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Increased Resistance to Anticancer Therapy of Mouse Cells Lacking the Poly(ADP-ribose) Polymerase Attributable to Up-Regulation of the Multidrug Resistance Gene Product P-Glycoprotein¹

Gabriele Wurzer, Zdenko Herceg and Józefa Wsierska-Gdek²

Institute of Cancer Research, University of Vienna, A-1090 Vienna, Austria [G. W., J. W-G.], and International Agency for Research on Cancer, 69372 Lyon, France [Z. H.]

Mouse embryo fibroblasts lacking poly(ADP-ribose) polymerase (PARP)-1 express a barely detectable level of wild-type (wt) p53 protein. Doxorubicin at concentrations activating wt p53 in normal mouse embryo fibroblasts failed to induce it in mutant cells. wt p53 was only activated in response to a 10-fold higher doxorubicin dose. Treatment with higher doxorubicin concentrations was cytotoxic for normal but not for PARP-1 -/- cells. The latter was also resistant to other anticancer agents. The increased resistance of mutant cells to drugs resembled a unique phenomenon known as multidrug resistance (MDR). Interestingly, the MDR gene product P-glycoprotein was clearly up-regulated in PARP-1-deficient cells as compared with normal counterparts. Pretreatment with verapamil reversed the MDR phenotype.

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