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)

We determined the kinetic parameters that describe the effect of 20 different modulators of the multidrug resistance pump on the reversal of cytotoxin accumulation in a resistant strain of P388 leukemia cells (P388/ADR), and on the reversal of cell killing for these cells. When measured by a direct comparison of the amplitude of the pertinent protocol (accumulation or cell killing), the Ki for reversal of accumulation was generally some four or five times larger than that for reduction of cytotoxicity. We showed that this was only an apparent discrepancy, since a full theoretical analysis of the two protocols allowed the intrinsic Ki to be obtained for the two procedures and these computed Ki values were then almost identical. We found that for six of the modulators studied (namely, cyclosporin A, quinidine, dipyridamole, propafenone, mefloquine, tamoxifen) the extent of pump reversal should be better than 90% at tolerated plasma levels culled from the literature.
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PMID:Kinetic parameters for reversal of the multidrug pump as measured for drug accumulation and cell killing. 861 10

Parental and multidrug resistant HL60 leukemia cell lines were used to study coupling of expression of apoptotic/cytostatic (bcl-2, bax, bclxL, p21/Waf1, and c-myc) genes during differentiation. The multidrug resistant HL60 cell line, HL60/ADR, was less sensitive than parental cells to cytostatic activity of low (0.4-2 ng/ml) doses of PMA. However, during treatment with standard differentiating doses of PMA (10 ng/ml), no difference between the two cell lines in cytostasis and differentiation was found. Downregulation of c-myc and upregulation of p21/Waf1 proteins showed the same time-course in both cell lines. The bcl-2 mRNA was rapidly downregulated while bax and bclxL gene expression was not altered in both differentiating HL60 and HL60/ADR cells. Significant downregulation of bcl-2 protein occurred only in parental HL60 cells. In HL60/ADR, despite rapid cessation of bcl-2 protein synthesis, almost no change in steady-state bcl-2 protein level was found. The lack of bcl-2 protein downregulation was a result of the prolonged half-life of this protein in HL60/ADR cells. Thus, although downregulation of bcl-2 mRNA is coupled to differentiation, actual loss of bcl-2 protein is not required for accomplishment of the differentiation program.
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PMID:bcl-2 protein downregulation is not required for differentiation of multidrug resistant HL60 leukemia cells. 862 7

We have previously shown that the multidrug resistance protein (MRP) mediates the ATP-dependent membrane transport of the endogenous glutathione conjugate leukotriene C4 (LTC4) and of structurally related anionic conjugates of lipophilic compounds [Jedlitschky, Leier, Buchholz, Center and Keppler (1994) Cancer Res. 54, 4833-4836; Leier, Jedlitschky, Buchholz, Cole, Deeley and Keppler (1994) J. Biol. Chem. 269, 27807-27810]. We demonstrate in the present study that MRP also mediates the ATP-dependent transport of GSSG, as shown in membrane vesicles from human leukaemia cells overexpressing MRP (HL60/ADR cells) or HeLa cells transfected with an MRP expression vector (HeLa T5 cells) in comparison with the respective parental or control cells. The Km value for ATP-dependent transport of GSSG was 93 +/- 26 microM (mean value +/- S.D., n=5) in membrane vesicles from HeLa T5 cells. GSH, at a concentration of 100 microM, was not a substrate for any significant ATP-dependent MRP-mediated transport. The transport of GSSG was competitively inhibited by LTC4, by the leukotriene D4 receptor antagonist 3-([{3-(2-[7-chloro-2-quinolinyl]ethenyl)phenyl}-{(3-dimethylamino-3- oxopropyl)-thio}-methyl]thio)propanoic acid (MK 571) and by S-decylglutathione, with K1 values of 0.3, 0.6 and 0.7 microM respectively. These studies identify MRP as the membrane glycoprotein which mediates the ATP-dependent export of GSSG from these cells.
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PMID:ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. 867 53

The therapeutic effects of fibroblast-mediated human interferon-alpha (IFN-alpha) gene therapy, alone or in combination with Doxorubicin (Dox), a chemotherapeutic agent, on the human leukemia-bearing nude mice were investigated. An NIH3T3 fibroblast clone (NIH3T3-IFN-alpha +) secreting the highest level of human IFN-alpha was obtained from the human IFN-alpha gene-transfected fibroblasts. Three days after i.p. Implantation of NIH3T3-IFN-alpha + cells, a certain level of human IFN-alpha could be detected in the sera from the implanted mice. After the NIH3T3-IFN-alpha + cells were implanted intraperitoneally into leukemia-bearing nude mice, the growth of leukemia was inhibited and the survival time of the leukemia-bearing mice was prolonged. The growth of leukemia was inhibited more obviously and the survival rate of the mice increased significantly when NIH3T3-IFN-alpha + cells were implanted in combination with Dox. These results demonstrate that fibroblast-mediated human IFN-alpha gene therapy is effective in treating leukemia and may achieve a better therapeutic effect when combined with Dox.
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PMID:Treatment of leukemia with fibroblast-mediated interferon-alpha gene therapy alone or in combination with doxorubicin. 868 76

