Expression, Amplification, and Transfer of DNA Sequences Associated with Multidrug Resistance

1988 ◽  
pp. 243-257 ◽  
Author(s):  
MICHAEL M. GOTTESMAN ◽  
IRA PASTAN ◽  
SHIN-ICHI AKIYAMA ◽  
ANTONIO T. FOJO ◽  
DING-WU SHEN ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences

Expression of hamster P-glycoprotein and multidrug resistance in DNA-mediated transformants of mouse LTA cells

1987 ◽  
Vol 7 (2) ◽  
pp. 718-724
Author(s):  
K L Deuchars ◽  
R P Du ◽  
M Naik ◽  
D Evernden-Porelle ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Recipient Mouse ◽  
Strongly Correlated ◽  
Wild Type ◽  
Glycoprotein P ◽  
Single Drug ◽  
P Glycoprotein

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.

New Aspects on the Safety of Multidrug-Resistance 1 Gene Transfers: No Indication for Clonal Dominance after Long-Term Follow-Up in a Primate Transplantation Model.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2108-2108
Author(s):  
Farastuk Bozorgmehr ◽  
Eike C. Buss ◽  
Stephanie Laufs ◽  
K. Zsuzsanna Nagy ◽  
Stephanie Sellers ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multidrug Resistance ◽  
Gene Transfer ◽  
Hematopoietic Stem Cells ◽  
Dna Sequences ◽  
Retroviral Vectors ◽  
Retroviral Vector ◽  
Hematopoietic Stem ◽  
Leukaemia Virus ◽  
Multidrug Resistance 1 Gene

Abstract It is of concern whether the introduction of a transgene into hematopoietic stem cells by retroviral vectors will lead to an alteration of the growth and engraftment characteristics. Earlier studies in mice indicated that retroviral multidrug-resistance 1 gene transfer may be associated with a myeloproliferative disorder. In human or primate cells this could not be reproduced in bulk cell populations. Analysis on the clonal level were lacking. One method to study the in vivo behaviour of repopulating progenitor and stem cells is marking the cells with replication-incompetent retroviral vectors that integrate into identifiable host DNA sequences, thus allowing the tracking of cell progeny based on unique proviral insertion sites. In this study CD34-enriched peripheral blood stem cells from 2 rhesus macaque monkeys were split into two aliquots and transduced either with a multidrug-resistance 1 gene-retroviral vector based on the Harvey murine sarcoma virus (HaMDR1-vector) or a NeoR-retroviral vector based on the Moloney murine leukaemia virus (G1Na-vector). After autologous retransplantation, DNA from blood and bone marrow was collected at different time points in a period of 4 years and the animals are still alive. By using a highly sensitive and specific ligation-mediated polymerase chain reaction (LM-PCR) followed by sequencing of vector integration sites, we found in animal M120 32 different contributing hematopoietic clones 8 weeks and 50 weeks after transplantation and in animal M038 17 clones 58 weeks after transplantation. Based on the difference between the sequences of the HaMDR1-LTR and the G1Na-LTR, the clones can be allocated definitely to one of the two vectors. Remarkably, 36 clones descend from the G1Na-vector, whereas only 13 clones descend from the HaMDR1-vector. We conclude that hematopoiesis in these monkeys is polyclonal for prolonged periods after transplantation and that MDR1 gene transfer does not confer a proliferative advantage over vector-control-transduced hematopoietic stem cells.

scholarly journals Expression of hamster P-glycoprotein and multidrug resistance in DNA-mediated transformants of mouse LTA cells.

1987 ◽  
Vol 7 (2) ◽  
pp. 718-724 ◽  
Author(s):  
K L Deuchars ◽  
R P Du ◽  
M Naik ◽  
D Evernden-Porelle ◽  
N Kartner ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Dna Sequences ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Recipient Mouse ◽  
Strongly Correlated ◽  
Wild Type ◽  
Glycoprotein P ◽  
Single Drug ◽  
P Glycoprotein

