Identification of members of the P-glycoprotein multigene family.

Abstract

Overproduction of P-glycoprotein is intimately associated with multidrug resistance. This protein appears to be encoded by a multigene family. Thus, differential expression of different members of this family may contribute to the complexity of the multidrug resistance phenotype. Three lambda genomic clones isolated from a hamster genomic library represent different members of the hamster P-glycoprotein gene family. Using a highly conserved exon probe, we found that the hamster P-glycoprotein gene family consists of three genes. We also found that the P-glycoprotein gene family consists of three genes in mice but has only two genes in humans and rhesus monkeys. The hamster P-glycoprotein genes have similar exon-intron organizations within the 3' region encoding the cytoplasmic domains. We propose that the hamster P-glycoprotein gene family arose from gene duplication. The hamster pgpl and pgp2 genes appear to be more closely related to each other than either gene is to the pgp3 gene. We speculate that the hamster pgpl and pgp2 genes arose from a recent gene duplication event and that primates did not undergo this duplication and therefore contain only two P-glycoprotein genes.Tumors that become resistant to antineoplastic drugs often render cancer chemotherapy ineffective (13). Cell lines selected for resistance in vitro to a single cytotoxic drug have been used to study the molecular mechanism of this phenomenon. These cell lines are also cross-resistant to a wide range of structurally and functionally unrelated drugs, and their patterns of cross-resistance are complex and variable, depending on the drugs used for selection (13). The basis of multidrug resistance (MDR) appears to be reduced net cellular accumulation of drugs resulting from an energydependent increase in drug efflux (5,20,33).Overproduction of a 170,000-dalton membrane glycoprotein termed P-glycoprotein is intimately associated with expression of the MDR phenotype (21-23). Transfection experiments (8,16,36) have demonstrated that overproduction of P-glycoprotein is sufficient to cause MDR. Analyses of partial and full-length cDNAs encoding P-glycoprotein from hamster (11,12), mouse (15,17), and human (3, 37; A. M. van der Bliek, P. M. Kooiman, C. Schneider, and P. Borst, Gene, in press) cells have shown that P-glycoprotein is a highly conserved protein which appears to be tandemly duplicated. Each duplicated half consists of six potential membrane-spanning regions and a putative nucleotidebinding site, features compatible with the proposed role of P-glycoprotein as an energy-dependent pump (3,12,15). The highest level of amino acid sequence homology occurs in the cytoplasmic domains encompassing the nucleotide-binding sites and the C-terminal domain (17, 37). Each half of the protein also has a high degree of primary amino acid sequence and structural homology with bacterial transport proteins, particularly hemolysin B (12), suggesting that they evolved independently from a common ancestral gene.A family of closely related genes, referred to as ...

Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study

“…Patients were stratified by age (Յ 55 years versus Ͼ 55 years) and disease type and randomly assigned to treatment with cytarabine (AraC) 3 g/m 2 daily administered on induction days 1 to 5 by 3-hour intravenous infusion, followed by DNR 45 mg/m 2 per day administered by continuous infusion on days 6 to 8, or the same regimen with CsA. 16 CsA was administered by 72-hour continuous intravenous infusion at a dosage of 16 mg/kg per day concurrently with DNR, following a 2-hour intravenous loading dose (6 mg/kg) and 6-hour infusion of CsA (4 mg/kg) on day 6 to ensure achievement of steady state prior to DNR administration.…”

“…1,2 In human leukemias and other malignancies, Pgp functions as an adenosine triphosphate (ATP)-dependent multidrug exporter with broad specificity for natural product-derived antineoplastics. 3 Overexpression of Pgp is associated with reduced cellular accumulation and relative in vitro resistance to anthracyclines that can be overcome by concurrent exposure to Pgp antagonists such as cyclosporine A (CsA).…”

Experimental Mallory Body Formation Is Accompanied by Modulation of the Expression of Multidrug–Resistance Genes and Their Products

“…[26][27][28][29][30][31] The class I (MDR1 in humans, mdr1a [or mdr3] and 1b [or mdr1] in rodents) isoforms have been Mallory bodies (MBs) are characteristic cytoplasmic inclu-directly associated with drug resistance, 22,23,25,32,33 whereas sions associated with alcoholic hepatitis and with a diversity the class II isoform (MDR2 in humans and mdr2 in rodents) of other chronic liver disorders of apparently unrelated etiolo-functions as a phospholipid transporter. 34,35 Immunohistogies, including long-lasting cholestasis, Wilson's disease, chemical analyses have shown that Pgp is expressed on the metabolic disorders, and hepatocellular neoplasms.…”

Identification of Important Compounds Isolated from Natural Sources that Have Activity Against Multidrug-resistant Cancer Cell Lines: Effects on Proliferation, Apoptotic Mechanism and the Efflux Pump Responsible for Multi-resistance Phenotype

“…Pgp1 (ABCB1/MDR1) was isolated from Chinese hamster cell lines in the laboratory of Victor Ling in 1976 and its amino acid sequence determined by the same investigating laboratory in 1989 (7). From these and other studies involving the human Pgp1, the structure of Pgp1, as it may appear on the plasma membrane of an MDR cancer cell, is presented by Figure 1.…”