Evaluation of Prognostic Factors, including Duodenal P-Glycoprotein Expression, in Canine Chronic Enteropathy

The aim of this retrospective single-center study was to evaluate which factors, including expression of P-glycoprotein (P-gp), a membrane-bound protein involved in multiple drug resistance, could predict the response to treatment in canine immunosuppressant-responsive enteropathy (IRE). Dogs with IRE or non-responsive enteropathy (NRE) that were examined from 2005 to 2014 were included and were divided into two groups (IRE vs. NRE). Signalment, history, and clinical and laboratory findings were collected. P-glycoprotein immunohistochemistry was carried out on duodenal biopsies of both groups stored in our biobank, and immunophenotyping and molecular clonality were performed on the NRE samples. Ninety-two dogs were enrolled, 73 IRE (79.3%) and 19 NRE (20.7%), with a prevalence of pure breed (78.3% vs. 21.7%) and male dogs (p < 0.001). Factors associated with a worse prognosis were previous treatment with steroids (p = 0.033) and lower serum total protein concentration (p = 0.005). Clonality testing on the NRE duodenal biopsies showed 5/16 clonal responses, assuming a latent undiagnosed lymphoma as a possible cause of the NRE.

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Chemosensitizing multiple drug resistance of human carcinoma by bicyclol involves attenuated P-glycoprotein, GST-P and Bcl-2

Cancer Biology & Therapy ◽

10.4161/cbt.5.5.2655 ◽

2006 ◽

Vol 5 (5) ◽

pp. 536-543 ◽

Cited By ~ 14

Author(s):

Bing Zhu ◽

Geng Tao Liu ◽

Yong Mei Zhao ◽

Ruo Su Wu ◽

Samuel J Strada

Keyword(s):

Drug Resistance ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Human Carcinoma ◽

P Glycoprotein

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N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene), a chemopotentiating agent with hormetic effects on DNA synthesis in vitro, may improve survival in patients with metastatic breast cancer

Human & Experimental Toxicology ◽

10.1177/0960327108090751 ◽

2008 ◽

Vol 27 (2) ◽

pp. 143-147 ◽

Cited By ~ 5

Author(s):

Lorne J Brandes

Keyword(s):

Breast Cancer ◽

Dna Synthesis ◽

Cancer Cells ◽

Multiple Drug Resistance ◽

Metastatic Breast ◽

Chemotherapeutic Agents ◽

Multiple Drug ◽

Glycoprotein P ◽

Hormetic Effect

N,N-diethyl-2-[4-(phenylmethyl) phenoxy] ethanamine (DPPE; tesmilifene) is a novel anti-histaminic and chemopotentiating agent that has a hormetic effect on DNA synthesis in MCF (Michigan Cancer Foundation)-7 human breast cancer cells in vitro and stimulates the growth of experimental tumors in rodents. In a prospectively randomized phase three trial (NCIC MA.19), 152 patients who were co-administered DPPE and doxorubicin survived 50% longer ( P < 0.03) than 153 patients who were administered the same dose and schedule of doxorubicin alone. At clinically relevant in vitro concentrations that do not inhibit the P-glycoprotein (P-gp) pump, DPPE selectively sensitizes the cancer cells that express the multiple drug resistance phenotype, making them more susceptible to the cytotoxic effects of chemotherapeutic agents, including anthracyclines and taxanes. Based on its previously demonstrated interaction with histamine at CYP3A4, a P450 that metabolizes arachidonic acid, and its induction of high levels of prostacyclin in the gut of rodents, modulation by DPPE of the intracellular concentration of arachidonate products, such as hydroxyeicosatetraeinoic acids, implicated in increased cancer cell proliferation and metastasis, is postulated.

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Canine mammary carcinoma cell line are resistant to chemosensitizers: verapamil and cyclosporin A

Polish Journal of Veterinary Sciences ◽

10.2478/pjvs-2014-0002 ◽

2014 ◽

Vol 17 (1) ◽

pp. 9-17 ◽

Cited By ~ 5

Author(s):

M. Król ◽

K.M. Pawłowski ◽

K. Majchrzak ◽

J. Mucha ◽

T. Motyl

Keyword(s):

