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)

In view of the recent report of a myeloproliferative syndrome in mice that had received an MDR-1-transduced haemopoietic graft, we have investigated the potential effects of MDR-1 expression on primitive haemopoietic cell growth and differentiation. Retroviral gene transfer was used to achieve exogenous expression of either MDR-1 or truncated nerve growth factor receptor (tNGFR) in the multipotent murine haemopoietic progenitor cell line, FDCP-mix. Following gene transfer, clonal lines were derived and FACS analysis confirmed appropriate expression of each transgene. MDR-1 (but not tNGFR) expression was associated with verapamil-sensitive rhodamine efflux and resistance to killing by etoposide. When growth factor responsiveness, proliferative capacity and differentiation capacity were examined, MDR-1 expressing FDCP-mix cells exhibited a normal phenotype and mimicked the response of tNGFR-expressing or untransduced FDCP-mix cells. Thus, in the model system we have used, MDR-1 does not perturb haemopoietic cell growth and development and our data do not support a myeloproliferative role for MDR-1.
Leukemia 2002 Jan
PMID:Retroviral transfer and expression of human MDR-1 in a murine haemopoietic stem cell line does not alter factor dependence, growth or differentiation characteristics. 1184 Feb 69

Treatment of an established BCL1 leukaemia in mice showed that the use of hydrogels is advantageous in comparison with free doxorubicin (DOX), partially due to the different pharmacokinetic profile of the drug release. Pharmacologically active concentrations ranging from 100 to 800 ng/ml were detectable in the bloodstream for more than 4 days when DOX-loaded hydrogels were implanted into mice. Animals treated with free DOX survived for 35 days, survival of hydrogel-DOX treated animals increased up to 60 days and long-term survivors were achieved, when the second hydrogel was implanted 2 weeks after the first one. Hydrogels containing vinblastine (VLB) were ineffective. N-(2-hydroxypropyl)methacrylamide (HPMA) hydrogels were also used in combined therapy against multidrug resistant leukaemia P388-MDR to achieve a synergistic effect of both the cytostatic drug and chemosensitising agent. It was shown that when 4 times the maximal tolerated dose (MTD) of free DOX was incorporated into HPMA-hydrogels, tumour volume was reduced by approximately 50% after implantation of the hydrogel containing DOX and cyclosporine A (CsA) and survival was slightly prolonged.
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PMID:HPMA-hydrogels result in prolonged delivery of anticancer drugs and are a promising tool for the treatment of sensitive and multidrug resistant leukaemia. 1187 56

The novel prodrug of butyric acid, pivaloyloxymethyl butyrate (AN-9), a histone deacetylase inhibitor, shows great promise as an effective and relatively nontoxic anticancer agent for solid malignancies. However, little is known about its effects on hematopoietic malignancies. In this study, we show that 21 primary samples of acute leukemia were sensitive to the antiproliferative effects of AN-9, with a 50% inhibitory concentration (IC(50)) of 45.8 +/- 4.1 microM. In colony-forming assays, primary T-cell acute lymphoblastic leukemia (T-ALL) cells were 3-fold more sensitive to AN-9 than the normal hematopoietic progenitors, erythroid burst-forming units and granulocyte/monocyte colony-forming units. AN-9 induced apoptosis in the T-ALL cell line CEM. A common problem with cancer is chemoresistance, which is often typical of relapsed cancers. Remarkably, a T-ALL sample at diagnosis and an acute myeloid leukemia sample at relapse that were resistant to doxorubicin in vitro were sensitive to AN-9, with an IC(50) of 50 microM for both samples. More strikingly, samples from 2 infants with t(4;11) ALL obtained at diagnosis and relapse each were the most sensitive to AN-9, with IC(50) values of 25 microM and 17 microM, respectively. Furthermore, a doxorubicin-resistant clone of HL60, HL60/ADR, obtained by the transfection of the MDR-1 gene, was equally sensitive to AN-9 cytotoxicity as the parental cells. AN-9 induced the expression of p21 in an infant leukemia sample with 11q23 rearrangement, but not in T- or B-precursor ALL. Collectively, our results suggest that AN-9 is a selective agent for hematopoietic malignancies that can circumvent the mechanisms of chemoresistance limiting most conventional chemotherapy.
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PMID:The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines. 1238 33

Multidrug resistance has been a major problem in cancer chemotherapy. In this study, in vitro and in vivo modulations of MDR by ginsenoside Rg(3), a red ginseng saponin, were investigated. In flow cytometric analysis using rhodamine 123 as an artificial substrate, Rg(3) promoted accumulation of rhodamine 123 in drug-resistant KBV20C cells in a dose-dependent manner, but it had no effect on parental KB cells. Additionally Rg(3) inhibited [3H]vinblastine efflux and reversed MDR to doxorubicin, COL, VCR, and VP-16 in KBV20C cells. Reverse transcriptase-polymerase chain reaction and immuno-blot analysis after exposure of KBV20C cells to Rg(3) showed that inhibition of drug efflux by Rg(3) was due to neither repression of MDR1 gene expression nor Pgp level. Photo-affinity labeling study with [3H]azidopine, however, revealed that Rg(3) competed with [3H]azidopine for binding to the Pgp demonstrating that Rg(3) competed with anticancer drug for binding to Pgp thereby blocking drug efflux. Furthermore, Rg(3) increased life span in mice implanted with DOX-resistant murine leukemia P388 cells in vivo and inhibited body weight increase significantly.
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PMID:Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3). 1247 81

