This report presents quantitative analysis of the synergistic interaction of azidothymidine (AZT) and cladribine (CdA) in human H9-lymphoid cell lines sensitive and resistant to AZT (H9-araC cells). H9-araC cells obtained by cultivation of H9 cells in the presence of 0.5 muM arabinosyl-cytosine (araC) had lower deoxycytidine kinase and thymidine kinase (TK) activities and expressed cross-resistance to araC and AZT. The IC50 values of AZT and CdA were calculated by using median-effect analysis and CalcuSyn software. The IC50 values were 0.44 and 0.82 muM for CdA and 67.8 and 30,310 muM for AZT in H9 and H9-araC cells, respectively. However, when the drugs were used in combination the IC50 values of CdA and AZT were reduced to 0.12 and 15.5 muM in H9 cells and to 0.19 and 24.9 muM in H9-araC cells, respectively. Calculation of dose reduction index (DRI) indicated that at 50-90% growth inhibition level, the combination of the drugs caused 3.6-5.8-and 4.1-11.5-fold reduction in the dose of CdA and 4.4-37.6- and >1000-fold reduction in the dose of AZT in H9 and H9-araC cells, respectively. The combination index (CI) values simulated from these data suggested synergistic to very strong synergistic lymphocytotoxic effects of AZT combined with CdA. These findings suggest the potential usefulness of a double-targeted approach for designing efficacious therapeutics for the kinase deficient drug resistant tumors. (C) 2004 Elsevier Inc. All rights reserved.