Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas.

Abstract

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development ofMDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a wellstudied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3-to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a >80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.

Resistance of MCF7 human breast carcinoma cells to TNF-induced cell death is associated with loss of p53 function

“…The TNF resistance exhibited by MCF7/R-A1 and MCF7/Adr cells was not due to a lack of TNF receptor expression Zyad et al, 1994). Since MCF7/Adr cells exhibit the classical multidrug resistance (MDR) phenotype associated with overexpression of the Pglycoprotein, a membrane-associated drug e ux pump coded by the MDR1 gene (Fairchild et al, 1987), MDR1-transfected MCF7 cells (MCF7/MDR1) were also included in this study. As shown in Figure 1, MCF7/R-A1 and MCF7/Adr cells are highly resistant to the cytotoxic e ects of TNF compared to parental MCF7 and MCF7/MDR1 cells which are very sensitive to TNF-induced cytotoxicity.…”

“…TNF-resistant MCF7/ R-A1 cells were derived from the TNF-sensitive MCF7 after continuous exposure to increasing doses of recombinant TNF-a (Cai et al, 1996). MCF7/Adr cells were obtained by continuous exposure of MCF7 cells to increasing concentrations of adriamycin (Fairchild et al, 1987). MCF7/MDR1 cells (Clone 10.3, kindly provided by Dr R Clarke, Lombardi Cancer Research Centre, Washington) show a stable MDR phenotype in vitro and were obtained by infection of MCF7 cells with pHaMDR1/A retrovirus leading to constitutive expression of the MDR1 gene product.…”

Membrane microparticles mediate transfer of P-glycoprotein to drug sensitive cancer cells

“…Induction of the MDR1 gene has been earlier shown to occur after exposure to various stresses, including carcinogens, cocarcinogens, 31,32 antineoplastic agents, 33 differentiating agents, 34 protein kinase C activators 35 or heat shock. 36 MP incubation with drug-sensitive CCRF-CEM (MDR À ) cells may itself constitute a form of 'stress' resulting in an increase in transcription.…”

Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase π gene expression in primary and relapsed state adult and childhood leukaemias

“…Only three of the acute leukaemias examined in this work (ALL 5, ALL 7, ALL 13) are in remission at present, all of which showed distinct expression of the drug transporter gene, however (Table II). Recently, a coincidence of the absence of mdrl gene expresssion determined by PCR in untreated nonlymphocytic leukaemias and the remission frequency observed for this type of leukaemia was found (Noonan et al, 1990 (Fairchild et al, 1987;Burt & Thorgeirsson, 1988), after gestation in the endometrium of mice (Arceci et al, 1988), and by differentiating agents in a colon carcinoma cell line (Mickley et al, 1989). Moreover, we showed an increase of resistance and mdrl mRNA levels within 72 h in a multidrug-resistant CCRF-CEM subline (Gekeler et al, 1988), and more recently in the parental cell line CCRF-CEM (Noller et al, 1991) after treatment of the cells with actinomycin D. In all these cases the mdrl gene was expressed prior to the treatment albeit at distinctly lower levels.…”