We investigated the possibility of the proapoptotic lipid ceramide as an indicator of chemoresistance in leukemia. Doxorubicin (DOX) increased the ceramide level and apoptosis in drug-sensitive HL-60 cells but not in drug-resistant HL-60/ADR cells, under the condition that the uptake of DOX was not different between the two cell lines. In addition, exogenous N-acetylsphingosine (C2-ceramide) enhanced DOX-induced apoptosis in HL-60/ADR cells without affecting the expression of multidrug resistant-1 protein (MDR 1) and the uptake of DOX. A lower level of ceramide with higher activities of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) was detected in HL-60/ADR cells than in HL-60 cells. In contrast, HL-60/GCS cells, overexpressing GCS, significantly inhibited DOX-induced ceramide increase and apoptosis. These observations suggest the involvement of ceramide regulation in drug resistance of leukemia cells. In vivo, the level of ceramide was lower in chemoresistant leukemia patients (6.4 +/- 1.8 pmol/nmol phosphate; n = 14) than in chemosensitive patients (9.5 +/- 2.7 pmol/nmol phosphate; n = 9), and the activities of GCS and SMS were more than 2-fold higher in chemoresistant leukemia cells than in chemosensitive cells. MDR-1 protein was faintly expressed in one of four chemoresistant patients, but Bcl-2 were clearly detected in four patients. Therefore, it is suggested that a decrease of the ceramide level via activation of GCS and SMS is associated with the chemoresistant condition in leukemia, probably in relation to Bcl-2 but not to MDR-1 expression.
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PMID:Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia. 1253 95

Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor antitumor efficacy, systemic toxicity, and the induction of drug resistance. Here, we provide the first evidence that hydrolytically activated prodrugs may overcome these problems. For this purpose, VP16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate 2 novel prodrugs of VP16. First, we established a more than 3-log higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug-resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced multidrug resistance-1 gene (MDR-1)-mediated multidrug resistance in vitro in a newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1-mediated efflux. Third, in vivo studies showed a maximum tolerated dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only the mice treated with this prodrug revealed a complete and long-lasting regression of established, drug-resistant leukemia. In summary, the hydrolytically activated etoposide prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro and in vivo and provide proof of concept for a highly promising new strategy for the treatment of MDR-1 drug-resistant malignancies.
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PMID:Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia. 1262 53

The ability of cancer cells to become simultaneously resistant to different drugs is a significant impediment to successful chemotherapy. 99mTc-MIBI has been reported to be a transport substrate for P-glycoprotein (Pgp). The aim of the study was to ascertain the relationship between the degree of 99mTc-MIBI uptake and the level of Pgp expression in patients with newly diagnosed leukaemia. A total of 26 patients (12 female and 14 male; mean age 46.8+/-3.7 years) with newly diagnosed leukaemia were included in the study. None of the patients had been previously treated with chemotherapy. Images were obtained 20 min post-injection of 740 MBq 99mTc-MIBI. Whole-body and planar spot images of the pelvis and thorax were acquired. The uptake of the MIBI in the bone marrow was evaluated using a qualitative and also a quantitative scoring system with determination of the tumour-to-background (T/B) ratios. Flow cytometry was performed for determining the Pgp expression of the blast cells in the bone marrow aspiration samples. There was a statistically significant inverse relationship between the Pgp level in numeric values and both mean qualitative (P<0.001; r=-0.665) and quantitative (P=0.001; r=-0.606) results of 99mTc-MIBI imaging. Both the mean qualitative score and the T/B ratios were higher in patients who were Pgp negative than in those who were Pgp positive (P<0.001 and P<0.001, respectively). These data indicate that an increased level of Pgp expression is correlated with a low accumulation of 99mTc-MIBI in bone marrow of patients with leukaemia. 99mTc-MIBI bone marrow imaging, as a method of functional imaging, can give in vivo information concerning the functional expression of the MDR phenotype in patients with untreated leukaemia.
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PMID:Assessment of the P-glycoprotein expression by 99mTc-MIBI bone marrow imaging in patients with untreated leukaemia. 1267 68

