Dexrazoxane significantly impairs the induction of doxorubicin resistance in the human leukaemia line, K562

Dexrazoxane combined with doxorubicin (+ 5-fluorouracil + cyclophosphamide - the FAC regime) leads to a significant decrease in doxorubicin cardiotoxi city and a significant increase in median survival time for patients with a dvanced breast cancer responsive to FAC. The reason for this increase in su rvival may be due to interference with the mechanism involved in the emerge nce of multidrug resistance (MDR). In order to test this hypothesis, we ind uced resistance to doxorubicin in the K562 cell line by growing cells in in creasing concentrations of doxorubicin (10-30 nM) in the presence and absen ce of dexrazoxane (20 nM). The doxorubicin sensitivity of all resultant sub lines was measured using the MTT assay. Flow cytometry was used to assess t he MDRI phenotype, measuring P-glycoprotein expression with MRK 16 antibody and drug accumulation in the presence and absence of PSC 833 for functiona l P-glycoprotein. Long-term growth in doxorubicin increased the cellular re sistance (IC50) of K562 cells in a concentration-dependent manner (r(2) = 0 .908). Doxorubicin resistance was not induced in the presence of dexrazoxan e (P < 0.0001) for several months. In parallel, the expression of functiona l P-glycoprotein was delayed after concomitant addition of dexrazoxane to t he selecting medium (P < 0.001). Dexrazoxane did not act as a conventional modulator of P-glycoprotein. These results suggest that dexrazoxane may del ay the development of MDR1, thus allowing responders to the FAC regime to c ontinue to respond. (C) 2001 Cancer Research Campaign.