Using the National Cancer Institute Anticancer Drug Screen to Assess the Effect of MRP Expression on Drug Sensitivity Profiles

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Vol. 54, Issue 5, 802-814, November 1998

Using the National Cancer Institute Anticancer Drug Screen to Assess the Effect of MRP Expression on Drug Sensitivity Profiles

M. Alvarez, R. Robey, V. Sandor, K. Nishiyama, Y. Matsumoto, K. Paull, S. Bates, and T. Fojo

Departamento Hematologia-Oncologia, Universidad Catolica de Chile, Santiago, Chile (M.A.), Medicine Branch, Division of Clinical Sciences, National Cancer Institute (R.R., V.S., K.N., Y.M., S.B., T.F.), and Information Technology Branch, Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 (K.P.)

The MRP gene contributes to one form of multidrug resistance. To identify drugs interacting with MRP, we measured MRP mRNAexpression by quantitative PCR in 60 cell lines of the NationalCancer Institute Anticancer Drug Screen. Expression was detectedin all cell lines (highest in lung carcinomas and central nervoussystem tumors) with a range of 14-fold. A mean graph of MRP mRNAlevels was constructed to determine Pearson correlation coefficients(PCCs) with mean graphs of >40,000 compounds using the COMPAREanalysis. Only 20 compounds had PCCs of $>=$ 0.500. The PCCs for VP-16,doxorubicin, and vincristine were 0.008, 0.13, and 0.257, respectively.Initially, 36 compounds with PCCs of $>=$ 0.428 were analyzed usingtwo MRP-overexpressing cell lines; low levels of cross-resistancewas demonstrated for 23 compounds (1.3-9.4-fold). Twenty-fourcompounds also were available for further studies. Using a fluorescenceactivated cell sorter assay to measure competition of calceinefflux from MRP-overexpressing cells, 10 compounds were foundto increase calcein retention by $>=$ 2-fold. Ten compounds also wereable to reduce ATP-dependent [³H]LTC₄ transport into vesicles from MRP-overexpressing cells.These results contrast with previous studies with MDR-1 in whichhigh correlations were found and confirmed for a large numberof compounds. Although other assays may be more revealing, inthese unselected cell lines, MRP mRNA expression was a poor predictorof drug sensitivity. This raises the possibility that other factors,including conjugating enzymes, glutathione levels, or other transporters,confound the MRPeffect.

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