Synergistic cytotoxicity of AZT plus alpha and gamma interferon in chronic myeloid leukemia cell line K562*

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Abstract
We have previously reported that the antineoplastic activity of 3′ ‐azido 3′ deoxythymidine (AZT) can be increased by drugs that inhibit “de novo” thymidylate synthesis, such as 5‐fluorouracil, methotrexate and hydroxyurea. In the present study we tested the combinations AZT + alpha interferon (IFN) and AZT + gamma IFN on in vitro growth of the human acute‐phase chronic myeloid leukemia (CML) cell line K562. After 72 hours incubation, not only AZT + α‐IFN but also AZT + γ‐IFN were synergistic in inhibiting K562 growth, as demonstrated by isobologram analysis of the data. This enhanced cytotoxicity was confirmed by the evaluation of [3H]AZT incorporation into cellular DNA, that was increased by 50% and 222% in the presence of α‐ and γ‐IFN, respectively. The addition of 50 μmol/l thymidine to the culture medium was able to reduce the cytotoxicity of the drug combinations to the degree observed with each compound alone; furthermore, the increased incorporation of AZT into DNA was completely reversed. These data indicate the existence of a biochemical interaction between AZT and IFNs that results in an increased cytotoxic effect. While the combination AZT + α‐IFN is currently being tested in HIV‐related malignancies, AZT + γ‐IFN is new and deserves further study in human CML acute and chronic phase models, in view of possible clinical applications.