PMID- 9713996
OWN - NLM
STAT- MEDLINE
DCOM- 19980930
LR  - 20191024
IS  - 1045-2257 (Print)
IS  - 1045-2257 (Linking)
VI  - 23
IP  - 1
DP  - 1998 Sep
TI  - Cytogenetic and molecular characterization of random chromosomal rearrangements 
      activating the drug resistance gene, MDR1/P-glycoprotein, in drug-selected cell 
      lines and patients with drug refractory ALL.
PG  - 44-54
AB  - Drug resistance, both primary and acquired, is a major obstacle to advances in 
      cancer chemotherapy. In vitro, multidrug resistance can be mediated by 
      P-glycoprotein (PGY1), a cell surface phosphoglycoprotein that acts to efflux 
      natural products from cells. PGY1 is encoded by the MDR1 gene located at 7q21.1. 
      Overexpression of MDR1 has been demonstrated in many cancers, both in patient 
      tumors and in cell lines selected with a variety of chemotherapeutic agents. 
      Recent studies in drug-selected cell lines and patients samples have identified 
      hybrid mRNAs comprised of an active, but apparently random, gene fused 5' to 
      MDR1. This observation indicates that random chromosomal rearrangements, such as 
      translocations and inversions, leading to "capture" of MDR1 by constitutively 
      expressed genes may be a mechanism for activation of this gene following drug 
      exposure. In this study, fluorescence in situ hybridization (FISH) using whole 
      chromosome paints (WCP) and bacterial artificial chromosome (BAC)-derived probes 
      showed structural rearrangements involving 7q in metaphase and interphase cells, 
      and comparative genomic hybridization (CGH) revealed high levels of amplification 
      at chromosomal breakpoints. In an adriamycin-selected resistant colon cancer line 
      (S48-3s/Adr), WCP4/WCP7 revealed t(4;7)(q31;q21) and BAC-derived probes 
      demonstrated that the breakpoint lay between MDR1 and sequences 500-1000 KB 
      telomeric to it. Similarly, in a subline isolated following exposure to 
      actinomycin D (S48-3s/ActD), a hybrid MDR1 gene composed of heme oxygenase-2 
      sequences (at 16p13) fused to MDR1 was identified and a rearrangement confirmed 
      with WCP7 and a subtelomeric 16p probe. Likewise, in a paclitaxel-selected MCF-7 
      subline where CASP sequences (at 7q22) were shown to be fused to MDR1, WCP7 
      showed an elongated chromosome 7 with a homogeneously staining regions (hsr); 
      BAC-derived probes demonstrated that the hsr was composed of highly amplified 
      MDR1 and CASP sequences. In all three selected cell lines, CGH demonstrated 
      amplification at breakpoints involving MDR1 (at 7q21) and genes fused to MDR1 at 
      4q31, 7q22, and 16p13.3. Finally, in samples obtained from two patients with drug 
      refractory ALL, BAC-derived probes applied to archived marrow cells demonstrated 
      that a breakpoint occurred between MDR1 and sequences 500-1000 KB telomeric to 
      MDR1, consistent with a random chromosomal rearrangement. These results support 
      the proposal that random chromosomal rearrangement leading to capture and 
      activation of MDR1 is a mechanism of acquired drug resistance.
FAU - Knutsen, T
AU  - Knutsen T
AD  - Medicine Branch, Division of Clinical Sciences, NCI, NIH, Bethesda, Maryland 
      20892, USA. turidk@Box-t.nih.gov
FAU - Mickley, L A
AU  - Mickley LA
FAU - Ried, T
AU  - Ried T
FAU - Green, E D
AU  - Green ED
FAU - du Manoir, S
AU  - du Manoir S
FAU - Schrock, E
AU  - Schrock E
FAU - Macville, M
AU  - Macville M
FAU - Ning, Y
AU  - Ning Y
FAU - Robey, R
AU  - Robey R
FAU - Polymeropoulos, M
AU  - Polymeropoulos M
FAU - Torres, R
AU  - Torres R
FAU - Fojo, T
AU  - Fojo T
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Genes Chromosomes Cancer
JT  - Genes, chromosomes & cancer
JID - 9007329
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 1CC1JFE158 (Dactinomycin)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Chromosome Aberrations
MH  - Chromosome Disorders
MH  - Chromosomes, Human, Pair 7/*genetics
MH  - Dactinomycin/pharmacology
MH  - Doxorubicin/pharmacology
MH  - Drug Resistance, Microbial/genetics
MH  - Drug Resistance, Multiple/*genetics
MH  - Gene Expression Regulation/genetics
MH  - Gene Rearrangement
MH  - Genes, MDR/*genetics
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics
MH  - Tumor Cells, Cultured/drug effects/metabolism
EDAT- 1998/08/26 02:24
MHDA- 2000/06/20 09:00
CRDT- 1998/08/26 02:24
PHST- 1998/08/26 02:24 [pubmed]
PHST- 2000/06/20 09:00 [medline]
PHST- 1998/08/26 02:24 [entrez]
AID - 10.1002/(SICI)1098-2264(199809)23:1<44::AID-GCC7>3.0.CO;2-6 [pii]
AID - 10.1002/(sici)1098-2264(199809)23:1<44::aid-gcc7>3.0.co;2-6 [doi]
PST - ppublish
SO  - Genes Chromosomes Cancer. 1998 Sep;23(1):44-54. doi: 
      10.1002/(sici)1098-2264(199809)23:1<44::aid-gcc7>3.0.co;2-6.