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 radiotherapy in the treatment of cancer. To investigate this relationship, the CCRF-CEM (CEM) human T-cell leukaemia cell line was treated with fractionated gamma-radiation totalling 75 Gy (10 cycles of 1.5 Gy daily for 5 days). This produced the CEMRR subline which was 1.5-fold resistant to radiation compared with the parental CEM cells. The CEMRR subline was also resistant to daunorbicin, idarubicin and etoposide but not to paclitaxel, cis-platinum or chlorambucil. Treatment with 50 microM buthionine sulphoximine, an inhibitor of glutathione synthesis, reversed the daunorubicin resistance in the CEMRR subline. Multidrug resistance-associated protein (MRP) mRNA was 6-fold higher in the CEMRR subline than in the CEM cells, and there was no detectable expression of P-glycoprotein in either the CEM cells or the CEMRR subline. Treatment 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 CEMRR subline with similar treatment. We conclude that MRP is involved in the immediate response to radiation and it may account for the drug resistance that often develops following radiation treatment.
Harvie
R M
RM
Bill Walsh Cancer Research Laboratories, Clinical Oncology Department, Royal North Shore Hospital, St. Leonards, Australia.
Davey
M W
MW
Davey
R A
RA
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D019583:Dose Fractionation, Radiation; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology*; D005720:Gamma Rays; D006801:Humans; D007938:Leukemia / Q000628:therapy*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger / Q000032:analysis; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger