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)

Homoharringtonine (HHT) is a new drug with antileukemic activity which is currently tested for treatment of acute and chronic leukemias, either alone or in combination with other agents. Since HHT showed a low efficacy in refractory and relapsed acute leukemia and in the blastic phase of chronic myeloid leukemia (CML) which are frequently characterized by an overexpresion of the multidrug resistance (MDR)-related P170-glycoprotein, we postulated a relationship between the poor antileukemic effect of HHT in these leukemias and the expression of P170-glycoprotein. For this reason, sensitive (LOVO109 and CEM) and MDR (LOVO DX and CEM VLB) cell lines were exposed to HHT with or without some MDR modifiers, namely, Cyclosporine A (CyA), the Cyclosporine derivative SDZ PSC 833 (PSC), and the D-isomer of Verapamil (DVRP). It was found that MDR cells were about 15 times more resistant to HHT than non-MDR cells, and that resistance to HHT was significantly decreased by all the MDR modifiers that were tested. This in vitro study showed that HHT belongs to the category of MDR-related drugs, like anthracyclines, vinca alkaloids, epipodophylline derivatives, and taxol.
Leukemia 1995 Mar
PMID:MDR-related P170-glycoprotein modulates cytotoxic activity of homoharringtonine. 788 49

HL-60-R, a multi-drug-resistant (MDR) subclone of the human leukemia cell line HL-60, was selected in continuous culture in doxorubicin (DOX) in the absence of mutagenic agents. When compared to the parent line HL-60, HL-60-R showed greater relative resistance to vinblastine than to etoposide, or to the selecting agent DOX. Co-exposure to verapamil, a known modulator of MDR, partially increased its sensitivity to DOX and vinblastine. The HL-60-R cell line stained positively with the P-glycoprotein-specific monoclonal antibody (MAb), C219, whereas the HL-60 parent was negative. Southern analysis showed 32-fold amplification of the mdrI gene in HL-60-R, whereas slot-blot analysis demonstrated 70-fold over-expression of the specific mdrI message in HL-60-R compared to HL-60. Northern blot analysis revealed the presence of 2 species of messenger RNA of sizes 5.1 kb and 4.5 kb. No transcripts were detectable in the parent. Flow cytometric analysis showed significantly reduced cellular retention of DOX as well as rapid efflux from the drug-resistant cell line. HL-60-R proved to be nearly 4 times more resistant to hydrogen peroxide than its parent, and 1,000 times more resistant to inhibition of cellular glutathione synthesis by D,L-buthionine sulfoximine (BSO). Verapamil modulated DOX resistance in HL-60-R incompletely but, in the presence of glutathione depletion, nearly completely reversed DOX resistance. Elevated levels of glutathione and glutathione-peroxidase activity were demonstrated, thereby implicating enhanced activity of the glutathione/glutathione-peroxidase cycle as an additional basis for its resistance to DOX. These findings suggest that an enhanced capacity for detoxifying oxyradicals may contribute to anthracycline resistance in acute leukemia.
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PMID:P-glycoprotein and alterations in the glutathione/glutathione-peroxidase cycle underlie doxorubicin resistance in HL-60-R, a subclone of the HL-60 human leukemia cell line. 809 91

Inside-out membrane vesicles prepared from multidrug resistant human leukemic cells (CEM/VBL1000), but not from sensitive cells, transported [3H]-labelled vinblastine (VBL) in an ATP-dependent manner, reaching a plateau level by 15 min. The transport occurred with an apparent Km of 60 +/- 20nM. Verapamil (10 microM), and taxol (IC50 = 1 microM) prevented VBL uptake and evoked VBL diffusion from vesicles when added after VBL uptake had reached steady state. The channel forming agent alamethicin prevented net uptake of VBL and addition of alamethicin to the vesicles after the steady-state had been reached resulted in the rapid efflux of [3H]VBL. Very low concentrations of Triton X-100 (0.01 % v/v) also prevented net uptake of VBL, whilst addition of Triton X-100 and making the medium hypo-osmotic after the steady state had been reached caused the [3H]VBL to rapidly diffuse out of the vesicles. These observations indicate that VBL is actively transported into the lumen of inside-out vesicles from multidrug resistant leukaemia cells.
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PMID:Vinblastine transport by membrane vesicles from human multidrug-resistant CCRF-CEM leukaemia cells: inhibition by taxol and membrane permeabilising agents. 810 21

