Circumvention of ara-C resistance by aphidicolin in blast cells from patients with AML

Treatment failure in AML is often attributed to P-glycoprotein-associated m ultidrug resistance. However, the importance of increased DNA repair in res istant cells is becoming more apparent. In order to investigate the ability of the DNA repair inhibitor aphidicolin to modulate drug resistance, we co ntinually exposed blasts cells, isolated from 22 patients with AML, to a va riety of agents +/- 15 muM aphidicolin for 48 hours. Cell survival was meas ured using the MTT assay. Overall, there was no significant effect of aphid icolin on sensitivity to daunorubicin, doxorubicin, etoposide or fludarabin e. However, there was a marked increase in sensitivity to ara-C with a medi an 4.75-fold increase overall (range 0.8-80-fold; P < 0.005). The effect of aphidicolin was significantly greater in blast cells found resistant in vi tro to ara-C (8.9-fold compared to 2.12-fold, P < 0.01). This observation w as further validated by the correlation between ara-C LC50 and extent of mo dulation effect (P < 0.05). Cells isolated from 10 cord blood samples were also tested in order to establish the haematological toxicity of combining ara-C and aphidicolin. The therapeutic index (LC50 normal cells/tumour cell s) for ara-C + aphidicolin was higher than that for ara-C alone suggesting no increased myelotoxicity for the combination. Increased cytotoxicity with out increased haematotoxicity makes the combination of ara-C plus aphidicol in ideal for inclusion in future clinical trials. (C) 2001 Cancer Research Campaign.