We have shown that hemin (iron-protoporphyrin IX) selectively counteracts doxorubicin (Adriamycin, ADR)-induced cytotoxicity on human leukemia K-562 cells by preventing ADR from inhibiting mitochondrial cytochrome c oxidase (COX), a novel target site for anthracyclines. Here, we investigated whether or not (a) treatment with ADR promotes apoptosis and represses the expression of two COX genes (one nuclear and one mitochondrial) in human K-562 cells in the absence and presence of hemin, and (b) injection of hemin preserves bone-marrow cellularity in ADR-myelosuppressed rats. Cultured K-562 cells were incubated with varying concentrations of ADR.HCl (0.2 microM to 5 microM) in the presence and absence of hemin (30 microM) and assessed for DNA degradation, as well as for expression of mitochondrial COXII and nuclear COXIV genes by RNA Northern blot hybridization analysis. In parallel, we investigated whether or not hemin injected i.p. in myelosuppressed rats affected ADR-induced bone-marrow cytotoxicity. These studies have shown the following: (a) ADR caused a dose- and time-dependent DNA fragmentation, characteristic of apoptosis, in K-562 cells; (b) hemin reduced the frequency of cell death caused by ADR: this effect was specific for ADR, because hemin failed to prevent apoptosis induced by methotrexate (MTX) in these cells; (c) ADR suppressed expression of COXIV and COXII genes, and exposure of ADR-treated K-562 cells to hemin did not reverse this suppression; and (d) i.p. injection of hemin in ADR-myelosuppressed rats improved bone-marrow cellularity, promoted colony formation (CFU-GM and CFU-F), and stromal cell outgrowth; moreover, hemin increased WBC counts depressed 12 days after ADR treatment. These studies indicate that hemin is a selective inhibitor of ADR-induced apoptosis of human leukemia cells and preserves bone-marrow cellularity in rats injected with ADR.
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PMID:Effects of hemin on apoptosis, suppression of cytochrome c oxidase gene expression, and bone-marrow toxicity induced by doxorubicin (adriamycin). 876 69

Overexpression of P-glycoprotein (Pgp) by tumors results in multidrug resistance (MDR) to structurally unrelated oncolytics. MDR cells may be sensitized to these oncolytics when treated with a Pgp modulator. The present study evaluates LY335979 as a modulator both in vitro and in vivo. LY335979 (0.1 microM) fully restored sensitivity to vinblastine, doxorubicin (Dox), etoposide, and Taxol in CEM/VLB100 cells. LY335979 modulated Dox cytotoxicity even when LY335979 (0.5 microM) was removed 24 h prior to the cytotoxicity assay. LY335979 blocked [3H]azidopine photoaffinity labeling of the M(r) approximately 170,000 Pgp in CEM/VLB100 plasma membranes and competitively inhibited equilibrium binding of [3H]vinblastine to Pgp (Ki of approximately 0.06 microM). Treatment of mice bearing P388/ADR murine leukemia cells with LY335979 in combination with Dox or etoposide gave a significant increase in life span with no apparent alteration of pharmacokinetics. LY335979 also enhanced the antitumor activity of Taxol in a MDR human non-small cell lung carcinoma nude mouse xenograft model. Thus, LY335979 is an extremely potent, efficacious modulator that apparently lacks pharmacokinetic interactions with coadministered anticancer drugs and is, therefore, an exciting new agent for clinical evaluation for reversal of Pgp-associated MDR.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. 879 88

