Changing picture of cellular drug resistance in human leukemia

Nørgaard, Jan Maxwell; Olesen, Lene; Hokland, Peter

doi:10.1016/s1040-8428(03)00173-2

Cited by 28 publications

(29 citation statements)

References 138 publications

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“…In order to investigate whether the poor response of CML CD34 + cells to nilotinib was due to low intracellular accumulation we looked at the expression of mRNA using qPCR for the three main clinically relevant transporters MDR1, MRP1 and ABCG2 that have been previously associated with drug resistance in leukaemia (30,31). We found that all three efflux transporters are expressed in CD34 + CML cells, however hOCT1 was below the level of detection in normal or CML CD34 + cells.…”

Section: Nilotinib Is Not Effluxed By Clinically Relevant Drug Transpmentioning

confidence: 91%

Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters

et al. 2009

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Section: Nilotinib Is Not Effluxed By Clinically Relevant Drug Transpmentioning

confidence: 91%

Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters

et al. 2009

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“…18 In addition, some lymphoblastic leukemia patients overexpressing P-glycoprotein have activated the MDR1 USP. 13 We asked whether the MDR1 USP was also activated in PBMCs from CML patients at presentation.…”

Section: Mdr1 Usp-derived Transcripts Are Detected In Drug-resistant mentioning

confidence: 99%

Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

Raguz

Randle

Sharpe

et al. 2007

Intl Journal of Cancer

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Multidrug resistance, the phenomenon by which cells treated with a drug become resistant to the cytotoxic effect of a variety of other structurally and functionally unrelated drugs, is often associated with the expression of P-glycoprotein, an efflux membrane pump coded by the MDR1 (ABCB1) gene. Transcription from MDR1 can start at 2 promoters: a well-characterized downstream promoter and an as yet uncharacterized upstream promoter (USP). We have previously determined that the USP is activated in some drug-resistant cell lines, in primary breast tumors and in metastatic epithelial cells isolated from the lymph nodes of breast cancer patients. In this study, we report the cloning and characterization of the MDR1 USP and studied its association with chemotherapy response in breast cancer patients. Deletion analysis indicated that a nearby endogenous retroviral long terminal repeat is not responsible for promoter activation, and that the region within the first 400 nucleotides upstream from the transcription start point contained all the elements necessary for promoter activity in drug-resistant cells. We identified an element recognized by the transcription factor NF-IL6 (activated upon interleukin-6 exposure) which is necessary for promoter activity in drug-resistant cells and plays a role in the activation of the promoter in response to interleukin-6 in breast cancer MCF-7 cells. Although transcripts from this promoter are associated with translating polyribosomes, their low abundance makes the amount of synthesized P-glycoprotein insufficient to affect the response to first-line chemotherapy in patients with advanced breast cancer. ' 2007 Wiley-Liss, Inc.

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“…As in the case of ALL, several lines of evidence indicate that the particular prognosis of certain (cyto)genetically defined subgroups of AML have their particular prognosis due to the inherent cellular drug resistance of the leukaemic cells, e.g. decreased Ara-C resistance is found in AML of Down's syndrome patients (Zwaan et al, 2002a) and in AML-cells harbouring the pericentric chromosome 16 inversion (Nøorgaard et al, 2004), and increased Ara-C resistance is found in cells harbouring chromosome 5/7 abnormalities (Zwaan et al, 2002b). Cellular enzymes important to resistance towards Ara-C are listed in Table 2.…”

Section: Drug Resistance In Amlmentioning

confidence: 99%

“…2). Among the mechanisms that have been investigated in clinical trials are those caused by overexpression of P-gp/MDR1 (Legrand et al, 1999;Leith et al, 1999;Nøorgaard et al, 2004), MRP (Legrand et al, 1999;Leith et al, 1999;Michieli et al, 1999), LRP (Leith et al, 1999;Michieli et al, 1999) and apoptosis related proteins (Del Poeta et al, 2003). In one study it was found that MDR1 expression prior to treatment has a negative impact not only on complete response rate, but also on remission duration and on survival (Pirker et al, 1991).…”

Section: Drug Resistance In Amlmentioning

confidence: 99%

“…A major advance in the treatment of CML has the Analysis of functional efflux and effect of P-gp modulating agents advent of imatinib which has shown a striking activity in the chronic phase, in the accelerated phase, but less so in the blast phase (Nøorgaard et al, 2004). The whole field of drug resistance in human leukaemia and certainly in CML will, beyond any doubt, change dramatically within the next years as a consequence of the emergence of imatinib.…”

Section: Drug Resistance In CMLmentioning

confidence: 99%

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Genes of multidrug resistance in haematological malignancies

et al. 2006

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Since the early 1970s, multiple drug resistance has been known to exist in cancer cells and is thought to be attributable to a membrane-bound, energy-dependent pump protein (P-glycoprotein [P-gp]) capable of extruding various related and unrelated chemotherapeutic drugs. The development of refractory disease in haematological malignancies is frequently associated with the expression of one or several multidrug resistance (MDR) genes. MDR1, multidrug resistanceassociated protein (MRP) and lung-resistance protein (LRP) have been identified as important adverse prognostic factors. Recently it has become possible to reverse clinical MDR by blocking P-gp-mediated drug efflux. The potential relevance of these reversal agents of MDR as well as the potential new approaches to treat the refractory disease are discussed in this article. In addition, an array of different molecules and mechanisms by which resistant cells can escape the cytotoxic effect of anticancer drugs has now been identified. These molecules and mechanisms include apoptosis-related proteins and drug inactivation enzymes. Resistance to chemotherapy is believed to cause treatment failure in more than 50% patients. Clearly, if drug resistance could be overcome, the impact on survival would be highly significant. This review focuses on molecular mechanism of drug resistance in haematological malignancies with emphasis on molecules involved in MDR. In addition, it brings the survey of methods involved in determination of MDR, in particular P-gp/MDR1, MRP and LRP.

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Changing picture of cellular drug resistance in human leukemia

Cited by 28 publications

References 138 publications

Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters

Nilotinib concentration in cell lines and primary CD34+ chronic myeloid leukemia cells is not mediated by active uptake or efflux by major drug transporters

Production of P‐glycoprotein from the MDR1 upstream promoter is insufficient to affect the response to first‐line chemotherapy in advanced breast cancer

Genes of multidrug resistance in haematological malignancies

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