R-Verapamil (R-VPM), an enantiomer of racemic verapamil (VPM), has been recently reported to possess an activity equivalent to VPM in reverting drug resistance in vitro, without showing remarkable cardiovascular toxicity in animal models, even in doses three times higher than VPM. In this study, we assessed the effects of R-VPM in vitro, on clonogenic leukemia cells (CFU-L) from 15 patients with acute nonlymphoid leukemia (ANLL) at diagnosis, and on bone marrow erythroid (BFU-E) and myeloid (CFU-GM) progenitors from 15 healthy volunteers. On CFU-L, continuous exposure to VPM or R-VPM alone showed a slight inhibitory activity; in combination with daunorubicin (DNR), R-VPM proved more effective (mean IC50 of DNR: alone = 24.53 ng/ml +/- 6.2 SE, + VPM = 18.8 ng/ml +/- 4.6 SE, +R-VPM = 17.9 ng/ml +/- 4.8 SE). On CFU-GM, both VPM and R-VPM were minimally toxic at the lowest concentration used, but 30 microM VPM were significantly more toxic than R-VPM at the same dose (residual growth = 39.2% +/- 6.5% vs. 71.8% +/- 9.3% with R-VPM, p = 0.005). On BFU-E, both VPM and R-VPM caused more consistent growth inhibition; at high doses, VPM was again more toxic than R-VPM (33.4% +/- 12.8% vs 53.4% +/- 10.4% residual growth at 30 microM, p = 0.03). DNR toxicity on bone marrow was more greatly enhanced by VPM than R-VPM, and this difference was statistically significant on erythroid progenitor colony growth (p = 0.04). In conclusion, in comparison to VPM, R-VPM appeared to be at least equally effective on leukemic clonogenic cells and less toxic on normal bone marrow precursors, thus suggesting a possible safe use in vivo, even in concentrations that cannot be achieved with VPM, owing to its toxic effects.
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PMID:Comparative effects of racemic verapamil vs R-verapamil on normal and leukemic progenitors. 831 58

The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane phospholipids. This could lead directly (through changes in membrane permeability and fluidity) and/or indirectly (through inhibition of P-glycoprotein phosphorylation via inhibition of the phosphatidylserine-dependent protein kinase C or changes in the conformation and functioning of the membrane-integrated proteins via changes in the structure organization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artificial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the literature) and their ability to interact with phosphatidylserines. Trans- and cis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupromazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction of trans- and cis-flupentixol with the phospholipids studied are suggested to be responsible for their different MDR-reversing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MDR-reversing ability. Amiodarone showed very strong interactions with phosphatidylserines and is recommended for further MDR-reversal studies.
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PMID:Membrane interactions of some catamphiphilic drugs and relation to their multidrug-resistance-reversing ability. 854 89

Daunorubucin (DNR) accumulation studies as functional tests of the multidrug resistance (MDR1) gene product P-glycoprotein have produced diverging results when correlated to response to chemotherapy in acute leukaemia. To investigate possible reasons for this diversity a starvation experiment, based upon prolongation of medium exchange, was set up in the multidrug resistant cell line CEM/VBL100. DNR accumulation (1 microgram/ml) was measured flow cytometrically in the presence or absence of Verapamil (10 micromol/l). In cells permanently kept under ideal growth conditions, addition of Verapamil resulted in an average 90% increase in DNR enhancement in five successive experiments. In contrast, DNR accumulation increased by only 26% when the medium exchange was prolonged by 30 h to 42 h. This effect was not accompanied by changes in the MDR1 gene expression at the RNA or protein level. Consequently, 53 leukaemic blast samples of 30 newly diagnosed and 18 relapsed or refractory patients with acute leukaemia (ALL-18, AML-37) were processed without any delay and under the most stringent conditions possible. Evidence of the classical MDR phenotype was arbitrarily defined by a greater than 20% enhancement in DNR accumulation in response to Verapamil (10 micromol/l) or Cyclosporin A (3 micromol/l). Using this cutoff point for analysis of newly diagnosed leukaemia we found DNR uptake better correlated to response to treatment (p = 0.002) than P-gp detection by means of immunocytochemistry, using a panel of monoclonal antibodies (p = 0.03). We conclude that DNR accumulation studies are a sensitive method for predicting therapy outcome in acute leukaemia when performed with necessary precautions.
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PMID:Prolongation of medium exchange is associated with a decrease in function but not expression of the P-glycoprotein pump in leukaemic cells. 859 88