The antitumor activity of S 16020-2, a new olivacine derivative, was investigated in vivo and compared with that of Adriamycin and elliptinium acetate in a panel of murine (P388 leukemia, M5076 sarcoma, Lewis lung carcinoma, and B16 melanoma) and human (NCI-H460 non-small-cell lung and MCF7 breast carcinomas) tumor models. S 16020-2 given i.v. was active against P388 leukemia implanted i.p., s.c., or intracerebrally. The therapeutic effect of an intermittent schedule (administration on days 1, 5, 9) was superior to that of single-dose treatment, allowing the i.v. administration of high total doses of S 16020-2 and resulting in the cure of 60% of mice in the i.p. P388 model. In this model, S 16020-2 was more active than elliptinium acetate and showed a better therapeutic index than Adriamycin: > or = 8 versus 2. A good therapeutic effect of S 16020-2 was also observed in three P388 leukemia sublines displaying the classic multidrug-resistance phenotype, namely, P388/VCR, P388/VCR-20, and P388/MDRC.04, the latter being totally insensitive to vincristine and Adriamycin. However, S 16020-2 was not active against the P388/ADR leukemia, a model highly resistant to adriamycin in vivo. S 16020-2 was both more active than Adriamycin and curative in the M5076 sarcoma and Lewis lung carcinoma implanted s.c. In the B16 melanoma implanted i.p. or s.c., S 16020-2 was less active than Adriamycin. Against the NCI-H460 human tumor xenograft, S 16020-2 demonstrated activity superior to that of Adriamycin (T/C = 20% versus 43% on day 21). Against the MCF7 breast cancer xenograft, S 16020-2 was active, but less so than Adriamycin (T/C = 23% versus 9% on day 21), whereas elliptinium acetate was marginally active (T/C = 49% on day 24). The hematological toxicity of S 16020-2 given to B6D2F1 mice at pharmacological dose appeared to be less severe than that of Adriamycin, particularly in bone-marrow stem cells. These results demonstrate that S 16020-2 is a highly active antitumor drug in various experimental tumor models and is markedly more efficient than elliptinium acetate. Because of its pharmacological profile, which is globally different from that of Adriamycin, S 16020-2 is considered an interesting candidate for clinical trials.
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PMID:In vivo antitumor activity of S 16020-2, a new olivacine derivative. 882 92

Treatment results were evaluated in 45 children with acute myeloblastic leukemia (AML) treated on the ANLL-9205 protocol of the Children's Cancer Leukemia Study Group (CCLSG, Japan). In this protocol, terarubicin (THP-ADR), vincristine and continuous infusion of cytosine arabinoside (Ara C) were applied for remission induction therapy (AVC), and VP16+ high dose Ara C were used sequentially for 32 or 48 weeks. Eleven patients received stem cell transplantation. Thirty-eight out of the 43 eligible patients (88.4%) achieved complete remission, and the overall 3-year event-free survival (EFS) was 55.6% (S.E.,10%). This favorable response was attributed mainly to the high induction rate of patients with the M5, M7 FAB subtypes and higher WBC counts (> or = 10 x 10(9)/L). There was no difference in the 3-year EFS of these patients who discontinued treatment between 32 weeks and 48 weeks. Serious toxicities were not observed in this study. These findings suggest that the ANLL-9205 protocol is an effective and safe treatment regimen for childhood AML. When comparing the treatment period of 32 or 48 weeks, the difference was not statistically significant.
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PMID:[Myelogenous leukemia in children. ANLL9205 study by Children's Cancer and Leukemia Study Group (CCLSG)]. 905 63

Resistance-modifying agents (RMAs) such as Verapamil have been proved to be effective in reversing multi-drug resistance (MDR) in many in vitro assays. In this study we have investigated the efficacy of Dex-Verapamil, the R-isomer of Verapamil, as a chemosensitizer in a murine leukemia cell line (P388) and in its resistant counterpart (P388/Dx) expressing a typical MDR phenotype. We have examined in vivo the effect of the co-administration of Dex-Verapamil and Doxorubicin in mice transplanted with P388 or P388/Dx cells. Mice treated with the combination of Doxorubicin plus RMA had a significant increase in survival rate as compared to controls; however, the effect was modest. On the contrary, in vitro Dex-Verapamil can enhance Doxorubicin cytotoxicity in P388/Dx cells with a much greater effect depending on the treatment scheme used, by increasing the intracellular content of drug. Taken together our data indicate that Dex-Verapamil can indeed increase the sensitivity to Doxorubicin in resistant cells, but the limited efficacy shown in vivo demonstrates that this phenomenon is strongly dependent on the treatment scheme used and on the maintenance of constantly elevated serum levels.
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PMID:Effects of Dex-Verapamil on Doxorubicin cytotoxicity in P388 murine leukemia cells. 919 59

A multidrug-resistant murine lymphoid leukemia P388/ADR overexpresses P-glycoprotein (P-gp), an active transporter that pumps cytotoxic drugs out of cells and a product of mdr1 gene. Cytotoxic T lymphocytes (CTL) that showed cytotoxicity against P388/ADR were generated from mixed lymphocyte tumor cell culture. CTL do not kill drugsensitive parental P388 (P388/parent) that does not express P-gp. Monoclonal antibody against P-gp inhibited cytotoxic activity. Similar results were obtained in another multidrug-resistant cell line P388/VP-16. Cytotoxic activity was mediated by Thy1+ CD4- CD8+ T-cells. When P388/ADR was treated with murine IL-4, expression of P-gp was downregulated. Monoclonal antibody against interleukin-4 (IL-4) abrogated the IL-4-induced suppression of P-gp. Cytolytic activity of CTL against IL-4-treated P388/ADR was dose dependently inhibited. These results suggest that P-gp is immunogenic and can be a target of CTL in this murine leukemia model.
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PMID:Cytotoxic T-lymphocytes recognizing P-glycoprotein in murine multidrug-resistant leukemias. 926 May 76


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