Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance.

Mickisch, G.; Merlino, Glenn; Galski, Hanan; Gottesman, Michael M.; Pastan, Ira

doi:10.1073/pnas.88.2.547

Cited by 141 publications

(67 citation statements)

References 23 publications

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“…The normal distribution of Pgp expression suggests that its physiological role may be to expel naturally occurring toxins from the cell (2). This hypothesis is consistent with the substrate specificity of P-gp that is highest against naturally occurring chemotherapeutic agents (30).…”

Section: Introductionsupporting

confidence: 71%

Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Gant¹,

Schrenk²,

Silverman³

et al. 1994

Environmental Health Perspectives

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Previously we have demonstrated that several xenobiotics can induce multidrug (mdr) gene expression in cultures of primary isolated hepatocytes.One of the best of these xenobiotic inducers in rat hepatocytes is 2-acetylaminofluorene (2-AAF), which induces mdr expression by an enhancement of mdr gene transcription. In all species studied to date, AAF is extensively and variously metabolized. In this study we have sought to determine if AAF per se or a metabolite is responsible for mediating the increase in mdr gene transcription and expression. This study demonstrates that AAF per se is not active, but that the effect of AAF we have observed on mdr gene transcription and expression in the rat is due to the formation of a reactive metabolite(s). Our data indicate that this reactive metabolite is probably N-acetoxy-2-aminofluorene or the sulfate ester of N-hydroxy-AAF. The requirement for the formation of one of these metabolites may explain the differences in species response to AAF, in terms of mdr gene expression, that we have observed. We hypothesize that the mechanism by which mdr gene transcription is increased in response to AAF involves a covalent interaction between a reactive metabolite and an mdr gene regulatory protein. Our current work is concerned with the exploration of this hypothesis. -Environ Health Perspect 102(Suppl 6): 209-212 (1994)

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Section: Introductionsupporting

confidence: 71%

Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Gant¹,

Schrenk²,

Silverman³

et al. 1994

Environmental Health Perspectives

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“…administration is striking because paclitaxel is an excellent P-gp substrate (24,25). Nonetheless, even with P-gp present, Mrp2 is an important determinant for the disposition of paclitaxel in vivo.…”

Section: Mdr1a/1bmentioning

confidence: 99%

Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics

Lagas¹,

Vlaming²,

Tellingen

et al. 2006

Clinical Cancer Research

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Purpose: P-glycoprotein (P-gp; ABCB1) efficiently transports lipophilic amphipathic drugs, including the widely used anticancer drug paclitaxel (Taxol). We found previously that human multidrug resistance protein 2 (MRP2; ABCC2) also transports paclitaxel in vitro, and although we expected that paclitaxel pharmacokinetics would be dominated by P-gp, the effect of Mrp2 was tested in vivo. Experimental Design: We generated and characterized Mdr1a/1b/Mrp2 À/À mice, allowing assessment of the distinct roles of Mrp2 and Mdr1a/1b P-gp in paclitaxel pharmacokinetics. Results: Surprisingly, the effect of Mrp2 on i.v. administration of paclitaxel was as great as that of P-gp. The area under plasma concentration-time curve (AUC) i.v. in both Mrp2À/À and Mdr1a/ 1b À/À mice was 1.3-fold higher than in wild-type mice, and in Mdr1a/1b/Mrp2 À/À mice, a 1.7-fold increase was found. In spite of this similar effect, Mrp2 and P-gp had mostly complementary functions in paclitaxel elimination. Mrp2 dominated the hepatobiliary excretion, which was reduced by 80% in Mrp2 À/À mice. In contrast, P-gp dominated the direct intestinal excretion, with a minor role for Mrp2. The AUC oral of paclitaxel was 8.5-fold increased by Mdr1a/1b deficiency but not affected by Mrp2 deficiency. However, in the absence of Mdr1a/1b P-gp, additional Mrp2 deficiency increased the AUC oral another 1.7-fold. Conclusions:Thus far, Mrp2 was thought to mainly affect organic anionic drugs in vivo. Our data show that Mrp2 can also be a major determinant of the pharmacokinetic behavior of highly lipophilic anticancer drugs, even in the presence of other efficient transporters.Variation in MRP2 activity might thus directly affect the effective exposure to paclitaxel, on i.v. administration, but also on oral administration, especially when P-gp activity is inhibited.

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“…The capability ofthe 5' untranslated regions of picornaviruses to direct internal translation initiation from bi-and polycistronic constructs has been reported recently (13)(14)(15) (9)(10)(11). In our study, increased drug concentrations select for cells that synthesize higher amounts of bicistronic transcript, influencing positively the expression of both, P-glycoprotein and GC.…”

Section: Discussionmentioning

confidence: 65%

“…The (8). The bone marrow of these mice was shown to be resistant to doxorubicin, taxol, VP-16, and other cytotoxic substrates of P-glycoprotein (8,9). Two recent reports demonstrate that the MDR] gene allows selection in vivo with taxol of mouse bone marrow cells transduced in vitro with an MDR] retrovirus (10,11).…”

mentioning

confidence: 99%

Drug-selected coexpression of human glucocerebrosidase and P-glycoprotein using a bicistronic vector.

Aran

Gottesman

Pastan

1994

Proc. Natl. Acad. Sci. U.S.A.

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Bicistronic cassettes under control of a single promoter have recently been suggested as useful tools for coordinate expression of two different foreign proteins in mammalian cells. Using the long 5' untranslated region of encephalomyocarditis virus as translational enhancer of the second gene, a bicistronic unit composed of cDNA for human P-glycoprotein [the product of the multidrug resistance gene, MDR1 (also called PGY1)] as selectable marker and cDNA for human glucocerebrosidase (GC; EC 3.2.1.45) (a membrane-associated lysosomal hydrolase) was constructed. NIH 3T3 cells transfected with a Harvey murine sarcoma virus retroviral vector carrying this bicistronic cassette (pHaMCG) express active P-glycoprotein and GC and expression of both proteins augments coordinately with selection for increased colchicine resistance. Percoll gradient analysis of homogenates showed that GC was targeted to the lysosomal fraction. The ability to select for expression of GC with natural product drugs after introduction of the pHaMCG retroviral vector may be useful in gene therapy strategies for Gaucher disease.

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Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance.

Cited by 141 publications

References 23 publications

Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Requirement for Metabolic Activation of Acetylaminofluorene to Induce Multidrug Gene Expression

Multidrug Resistance Protein 2 Is an Important Determinant of Paclitaxel Pharmacokinetics

Drug-selected coexpression of human glucocerebrosidase and P-glycoprotein using a bicistronic vector.

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