| Description | the protein is called P-glycoprotein; 170 kDa transmembrane glycoprotein which includes 10-15 kDa of N-term glycosylation; the N-term half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP binding site, and then a second section with 6 transmembrane domains and an ATP binding site which shows over 65% of amino acid similarity with the first half of the polypeptide |
| Expression | normally expressed at secretory surface of a number of tissues, including biliary canaliculi, proximal tubules of the kidney, intestinal and colonic epithelium; hematopoietic stem cells express high levels of P-glycoprotein; overexpressed in many multidrug resistant cell lines and in tumor cells resistant to chemotherapy |
| Localisation | mainly at the cell membrane, with a secondary localisation at the Golgi apparatus |
| Function | the P-glycoprotein is an energy-dependent efflux pump involved in extrusion of many types of lypophilic coumpounds; it may acts in normal tissues as a protective mechanism against noxious xenobiotics and as a transporter of endogenous substrates; in tumour cells, the drug efflux pump results in a decrease in intracellular drug concentration |
| Homology | closely related gene to MDR3 (also called PGY3), located at the same chromosomal site but not implicated in multidrug resistance; there are 3 murine homolog genes (mdr1, mdr2, mdr3) out of which only 2 (mdr1 and mdr3) are involved in multidrug resistance; member of a large superfamily of transmembrane transporter proteins named ATP Binding Cassette (ABC) transporters or Traffic ATPases; structural homology with other ABC transporter proteins (CFTR, MRP) |
| Entity | tumor cells resistance |
| Disease | tumor cells resistance to a wide variety of antineoplasic agents: doxorubicin, daunorubicin, vinblastine, vincristine, colchicine, actinomycine D, etoposide, tenoposide, mitoxantrone, homoharringtonine; this phenomenon is named "multidrug resistance" (MDR); P-glycoprotein is the main protein responsible for the MDR phenotype; however, other agents may be involved in MDR, independently or in association with P-glycoprotein: "multidrug resistant associated protein" (MRP), "lung resistance protein" (LRP), "anthracycline associated resistance protein" (ARX) |
| | |
| Entity | leukemias |
| Disease | In leukemia, MDR1 overexpression is observed in patients with a lower complete remission rate and with a shortening of overall survival; frequently associated with intermediate and poor prognosis karyotype; in ANLL, approximately 50% of patients are MDR positive at diagnosis (range 22-70%) and the MDR phenotype is more frequently observed in CD34+ leukemias; in ALL, the average number of MDR-positive cases is 22% at diagnosis |
| | |
| Entity | tumour cell lines: in numerous continuous tumour cell lines which acquired experimentally a MDR phenotype when cultured with progressively increasing drug concentration, the acquisition of MDR was associated with hyperexpression of P-glycoprotein; for the higher levels of expression, southern blots revealed an increase in the number of copies of the MDR1 gene per cell |
| Cytogenetics | the genomic amplification of MDR1 appears as extrachromosomic "double-minute chromosomes" (DM) or intrachromosomic "homogeneous staining regions" (HSR) |
| Oncogenesis | amplification |
| | |
| Autonomously replicating episomes contain mdr1 genes in a multidrug-resistant human cell line. |
| Ruiz JC, Choi KH, von Hoff DD, Roninson IB, Wahl GM |
| Molecular and cellular biology. 1989 ; 9 (1) : 109-115. |
| PMID 2648129 |
| |
| Multidrug resistance in acute myeloid leukemia. |
| Baer MR, Bloomfield CD |
| Journal of the National Cancer Institute. 1991 ; 83 (10) : 663-665. |
| PMID 2023265 |
| |
| Double minute chromosomes carrying the human multidrug resistance 1 and 2 genes are generated from the dimerization of submicroscopic circular DNAs in colchicine-selected KB carcinoma cells. |
| Schoenlein PV, Shen DW, Barrett JT, Pastan I, Gottesman MM |
| Molecular biology of the cell. 1992 ; 3 (5) : 507-520. |
| PMID 1611154 |
| |
| Cell biological mechanisms of multidrug resistance in tumors. |
| Simon SM, Schindler M |
| Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (9) : 3497-3504. |
| PMID 7909602 |
| |
| A YAC-based contig of 1.5 Mb spanning the human multidrug resistance gene region and delineating the amplification unit in three human multidrug-resistant cell lines. |
| Torigoe K, Sato S, Kusaba H, Kohno K, Kuwano M, Okumura K, Green ED, Tsui LC, Scherer SW, Schlessinger D, Wada M |
| Genome research. 1995 ; 5 (3) : 233-244. |
| PMID 8593611 |
| |
| P-glycoprotein multidrug resistance and cancer. |
| Bosch I, Croop J |
| Biochimica et biophysica acta. 1996 ; 1288 (2) : F37-F54. |
| PMID 8876632 |
| |
| P-glycoprotein and multidrug resistance. |
| Gottesman MM, Pastan I, Ambudkar SV |
| Current opinion in genetics & development. 1996 ; 6 (5) : 610-617. |
| PMID 8939727 |
| |
| The MDR phenotype in hematologic malignancies: prognostic relevance and future perspectives. |
| Hegewisch-Becker S, Hossfeld DK |
| Annals of hematology. 1996 ; 72 (3) : 105-117. |
| PMID 8766251 |
| |
| Sequential emergence of MRP- and MDR1-gene over-expression as well as MDR1-gene translocation in homoharringtonine-selected K562 human leukemia cell lines. |
| Zhou DC, Ramond S, Viguie F, Faussat AM, Zittoun R, Marie JP |
| International journal of cancer. Journal international du cancer. 1996 ; 65 (3) : 365-371. |
| PMID 8575859 |
| |
| Multidrug resistance gene expression in acute myeloid leukemia: major prognosis significance for in vivo drug resistance to induction treatment. |
| Hunault M, Zhou D, Delmer A, Ramond S, Viguiˆ© F, Cadiou M, Perrot JY, Levy V, Rio B, Cymbalista F, Zittoun R, Marie JP |
| Annals of hematology. 1997 ; 74 (2) : 65-71. |
| PMID 9063375 |
| |
| Functional expression of MDR-1 in acute myeloid leukemia: correlation with the clinical-biological, immunophenotypical, and prognostic disease characteristics. |
| Martˆ‚nez A, San Miguel JF, Valverde B, Bˆ°rez A, Moro MJ, Garcˆ‚a-Marcos MA, Pˆ©rez-Simˆ„n JA, Vidriales B, Orfao A |
| Annals of hematology. 1997 ; 75 (3) : 81-86. |
| PMID 9368475 |
| |
| MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia. |
| van den Heuvel-Eibrink MM, van der Holt B, te Boekhorst PA, Pieters R, Schoester M, Lˆwenberg B, Sonneveld P |
| British journal of haematology. 1997 ; 99 (1) : 76-83. |
| PMID 9359506 |
| |
| The prognostic significance of the expression and function of multidrug resistance transporter proteins in acute myeloid leukemia: studies of the Southwest Oncology Group Leukemia Research Program. |
| Willman CL |
| Seminars in hematology. 1997 ; 34 (4 Suppl 5) : 25-33. |
| PMID 9408958 |
| |