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Chapter 57 Pharmacology and Molecular Mechanisms of Antineoplastic Agents for Hematologic Malignancies 879

P-Glycoprotein (ABC-B1 Transporter) gene has 28 exons and codes for a protein of 1280 amino acids. The
PGP molecule has two homologous halves, each with a hydrophobic
region containing six transmembrane domains and a hydrophilic
Structure and Function region containing an ATP-binding site. N-linked glycosylation occurs
on the extracellular side (Fig. 57.10). PGP is a member of the ABC
The ABC superfamily of membrane transporters mediates the cross- superfamily, which includes, among more than 100 others, the MRP;
membrane flux of xenobiotics, naturally occurring toxic compounds, the pfmdr pump in Plasmodium falciparum, which results in chloro-
drugs, peptides, and ions. The ABC family has a profound impact quine resistance; STE6, the transporter of the “a” peptide mating
on homeostasis and is critically important to proliferation and dif- factor in yeast; the cystic fibrosis transmembrane conductance regula-
ferentiation signals in normal progenitor cells. It also mediates drug tor (CFTR); and the TAP-1 and TAP-2 proteins that transport
sensitivity. The terminology remains challenging because many earlier antigenic peptides for association with class I molecules and surface
works referred to PGP and MRP, but the more recent consensus on antigen presentation. MRP has been demonstrated in several MDR
the ABC superfamily has created a more simple approach going mammalian cell lines and in human tumors (see later), but a recent
forward. PGP (ABC-B1 transporter) has been the subject of intense study in human tumor cell lines has shown TAP overexpression
biochemical and clinical studies since it was first discovered in drug- associated with MRP, as well as drug resistance resulting from trans-
resistant cell lines more than 20 years ago. The biochemistry of PGP fection of the TAP genes.
has been reviewed in detail by several investigators. This phosphory- PGP has a broad specificity for hydrophobic compounds and can
lated glycoprotein has a molecular mass of approximately 170 kDa both reduce the influx of drugs into the cytosol and increase efflux
and is localized to the plasma membrane, where it functions as a drug from the cytosol. To accomplish the former, this “hydrophobic
efflux pump (Table 57.7). The ATP-dependent extrusion of antineo- vacuum cleaner” must detect drugs and expel them while they are
plastic agents confers a relative level of resistance to the cell that still in the plasma membrane. Drugs are thought to be effluxed from
overexpresses PGP. Recently, the family of drug-transporting proteins the cytosol through a single barrel of the PGP transporter, although
has been more carefully characterized, leading to the use of the term an exact mechanism has been lacking. A recent study has used electron
ATP-binding cassette transporters. The observation of double-minute microscopy to generate an initial structure of PGP to 2.5-nm resolu-
chromosomes and homogeneously staining regions in several MDR tion. The structure was further refined by three-dimensional recon-
cell lines suggested that gene amplification is involved in PGP- structions from single-particle image analysis of detergent-solubilized
mediated MDR. The human MDR1 gene, which codes for PGP and PGP and by Fourier projection maps of small crystalline arrays of
is involved in antitumor drug resistance, and the human MDR2 gene PGP. This demonstrates that PGP is monomeric, with the shape of
(the product of which is expressed by hepatocytes) are located very a cylinder 10 nm in diameter with a maximum height (in the plane
near each other on human chromosome 7q21.1. The human MDR1 of the membrane) of 8 nm (see Fig. 57.10). Approximately half of

TABLE Characteristics of Three Mechanisms of Multidrug Resistance That Result From Overexpression of PGP, Multidrug Resistance-
57.7 Associated Protein, or Lung Resistance-Related Protein
PGP MRP LRP
Gene on chromosome 7q21.1 16p13.1 16p11.2
Protein
Molecular mass 170 kDa 190 kDa 110 kDa
Cellular location Plasma membrane Plasma membrane Cytoplasm ≫ nuclear membrane
Function Efflux pump, chloride channel Drug transporter Major vault protein (nucleocytoplasmic
transport?)
Energy source ATP ATP
Posttranslational modifications N-glycosylation, phosphorylation N-glycosylation, phosphorylation No N- or O-glycosylation
Analogs Member ABC superfamily Member ABC superfamily; GS-X pump,
MOAT, LTC 4 transport
Drug-Resistance Phenotype
Antitumor agents Act-D, m-AMSA, dauno, dox, Act-D, chlor, CDDP-GSH, dauno, dox, Carbo, CDDP, dox, mel, vcr, VP-16
epi, ida, mito-C epi, mel, tax (low), vbl (low), vcr,
VM-26, VP-16
(Low), mtz, nav, tax, txtr, tpt As, Cd, colch (low), GSH
(low), vbl, vcr, VM-26, VP-16
Other drugs Colch, rhod Conjugates, GSSG, LT 4 , Sb
Reversing agents CSA, FK506, nifed, PSC833, CSA, gnstn, indo, nicard, prbn,
quin, rap, verap PSC833, verap, VX-710
+
Normal hematopoietic tissues NK (CD56 ) T cells, suppressor PBMNs (especially T cells), red blood Macrophages
+
+
with increased expression T cells (CD8 ), B cells, CD34 cell membranes; liver and spleen
stem cells low level
Prognostic significance AML, MM, NHL AML (inv 16) AML, ALL
ABC, ATP-binding cassette; act-D, actinomycin D; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; As, arsenicals; ATP, adenosine triphosphate; carbo,
carboplatin; Cd, cadmium; CDDP-GSH; cisplatin glutathione conjugate; chlor, chlorambucil; colch, colchicine; CSA, cyclosporin A; dauno, daunomycin; dox, doxorubicin;
epi, epirubicin; gnstn, genistein; GS-X, glutathione conjugate; GSSG, oxidized glutathione; ida, idarubicin; indo, indomethacin; LRP, lung resistance-related protein;
LTC 4, cysteinyl leukotriene; m-AMSA, amsacrine; mel, melphalan; mito-C, mitomycin C; MM, multiple myeloma; MRP, multidrug resistance-associated protein;
MOAT, multispecific organic anion transporter; mtz, mitoxantrone; nav, navelbine; NHL, non-Hodgkin lymphoma; nicard, nicardipine; NK, natural killer; nifed, nifedipine;
PGP, P-glycoprotein; prbn, probenecid; quin, quinidine; rap, rapamycin; rhod, rhodamine; Sb, antimonials; tax, taxol; tpt, topotecan; txtr, taxotere; vbl, vinblastine;
vcr, vincristine; verap, verapamil; VM-26, teniposide; VP-16, etoposide.