Cyclosporin A ◽

Cell Lines ◽

Lung Metastases ◽

Multiple Drug Resistance ◽

Clinical Problem ◽

Multiple Drug ◽

Glycoprotein P ◽

Membrane Pump ◽

Over Expression ◽

Cancer Chemoresistance

Abstract Cancer chemotherapy can fail in many ways. One of the most significant is the development of multiple drug resistance (MDR), which constitutes a serious clinical problem. The development of MDR relates to the expression of a major membrane pump, P-glycoprotein (P-gp). Thus, currently one of the goals of experimental and clinical oncology is to decrease its activity. So far, many different P-gp inhibitors are available, but their efficacy is still questionable and requires further study. The aim of our study was to assess an impact of classical P-gp inhibitors (verapamil and cyclosporin A) in the reversion of multidrug resistance in canine mammary cancer cells. We used two cell lines isolated from mammary tumors and two cell lines isolated from their lung metastases. All of them showed P-gp over-expression confirmed using Real-time rt-PCR, Skan^R screening station and confocal microscopy. The FACS analysis showed that in three of the examined cell lines, treatment with verpamil/cyclosporin A was ineffective to reverse cancer chemoresistance. However, more studies in this field are required.

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In Situ Biochemical Demonstration That P-Glycoprotein Is a Drug Efflux Pump with Broad Specificity

The Journal of Cell Biology ◽

10.1083/jcb.148.5.863 ◽

2000 ◽

Vol 148 (5) ◽

pp. 863-870 ◽

Cited By ~ 30

Author(s):

Yu Chen ◽

Sanford M. Simon

Keyword(s):

Fluorescent Protein ◽

Efflux Pump ◽

Multiple Drug Resistance ◽

Living Cells ◽

Drug Accumulation ◽

Multiple Drug ◽

Gfp Expression ◽

Active Efflux ◽

P Glycoprotein ◽

Wide Range

While P-glycoprotein (Pgp) is the most studied protein involved in resistance to anti-cancer drugs, its mechanism of action is still under debate. Studies of Pgp have used cell lines selected with chemotherapeutics which may have developed many mechanisms of resistance. To eliminate the confounding effects of drug selection on understanding the action of Pgp, we studied cells transiently transfected with a Pgp-green fluorescent protein (GFP) fusion protein. This method generated a mixed population of unselected cells with a wide range of Pgp-GFP expression levels and allowed simultaneous measurements of Pgp level and drug accumulation in living cells. The results showed that Pgp-GFP expression was inversely related to the accumulation of chemotherapeutic drugs. The reduction in drug concentration was reversed by agents that block multiple drug resistance (MDR) and by the UIC2 anti-Pgp antibody. Quantitative analysis revealed an inverse linear relationship between the fluorescence of Pgp-GFP and MDR dyes. This suggests that Pgp levels alone limit drug accumulation by active efflux; cooperativity between enzyme, substrate, or inhibitor molecules is not required. Additionally, Pgp-GFP expression did not change cellular pH. Our study demonstrates the value of using GFP fusion proteins for quantitative biochemistry in living cells.

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Different types of non-P-glycoprotein mediated multiple drug resistance in children with relapsed acute lymphoblastic leukaemia

British Journal of Cancer ◽

10.1038/bjc.1992.146 ◽

1992 ◽

Vol 65 (5) ◽

pp. 691-697 ◽

Cited By ~ 43

Author(s):

R Pieters ◽

T Hongo ◽

AH Loonen ◽

DR Huismans ◽

HJ Broxterman ◽

...

Keyword(s):

Drug Resistance ◽

Acute Lymphoblastic Leukaemia ◽

Lymphoblastic Leukaemia ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

P Glycoprotein ◽

Different Types

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DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression.

Molecular and Cellular Biology ◽

10.1128/mcb.2.8.881 ◽

1982 ◽

Vol 2 (8) ◽

pp. 881-889 ◽

Cited By ~ 115

Author(s):

P G Debenham ◽

N Kartner ◽

L Siminovitch ◽

J R Riordan ◽

V Ling

Keyword(s):

Drug Resistance ◽

Plasma Membranes ◽

Multiple Drug Resistance ◽

Chinese Hamster ◽

Surface Glycoprotein ◽

Multiple Drug ◽

Cell Surface Glycoprotein ◽

Resistance Phenotype ◽

P Glycoprotein ◽

Wide Range

Colchicine-resistant Chinese hamster ovary (CHO) cell mutants whose resistance results from reduced drug permeability have been isolated previously in our laboratories. This reduced permeability affects a wide range of unrelated drugs, resulting in the mutants displaying a multiple drug resistance phenotype. A 170,000-dalton cell surface glycoprotein (P-glycoprotein) was identified, and its expression appears to correlate with the degree of resistance. In this study we were able to confer the multiple drug resistance phenotype on sensitive mouse L cells by DNA-mediated gene transfer of DNA obtained from the colchicine-resistant mutants. P-glycoprotein was detected in plasma membranes of these DNA transformants by staining with an antiserum raised against membranes of mutant CHO cells. These results are consistent with a causal relationship between P-glycoprotein expression and the multiple drug resistance phenotype.

