-termini of both the native and mutant transcripts from both P388/ADR/3 and P388/ADR/7 cells. DNA sequence analysis revealed that the shorter 4.5-kilobase transcript: (a) encodes topoisomerase II alpha until nucleotide position 3494, at which point the sequence diverges for the remaining 956 bases; (b) contains a polyadenylation signal distinct from the native transcript; and (c) contains an open reading frame predicting a truncated topo II alpha fusion protein. Of great interest was the finding that the non-topo II alpha 956-base sequence in the shorter transcript encodes the promoter, exon I, and part of the first intron of the murine retinoic acid receptor alpha gene locus in the antisense orientation, suggesting that a rearrangement on chromosome 11 in the drug-resistant cells led to a gene fusion event between the loci encoding topo II alpha and retinoic acid receptor alpha.
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PMID:Characterization of a DNA topoisomerase IIalpha gene rearrangement in adriamycin-resistant P388 leukemia: expression of a fusion messenger RNA transcript encoding topoisomerase IIalpha and the retinoic acid receptor alpha locus. 826 98

Cytotoxic drugs used in chemotherapy of leukemias and solid tumors cause apoptosis in target cells. In lymphoid cells the CD95 (APO-1/Fas)/CD95 ligand (CD95-L) system is a key regulator of apoptosis. Here we describe that doxorbicin induces apoptosis via the CD95/CD95-L system in human leukemia T-cell lines. Doxorubicin-induced apoptosis was completely blocked by inhibition of gene expression and protein synthesis. Also, doxorbicin strongly stimulates CD95-L messenger RNA expression in vitro at concentrations relevant for therapy in vivo. CEM and jurkat cells resistant to CD95-mediated apoptosis were also resistant to doxorbicin-induced apoptosis . Furthermore, doxorbicin-induced apoptosis was inhibited by blocking F(ab')2 anti-APO-1 (anti-CD95) antibody fragments. Expression of CD95-L mRNA and protein in vitro was also stimulated by other cytotoxic drugs such as methotrexate. The finding that apoptosis caused by anticancer drugs may be mediated via the CD95 system provides a new molecular insight into resistance and sensitivity toward chemotherapy in malignancies.
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PMID:Involvement of the CD95 (APO-1/FAS) receptor/ligand system in drug-induced apoptosis in leukemia cells. 861 18


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