Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia

1989 ◽  
Vol 9 (10) ◽  
pp. 4357-4363
Author(s):  
H Galski ◽  
M Sullivan ◽  
M C Willingham ◽  
K V Chin ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Transgenic Mice ◽  
Bone Marrow Cells ◽  
Efflux Pump ◽  
Multidrug Resistance Gene ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Leukocyte Counts ◽  
Actin Promoter

The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly expressed in bone marrow and spleen. Immunofluorescence localization studies showed that P-glycoprotein was present on bone marrow cells. Furthermore, leukocyte counts of the transgenic mice treated with daunomycin did not fall, indicating that their bone marrow was resistant to the cytotoxic effect of the drug. Since bone marrow suppression is a major limitation to chemotherapy, these transgenic mice should serve as a model to determine whether higher doses of drugs can cure previously unresponsive cancers.

scholarly journals Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia.

1989 ◽  
Vol 9 (10) ◽  
pp. 4357-4363 ◽  
Author(s):  
H Galski ◽  
M Sullivan ◽  
M C Willingham ◽  
K V Chin ◽  
M M Gottesman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Transgenic Mice ◽  
Bone Marrow Cells ◽  
Efflux Pump ◽  
Multidrug Resistance Gene ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Leukocyte Counts ◽  
Actin Promoter

The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly expressed in bone marrow and spleen. Immunofluorescence localization studies showed that P-glycoprotein was present on bone marrow cells. Furthermore, leukocyte counts of the transgenic mice treated with daunomycin did not fall, indicating that their bone marrow was resistant to the cytotoxic effect of the drug. Since bone marrow suppression is a major limitation to chemotherapy, these transgenic mice should serve as a model to determine whether higher doses of drugs can cure previously unresponsive cancers.

scholarly journals Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1087-1093 ◽  
Author(s):  
GH Mickisch ◽  
I Aksentijevich ◽  
PV Schoenlein ◽  
LJ Goldstein ◽  
H Galski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Transgenic Mice ◽  
Dose Escalation ◽  
Blot Analysis ◽  
Messenger Rna ◽  
Bone Marrow Cells ◽  
Selective Advantage ◽  
Mdr1 Gene ◽  
Human Mdr1

Abstract Many human cancers that are initially responsive to chemotherapy eventually fail to respond to treatment. For some drugs, dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow (BM) limit cytotoxic therapy. Approaches to prevent or circumvent BM toxicity are therefore a high priority of research on dose escalation protocols. In this study, we have transplanted BM cells from transgenic mice that constitutively express physiologic amounts of a functional human multidrug resistance (MDR1) cDNA to lethally irradiated C57BL/6 x SJL F1 mice (n = 36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and BM specimens as indicated by Southern blot analysis, and expressed MDR1 messenger RNA in BM samples as detected by slot blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal BM were drug sensitive. Finally, the chemoprotection afforded by the MDR1 gene could readily be reversed by adding chemosensitizers such as cyclosporin A and R-verapamil to chemotherapy. Hence, it appears that BM cells expressing the human MDR1 gene maintain this function after transplantation to host animals for a minimum of 10 months, and confer multidrug resistance to these BM recipients. This selective advantage conferred by expression of the MDR1 cDNA suggests a strategy for the use of MDR1 gene therapy in cancer chemotherapy and for the introduction of otherwise nonselectable genes into BM.

