EXPRESSION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN GENE IN REFRACTORY LYMPHOMA - QUANTITATION BY A VALIDATED POLYMERASE CHAIN-REACTION ASSAY

Previous work investigating the role of MDR-1 overexpression in relaps ed and refractory lymphoma led us to investigate a possible role for m ultidrug resistance-associated protein (MRP) as a cause of resistance in patients who did not overexpress MDR-1. A quantitative polymerase c hain reaction (PCR) method for measuring MRP expression was validated. Immunoblot analysis suggested that no major discrepancy was present b etween mRNA expression and protein levels. MRP levels were found to be independent of sample tumor content by immunophenotyping, suggesting that the presence of normal cells had no significant impact on measure ments of MRP expression. We evaluated MRP in 55 biopsy samples from 40 patients with refractory lymphoma enrolled on a trial of infusional c hemotherapy (EPOCH), Pre- and post EPOCH samples were available from 1 5 patients. MRP levels were also evaluated in 16 newly diagnosed, untr eated lymphoma patient samples. No significant difference in MRP mRNA expression was noted between pre- and post-EPOCH groups. Also, MRP lev els in the newly diagnosed patient samples were not significantly diff erent from either pre- or post-EPOCH groups. Two of 15 paired pre- and post-EPOCH patient samples exhibited overexpression of MRP after EPOC H chemotherapy, with measured increases of 10-fold and 18-fold. We con clude that MRP overexpression is not responsible for non-P-glycoprotei n (Pgp)-mediated drug resistance in the majority of these patients, al though it may be important in a subset of patients, Defining this subs et prospectively could aid in the development of clinical trials of MR P modulation in drug-resistant lymphoma. This is a US government work. There are no restrictions on its use.