Resistance to chemotherapeutic drugs is one of the major difficulties encountered during cancer chemotherapy. To detect genomic aberrations underlying the acquired drug resistance, we examined three cultured human myelomonocytic leukemia cell sublines each resistant to adriamycin (ADR), 1-beta-1-D-arabinofuranosylcytosine (ara-C), or vincristine (VCR), using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), RT-PCR, and western blot techniques. Chromosomes 7, 10 and 16 most conspicuously showed frequent aberrations among the resistant sublines as compared to the parental KY-821 cell line. In ADR-resistant cells, gains at 7q21, 16p12, 16p13.1-13.3, 16q11.1-q12.1, and losses at 7p22-pter, 7q36-qter, 10p12, 10p11.2-pter, 10q21-q25, 10q26-qter were notable. In ara-C-resistant cells, no remarkable gain or loss on chromosome 7, but losses at 10p14-pter, 10q26-qter and 16p11.2-p11.3 were observed. In VCR-resistant cells, gain at 7q21 and losses at 10p11-p13, 10p15 and 16p11.2-p13.3 were found. FISH identified amplified signals for the MDR-1 gene located at 7q21.1 in ADR- and VCR- but not ara-C-resistant cells, and for the MRP-1 gene located at 16p13.1 in ADR-resistant cells. These findings were validated at the mRNA and protein levels. Overlapping of the amplified MRP-1 gene with MDR-1 gene may play a critical part in the acquisition of resistance to ADR. Resistance to ara-C excluded MDR-1 gene involvement and highlighted other key genes such as MXR gene. Several other genes putatively involved in the development of drug resistance might lie in other aberrated chromosomal regions.
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PMID:Molecular cytogenetic characterization of drug-resistant leukemia cell lines by comparative genomic hybridization and fluorescence in situ hybridization. 1271 68

A series of 25 phenothiazines and structurally related compounds was investigated by QSAR (quantitative structure activity relationship) and 3D-QSAR methods with respect to their MDR (multidrug resistance) reversing activity in P388/ADR- murine leukemia cell line resistant to ADR (adriamycin). The objective was to outline structural properties important for the investigated activity. Different measures for MDR reversal were used and compared. Two 3D-QSAR approaches were applied-CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis). Both, neutral and protonated forms of the compounds were investigated. Molecular models with good predictive power were derived using a hydrophobic field alone and a combination of steric, hydrophobic, and hydrogen bond acceptor fields of the compounds. In the combined models highest contribution of the hydrogen bond acceptor field was noticed. Thus, the dominant role of the hydrophobic and hydrogen bond acceptor fields for MDR reversing activity of the investigated compounds was demonstrated. The structural regions responsible for the differences in anti-MDR activity were analyzed in respect to their hydrophobic, hydrogen bond acceptor and steric nature. The results may direct design of new phenothiazines and related compounds as MDR modulators.
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PMID:QSAR and 3D-QSAR of phenothiazine type multidrug resistance modulators in P388/ADR cells. 1278 59

The discoveries of a new antitumor agent (LY32262) (N-[2,4-dichlorobenzoyl]phenylsulfonamide) and a close analog (LY33169) are described. For this discovery, a disk-diffusion-soft-agar-colony-formation-assay was used to screen a portion of the Eli Lilly inventory, with the evaluation of each agent against normal cells, leukemic cells and several solid tumors, including a multidrug-resistant solid tumor (with marked selective cytotoxicity for Colon-38 and Human-Colon-15/MDR compared to normal fibroblasts and L1210 leukemic cells characterizing the discovery). In mice, LY32262 and/or LY33169 had curative activity against Colon Adenocarcinoma-38, Human Colon-116, Human Prostate LNCaP, and Human Breast WSU-Br-1. In addition, many other tumors were highly sensitive: Panc-03 = 2.4 log kill (LK); Panc-02 = 2.9-4.1 LK; Squamous Lung LC-12 = 2.1 LK; Colon-26 = 2.2 LK; AML1498 = 2.7 LK; Human Sm Cell Lung DMS-273 = 6.3 LK; Human Squamous Lung 165 = 3.7 LK; Human Ovarian BG-1 = 3.7 LK; Human Colon CX-1 (H29) = 1.6 LK; Human Colon-15/MDR (a p-glycoprotein positive multidrug resistant tumor) = 2.3 LK; Human CNS-gliosarcoma-SF295 = 3.8 LK. Several tumors were only marginally responsive or totally unresponsive: Mammary Adenocarcinoma-16/C = 0.6 LK; Mammary Adenocarcinoma-17 = no kill; Colon Adenocarcinoma-11 = no kill; L1210 leukemia = 1.3 LK; Human Prostate PC-3 = 0.5 LK; Human Adenosquamous Lung H125 = no kill; and Human Breast Adenocarcinoma MX-1 = 0.9 LK. There was no absolute tissue of origin correlation with antitumor efficacy, although colon tumors were most responsive and mammary tumors least responsive. The cause of the "hit and miss" efficacy has not been determined.
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PMID:Discovery and preclinical antitumor efficacy evaluations of LY32262 and LY33169. 1279 28


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