INCREASED MRP EXPRESSION IS ASSOCIATED WITH RESISTANCE TO RADIATION, ANTHRACYCLINES AND ETOPOSIDE IN CELLS TREATED WITH FRACTIONATED GAMMA-RADIATION

The failure of chemotherapy is often associated with the failure of ra diotherapy in the treatment of cancer, To investigate this relationshi p, the CCRF-CEM (GEM) human T-cell leukaemia cell line was treated wit h fractionated gamma-radiation totalling 75 Gy (10 cycles of 1.5 Gy da ily for 5 days), This produced the CEMRR subline which was 1.5-fold re sistant to radiation compared with the parental CEM cells, The CEMRR s ubline was also resistant to daunorubicin, idarubicin and etoposide bu t not to paclitaxel, cis-platinum or chlorambucil. Treatment with 50 m u M buthionine sulphoximine, an inhibitor of glutathione synthesis, re versed the daunorubicin resistance in the CEMRR subline, Multidrug res istance-associated protein (MRP) mRNA was 6-fold higher in the CEMRR s ubline than in the CEM cells, and there was no detectable expression o f P-glycoprotein in either the CEM cells or the CEMRR subline, Treatme nt of the CEM cells with 2 Gy of gamma-radiation caused an increase in MRP-mRNA within 4 hr which, by 24 hr, was greater than 5-fold that of the untreated CEM cells, No change in MRP mRNA was observed in the CE MRR subline with similar treatment, We conclude that MRP is involved i n the immediate response to radiation and it may account for the drug resistance that often develops following radiation treatment. (C) 1997 Wiley-Liss, Inc.