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Relationship of LRP-human major vault protein toin vitro and clinical resistance to anticancer drugs

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Abstract

Multidrug resistance (MDR) has been related to two members of the ABC-superfamily of transporters, P-glycoprotein (Pgp) and Multidrug Resistance-associated Protein (MRP). We have described a 110 kD protein termed the Lung Resistance-related Protein (LRP) that is overexpressed in several non-Pgp MDR cell lines of different histogenetic origin. Reversal of MDR parallels a decrease in LRP expression. In a panel of 61 cancer cell lines which have not been subjected to laboratory drug selection, LRP was a superior predictor forin vitro resistance to MDR-related drugs when compared to Pgp and MRP, and LRP's predictive value extended to MDR unrelated drugs, such as platinum compounds. LRP is widely distributed in clinical cancer specimens, but the frequency of LRP expression inversely correlates with the known chemosensitivity of different tumour types. Furthermore, LRP expression at diagnosis has been shown to be a strong and independent prognostic factor for response to chemotherapy and outcome in acute myeloid leukemia and ovarian carcinoma (platinum-based treatment) patients. Recently, LRP has been identified as the human major protein. Vaults are novel cellular organelles broadly distributed and highly conserved among diverse eukaryotic cells, suggesting that they play a role in fundamental cell processes. Vaults localise to nuclear pore complexes and may be the central plug of the nuclear pore complexes. Vaults structure and localisation support a transport function for this particle which could involve a variety of substrates. Vaults may therefore play a role in drug resistance by regulating the nucleocytoplasmic transport of drugs.

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Abbreviations

LRP:

Lung Resistance-related Protein

MVP:

Major Vault Protein

MDR:

Multidrug resistance

MRP:

Multidrug resistance-associated Protein

NPC:

Nuclear Pore Complex

Pgp:

P-glycoprotein

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Authors and Affiliations

  1. Department of Pathology, Free University Hospital, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands

    Miguel A. Izquierdo, George L. Scheffer, Marcel J. Flens & Rik J. Scheper

  2. Laboratory of Drug Discovery Research and Development, Developmental Therapeutic Program, Division of Cancer Treatment, National Cancer Institute, MD 21702-1201, Frederick, Maryland, USA

    Robert H. Shoemaker

  3. Department of Biological Chemistry, University of California School of Medicine, 90024-1737, Los Angeles, CA, USA

    Leonard H. Rome

Authors
  1. Miguel A. Izquierdo
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  2. George L. Scheffer
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  3. Marcel J. Flens
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  4. Robert H. Shoemaker
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  5. Leonard H. Rome
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  6. Rik J. Scheper
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Izquierdo, M.A., Scheffer, G.L., Flens, M.J. et al. Relationship of LRP-human major vault protein toin vitro and clinical resistance to anticancer drugs. Cytotechnology 19, 191–197 (1996). https://doi.org/10.1007/BF00744212

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