The overexpression of a plasma membrane glycoprotein, P-glycoprotein, is strongly correlated with the expression of multidrug resistance. This phenotype (frequently observed in cell lines selected for resistance to a single drug) is characterized by cross resistance to many drugs, some of which are used in cancer chemotherapy. In the present study we showed that DNA-mediated transformants of mouse LTA cells with DNA from multidrug-resistant hamster cells acquired the multidrug resistance phenotype, that the transformants contained hamster P-glycoprotein DNA sequences, that these sequences were amplified whereas the recipient mouse P-glycoprotein sequences remained at wild-type levels, and that the overexpressed P-glycoprotein in these cells was of hamster origin. Furthermore, we showed that the hamster P-glycoprotein sequences were transfected independently of a group of genes that were originally coamplified and linked within a 1-megabase-pair region in the donor hamster genome. These data indicate that the high expression of P-glycoprotein is the only alteration required to mediate multidrug resistance.

scholarly journals Chromosome-mediated gene transfer of multidrug resistance.

1986 ◽  
Vol 6 (11) ◽  
pp. 3785-3790 ◽  
Author(s):  
P Gros ◽  
D A Fallows ◽  
J M Croop ◽  
D E Housman
Keyword(s):  
Multidrug Resistance ◽  
Gene Transfer ◽  
Dna Sequences ◽  
Chinese Hamster ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Phenotypic Analysis ◽  
Susceptible Mouse ◽  
Resistant Phenotype ◽  
Multiple Copies

Multidrug resistance can be transferred from drug-resistant LZ Chinese hamster cells to drug-susceptible mouse LTA cells by chromosome-mediated gene transfer. Analysis of genomic DNA demonstrated the transfer of multiple copies of a DNA domain which is amplified in the donor multidrug-resistant cells. The transfer of 10 to 15 copies of the Chinese hamster gene was sufficient to produce a multidrug-resistant phenotype. Chromosome transferents exhibited overexpression of an mRNA of approximately 5 kilobases which has previously been demonstrated to be encoded by the amplified DNA domain of the donor LZ cells. Phenotypic analysis of individual clones selected in adriamycin showed the resistance to be pleiotropic. All clones tested demonstrated similar levels of cross-resistance to the drugs daunorubicin and colchicine. These results indicate that the DNA sequences transferred confer the complete multidrug-resistant phenotype on recipient cells and suggest that multidrug resistance is due to overexpression of the protein encoded by the 5-kilobase mRNA.

Chromosome-mediated gene transfer of multidrug resistance

1986 ◽  
Vol 6 (11) ◽  
pp. 3785-3790
Author(s):  
P Gros ◽  
D A Fallows ◽  
J M Croop ◽  
D E Housman
Keyword(s):  
Multidrug Resistance ◽  
Gene Transfer ◽  
Dna Sequences ◽  
Chinese Hamster ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Phenotypic Analysis ◽  
Susceptible Mouse ◽  
Resistant Phenotype ◽  
Multiple Copies

Multidrug resistance can be transferred from drug-resistant LZ Chinese hamster cells to drug-susceptible mouse LTA cells by chromosome-mediated gene transfer. Analysis of genomic DNA demonstrated the transfer of multiple copies of a DNA domain which is amplified in the donor multidrug-resistant cells. The transfer of 10 to 15 copies of the Chinese hamster gene was sufficient to produce a multidrug-resistant phenotype. Chromosome transferents exhibited overexpression of an mRNA of approximately 5 kilobases which has previously been demonstrated to be encoded by the amplified DNA domain of the donor LZ cells. Phenotypic analysis of individual clones selected in adriamycin showed the resistance to be pleiotropic. All clones tested demonstrated similar levels of cross-resistance to the drugs daunorubicin and colchicine. These results indicate that the DNA sequences transferred confer the complete multidrug-resistant phenotype on recipient cells and suggest that multidrug resistance is due to overexpression of the protein encoded by the 5-kilobase mRNA.

Localization of multidrug resistance-associated DNA sequences to human chromosome 7

1986 ◽  
Vol 12 (4) ◽  
pp. 415-420 ◽  
Author(s):  
A. Fojo ◽  
R. Lebo ◽  
N. Shimizu ◽  
J. E. Chin ◽  
I. B. Roninson ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Human Chromosome ◽  
Dna Sequences ◽  
Chromosome 7 ◽  
Human Chromosome 7
Sign in / Sign up

Export Citation Format

Share Document