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Expression of the multidrug resistance-associated protein gene in
refractory lymphoma: quantitation by a validated polymerase chain reaction
assay
Z Zhan, VA Sandor, E Gamelin, J Regis, B Dickstein, W Wilson, AT Fojo and SE Bates
National Institutes of Health, National Cancer Institute, Medicine Branch,
Bethesda, MD 20892, USA.
Previous work investigating the role of MDR-1 overexpression in relapsed
and refractory lymphoma led us to investigate a possible role for multidrug
resistance-associated protein (MRP) as a cause of resistance in patients
who did not overexpress MDR-1. A quantitative polymerase chain reaction
(PCR) method for measuring MRP expression was validated. Immunoblot
analysis suggested that no major discrepancy was present between 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 measurements of MRP expression.
We evaluated MRP in 55 biopsy samples from 40 patients with refractory
lymphoma enrolled on a trial of infusional chemotherapy (EPOCH). Pre- and
post-EPOCH samples were available from 15 patients. MRP levels were also
evaluated in 16 newly diagnosed, untreated lymphoma patient samples. No
significant difference in MRP mRNA expression was noted between pre- and
post-EPOCH groups. Also, MRP levels in the newly diagnosed patient samples
were not significantly different from either pre- or post-EPOCH groups. Two
of 15 paired pre- and post-EPOCH patient samples exhibited overexpression
of MRP after EPOCH chemotherapy, with measured increases of 10-fold and
18-fold. We conclude that MRP overexpression is not responsible for
non-P-glycoprotein (Pgp)-mediated drug resistance in the majority of these
patients, although it may be important in a subset of patients. Defining
this subset prospectively could aid in the development of clinical trials
of MRP modulation in drug-resistant lymphoma.
Volume 89,
Issue 10,
pp. 3795-3800,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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