The aim of these experimental and clinical studies was to determine if verapamil helps overcome multidrug resistance in tumor cells and in cancer patients. The effect of the calcium channel blocker verapamil on the antiproliferative activity of epirubicin (Farmorubicin, Farmitalia) was followed up in in vitro studies on two constant human leukemia cell lines: CEM/O (P-gp negative) and CEM/VCR 1000 with a positive multidrug resistant (MDR) phenotype. The MTT assay was used to study the antiproliferative activity. Verapamil in concentrations of 3 and 10 micrograms/ml enhanced by 10-fold and 19-fold, respectively, the effect of epirubicin in CEM/VCR 1000 cells and had no significant effect on epirubicin activity in CEM/O. Eleven patients with measurable stage IV breast cancer, clinically resistant to anthracycline treatment, received the FEC combination (5-fluorouracil-epirubicin-cyclophosphamide) twice with verapamil pretreatment, p.o. at the doses of 1280-2560 mg. There were two complete remissions (soft tissue metastases), four partial remissions (soft tissue metastases and lung metastases), and three stable diseases. These studies confirm the possibilities of overcoming multidrug resistance by the administration of verapamil in tumor cells and in cancer patients.
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PMID:Does verapamil help overcome multidrug resistance in tumor cell lines and cancer patients? 887 36

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

The drug GG918 has been specifically developed for overcoming MDR phenotype and is now in use in clinical trials. In this study, the effects of GG918 on leukemic cell were investigated using a 3 day MTT assay. Results showed that, in a highly resistant P-gp(+) leukemic cell line, 0.1 microM of GG918 gives rise to a 40-fold sensitization to daunorubicin (DNR) (residual resistance: 2.1), a 57-fold sensitization to mitoxantrone (residual resistance: 1.5), and a 3.3-fold sensitization to idarubicin (residual resistance: 2.9). When human AB serum was added to the incubation medium, 1 microM of GG918 was needed to observe the full P-gp modulation potency described above. The effect of 1 microM of GG918 was tested on 27 samples of poor prognosis acute leukemia (25 AML, two ALL). DNR sensitization (using the MTT assay) and modulation of rhodamine 123 uptake were monitored and used as criteria for comparing the in vitro modulation potency of this new compound to the potency of 10 microM of verapamil, which was used as reference. A good correlation (r = 0.8, P = 0.001) was observed between the results of the two tests. Eleven out of the 26 cases tested were MDR1(+) (42%), and showed a higher IC50 for DNR than the negative cases (861 +/- 1284 nM vs 187 +/- 246 nM, P = 0.05). GG918 was able to modulate the in vitro resistance to DNR in eight cases (seven MDR1(+), no MDR1(-), one non-tested). Verapamil did not increase DNR toxicity in four of these eight cases, but was more efficient in one other MDR1(+) case. In conclusion, the DNR sensitivity of the majority of the fresh AML samples expressing P-gp could be modulated in vitro by 1 microM of GG918.
Leukemia 1997 Sep
PMID:Effect of the multidrug inhibitor GG918 on drug sensitivity of human leukemic cells. 930 7

Previous reports suggest that resistance to mitoxantrone in different tumor cell lines is unrelated to the overexpression of p-glycoprotein. In order to determine the role of p-glycoprotein in the cellular pharmacology of mitoxantrone flow cytometry and confocal microscopy were used to study two human myeloid leukemia cell lines selected for resistance to mitoxantrone (HL-60MX2) and doxorubicin (HL-60DOX). To optimize the detection of intracellular mitoxantrone, we determined the maximum excitation (607 nm) and emission (684 nm) wavelength by fluorescence spectroscopy. The modified flow cytometric conditions using 568.2 nm laser emission for excitation and a 620 nm long pass filter for fluorescence collection resulted in a 1-log increase in sensitivity, compared with standard 488-nm laser excitation. Uptake and retention of mitoxantrone in the presence of verapamil, a calcium channel blocker known to inhibit p-glycoprotein, were analyzed. Our results showed no change in uptake and retention of the drug in p-glycoprotein-negative mitoxantrone-resistant HL-60MX2 cells and in its sensitive parental line, HL-60s. In contrast, 3.1- and 2.4-fold increases were found in uptake and retention of mitoxantrone in p-glycoprotein-positive cells (HL-60DOX) incubated with verapamil. Confocal microscopy of intracellular drug distribution demonstrated reduced nuclear uptake, which could be reversed by verapamil, in HL-60DOX. A characteristic punctate pattern was observed for the intracytoplasmic drug distribution in HL-60DOX and HL-60MX2 cells and was partially modified by the presence of verapamil in HL-60DOX cells. Verapamil increased cytotoxicity of mitoxantrone two-fold in HL-60DOX cells, 1.4-fold in HL-60MX2, and had no effect in HL-60s. Our study demonstrates that the cellular pharmacology of mitoxantrone is affected by p-glycoprotein and can be reversed at least in part by verapamil. Other mechanisms of resistance however, seem to play a determinant role in the modulation of mitoxantrone cytotoxicity.
Leukemia 1997 Dec
PMID:Cellular pharmacology of mitoxantrone in p-glycoprotein-positive and -negative human myeloid leukemic cell lines. 944 22


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