Expression of multidrug resistance gene mdr1 mRNA in a subset of normal bone marrow cells

1992 ◽  
Vol 81 (2) ◽  
pp. 145-152 ◽  
Author(s):  
Jean-Pierre Marie ◽  
Nathalie A. Brophy ◽  
Mohamed N. Ehsan ◽  
Yukoh Aihara ◽  
Named A. Mohamed ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Resistance Gene ◽  
Bone Marrow Cells ◽  
Normal Bone Marrow ◽  
Multidrug Resistance Gene ◽  
Normal Bone ◽  
Mdr1 Mrna ◽  
Marrow Cells

scholarly journals Transplantation of bone marrow cells from transgenic mice expressing the human MDR1 gene results in long-term protection against the myelosuppressive effect of chemotherapy in mice

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1087-1093 ◽  
Author(s):  
GH Mickisch ◽  
I Aksentijevich ◽  
PV Schoenlein ◽  
LJ Goldstein ◽  
H Galski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multidrug Resistance ◽  
Transgenic Mice ◽  
Dose Escalation ◽  
Blot Analysis ◽  
Messenger Rna ◽  
Bone Marrow Cells ◽  
Selective Advantage ◽  
Mdr1 Gene ◽  
Human Mdr1

Many human cancers that are initially responsive to chemotherapy eventually fail to respond to treatment. For some drugs, dose escalation that may be required for a cure cannot be achieved because sensitive tissues such as bone marrow (BM) limit cytotoxic therapy. Approaches to prevent or circumvent BM toxicity are therefore a high priority of research on dose escalation protocols. In this study, we have transplanted BM cells from transgenic mice that constitutively express physiologic amounts of a functional human multidrug resistance (MDR1) cDNA to lethally irradiated C57BL/6 x SJL F1 mice (n = 36). From 6 weeks to 10 months after the transplant, all animals contained MDR1 DNA in spleen and BM specimens as indicated by Southern blot analysis, and expressed MDR1 messenger RNA in BM samples as detected by slot blot analysis. In addition, these animals were resistant to the myelosuppressive effect of doxorubicin, daunomycin, taxol, vinblastine, vincristine, etoposide, and actinomycin D, whereas control animals that were reconstituted with normal BM were drug sensitive. Finally, the chemoprotection afforded by the MDR1 gene could readily be reversed by adding chemosensitizers such as cyclosporin A and R-verapamil to chemotherapy. Hence, it appears that BM cells expressing the human MDR1 gene maintain this function after transplantation to host animals for a minimum of 10 months, and confer multidrug resistance to these BM recipients. This selective advantage conferred by expression of the MDR1 cDNA suggests a strategy for the use of MDR1 gene therapy in cancer chemotherapy and for the introduction of otherwise nonselectable genes into BM.

scholarly journals Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues

2020 ◽  
Vol 13 (12) ◽  
pp. 453
Author(s):  
Małgorzata Anna Marć ◽  
Annamária Kincses ◽  
Bálint Rácz ◽  
Muhammad Jawad Nasim ◽  
Muhammad Sarfraz ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Treatment ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Positive Control ◽  
Biological Evaluation ◽  
Glycoprotein P ◽  
Drug Candidates ◽  
P Glycoprotein ◽  
Efflux Pump Inhibitors

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1–3) or a bioisosteric analogue core (compounds 4–6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

Cellular Characterization of Multidrug Resistance P-glycoprotein, Alpha Fetoprotein, and Neovascular Endothelium-Associated Antigens in Canine Hepatocellular Carcinoma and Cirrhotic Liver

2007 ◽  
Vol 44 (5) ◽  
pp. 600-606 ◽  
Author(s):  
R. E. Tashbaeva ◽  
D.-N. Hwang ◽  
G.-S. Song ◽  
N.-H. Choi ◽  
J.-H. Lee ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Multidrug Resistance ◽  
Alpha Fetoprotein ◽  
Multidrug Resistance Gene ◽  
Glycoprotein P ◽  
Endothelial Markers ◽  
Hepatic Diseases ◽  
P Glycoprotein ◽  
Cd34 Expression

