Synergistic cytotoxicity of AZT plus alpha and gamma interferon in chronic myeloid leukemia cell line K562.
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+alpha-IFN but also AZT+gamma-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 alpha- and gamma-IFN, respectively. The addition of 50 mumol/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+alpha-IFN is currently being tested in HIV-related malignancies, AZT+gamma-IFN is new and deserves further study in human CML acute and chronic phase models, in view of possible clinical applications.
Tosi
P
P
Istituto di Ematologia L. e A. Seràgnoli, Università di Bologna, Italy.
Visani
G
G
Ottaviani
E
E
Gamberi
B
B
Cenacchi
A
A
Tura
S
S
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000633:toxicity*; D007371:Interferon-gamma / Q000633:toxicity*; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D011994:Recombinant Proteins; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015215:Zidovudine / Q000378:metabolism / Q000633:toxicity*
D004273:DNA, Neoplasm; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D015215:Zidovudine; D007371:Interferon-gamma; D013936:Thymidine