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DNA-mediated transfer of multiple drug resistance and plasma membrane glycoprotein expression

Molecular and Cellular Biology ◽

10.1128/mcb.2.8.881-889.1982 ◽

1982 ◽

Vol 2 (8) ◽

pp. 881-889

Author(s):

P G Debenham ◽

N Kartner ◽

L Siminovitch ◽

J R Riordan ◽

V Ling

Keyword(s):

Drug Resistance ◽

Plasma Membranes ◽

Multiple Drug Resistance ◽

Chinese Hamster ◽

Surface Glycoprotein ◽

Multiple Drug ◽

Cell Surface Glycoprotein ◽

Resistance Phenotype ◽

P Glycoprotein ◽

Wide Range

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Co-amplification of double minute chromosomes, multiple drug resistance, and cell surface P-glycoprotein in DNA-mediated transformants of mouse cells

Molecular and Cellular Biology ◽

10.1128/mcb.4.3.500-506.1984 ◽

1984 ◽

Vol 4 (3) ◽

pp. 500-506

Author(s):

S M Robertson ◽

V Ling ◽

C P Stanners

Keyword(s):

Drug Resistance ◽

Multiple Drug Resistance ◽

Resistant Mutant ◽

Genetic System ◽

Cell Membrane Permeability ◽

Multiple Drug ◽

P Glycoprotein ◽

Double Minute ◽

Mouse Cells ◽

Double Minute Chromosomes

A genetic system comprised of mammalian cell mutants which demonstrate concomitant resistance to a number of unrelated drugs has been described previously. The resistance is due to reduced cell membrane permeability and is correlated with the presence of large amounts of a plasma membrane glycoprotein termed P-glycoprotein. This system could represent a model for multiple drug resistance which develops in cancer patients treated with chemotherapeutic drugs. We demonstrate here that the multiple drug resistance phenotype can be transferred to mouse cells with DNA from a drug-resistant mutant and then amplified quantitatively by culture in media containing increasing concentrations of drug. The amount of P-glycoprotein was correlated directly with the degree of drug resistance in the transformants and amplified transformants. In addition, the drug resistance and expression of P-glycoprotein of the transformants were unstable and associated quantitatively with the number of double minute chromosomes. We suggest that the gene for multiple drug resistance and P-glycoprotein is contained in these extrachromosomal particles and is amplified by increases in double minute chromosome number. The potential use of this system for manipulation of mammalian genes in general is discussed.

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Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation

Sarcoma ◽

10.1155/2008/874075 ◽

2008 ◽

Vol 2008 ◽

pp. 1-14 ◽

Cited By ~ 10

Author(s):

Flemming Brandt Sorensen ◽

Kenneth Jensen ◽

Michael Vaeth ◽

Henrik Hager ◽

Anette Mariane Daa Funder ◽

...

Keyword(s):

Drug Resistance ◽

Proliferative Activity ◽

Multiple Drug Resistance ◽

Multiple Drug ◽

Prognostic Impact ◽

Prognostic Variables ◽

P53 Expression ◽

P Glycoprotein ◽

Sufficient Power ◽

Mib 1

Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma.Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated regarding angiogenesis (CD34), proliferative activity (MIB-1), and the expression of p53 and MDR (P-glycoprotein (Pgp); clones JSB-1, C494, and MRK16). Quantitative and semiquantitative scores of immunoreactive cells were analyzed statistically along with retrospectively obtained clinicopathologic variables.Results. Chemotherapy reduced the rate of amputations (P=.00002). The Pgp was overexpressed (score ≥2) in 48% of the primary, diagnostic biopsies, and high Pgp correlated with high Pgp in postsurgical specimens (P=.003). In contrast, no such associations were disclosed for estimates of angiogenesis (P=.64) and p53 (P>.32), whereas the MIB-1 index was reduced in the post-chemotherapy specimens (P=.02). The overall, disease-specific survival was 47%, increasing to 54% in patients receiving pre-operative chemotherapy. Statistical analyses showed prognostic impact exclusively by patient age and type of osteosarcoma.Discussion. The studied series of patients documented already prior to the chemotherapy era, a rather excellent survival and estimates of angiogenesis, proliferation, p53, and Pgp expressions, did not demonstrate sufficient power to serve as predictors of treatment response or survival.

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