2-Chloro-2 ′-deoxyadenosine synergistically enhances azidothymidine cytotoxicity in azidothymidine resistant T-lymphoid cells

Abstract

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 μM arabinosyl-cytosine (araC) had lower deoxycytidine kinase and thymidine kinase (TK) activities and expressed cross-resistance to araC and AZT. The IC 50 values of AZT and CdA were calculated by using median-effect analysis and CalcuSyn software. The IC 50 values were 0.44 and 0.82 μM for CdA and 67.8 and 30,310 μM for AZT in H9 and H9-araC cells, respectively. However, when the drugs were used in combination the IC 50 values of CdA and AZT were reduced to 0.12 and 15.5 μM in H9 cells and to 0.19 and 24.9 μM 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.