P-glycoprotein (P-gp), which is encoded by the multidrug resistance gene (MDR-1); alpha fetoprotein (AFP); and vascular endothelium-associated antigens are well-known markers for human and canine hepatic diseases. We obtained liver tissues from 5 dogs with hepatocellular carcinoma (HCC) and 12 dogs with cirrhosis, and we performed histopathologic and immunohistochemical evaluations using anti-P-gp, anti-AFP, anti-CD31, and anti-CD34 antibodies. P-gp was expressed at higher levels in HCC than in cirrhotic livers ( P < .01), and was most commonly localized in biliary canaliculi and small ductuli. AFP was localized mainly in the cytoplasm in HCC ( P < .01) and in a few cases of cirrhosis. In both HCC and cirrhosis, the AFP-positive cells were morphologically similar to normal hepatocytes and showed an even cytoplasmic distribution of AFP. The endothelial markers CD31 and CD34 were used to investigate vascular distribution. CD31 was expressed strongly in the portal area and parenchyma in HCC, but it was rarely observed in the parenchyma in cirrhosis. CD34 expression could not be detected in both HCC and cirrhosis. This study constitutes the first comprehensive study of P-gp, AFP, and endothelial markers in canine HCC and cirrhosis. The importance of these markers in HCC and cirrhosis in dogs was demonstrated and provides a more accurate basis for a definitive diagnosis of HCC and cirrhosis in dogs.

Actin disruption inhibits endosomal traffic of P-glycoprotein-EGFP and resistance to daunorubicin accumulation

2007 ◽  
Vol 292 (4) ◽  
pp. C1543-C1552 ◽  
Author(s):  
Dong Fu ◽  
Basil D. Roufogalis
Keyword(s):  
Plasma Membrane ◽  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Efflux Pump ◽  
Early Endosome ◽  
Glycoprotein P ◽  
Intracellular Traffic ◽  
Functional Studies ◽  
P Glycoprotein ◽  
Green Fluorescent

Intracellular traffic of human P-glycoprotein (P-gp), a membrane transporter responsible for multidrug resistance in cancer chemotherapy, was investigated using a P-gp and enhanced green fluorescent fusion protein (P-gp-EGFP) in human breast cancer MCF-7 cells. The stably expressed P-gp-EGFP from a clonal cell population was functional as a drug efflux pump, as demonstrated by the inhibition of daunorubicin accumulation and the conferring of resistance of the cells to colchicine and daunorubicin. Colocalization experiments demonstrated that a small fraction of the total P-gp-EGFP expressed was localized intracellularly and was present in early endosome and lysosome compartments. P-gp-EGFP traffic was shown to occur via early endosome transport to the plasma membrane. Subsequent movement of P-gp-EGFP away from the plasma membrane occurred by endocytosis to the early endosome and lysosome. The component of the cytoskeleton responsible for P-gp-EGFP traffic was demonstrated to be actin rather than microtubules. In functional studies it was shown that in parallel with the interruption of the traffic of P-gp-EGFP, cellular accumulation of the P-gp substrate daunorubicin was increased after cells were treated with actin inhibitors, and cell proliferation was inhibited to a greater extent than in the presence of daunorubicin alone. The actin dependence of P-gp traffic and the parallel changes in cytotoxic drug accumulation demonstrated in this study delineates the pathways of P-gp traffic and may provide a new approach to overcoming multidrug resistance in cancer chemotherapy.

Co-delivery of doxorubicin and the traditional Chinese medicine quercetin using biotin–PEG2000–DSPE modified liposomes for the treatment of multidrug resistant breast cancer

RSC Advances ◽  
2016 ◽  
Vol 6 (114) ◽  
pp. 113173-113184 ◽  
Author(s):  
Jiulong Zhang ◽  
Yue Luo ◽  
Xiufeng Zhao ◽  
Xiaowei Li ◽  
Kexin Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multidrug Resistance ◽  
Chinese Medicine ◽  
Cancer Therapy ◽  
Traditional Chinese Medicine ◽  
Efflux Pump ◽  
Multidrug Resistant ◽  
Glycoprotein P ◽  
P Glycoprotein

At present, multidrug resistance (MDR) in cancer therapy is an international problem, which is caused mostly by the overexpressed P-glycoprotein (P-gp) efflux pump.

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