Modulation of methotrexate cytotoxicity with natural interferon upon human leukemia cell line HL-60.
The effect of alpha- and gamma-interferon on methotrexate cytotoxicity against human promyelocytic cell line HL-60 has been evaluated. Synergistic inhibition of proliferation is observed with the combination of methotrexate and gamma-interferon. Enhanced cytotoxic effect of methotrexate with alpha- or gamma-interferon is removed by adding thymidine to the growth medium. The depletion of folate pools caused by methotrexate is enhanced in presence of interferons, this depletion is also removed by adding thymidine to the growth media. Synchronization of HL-60 cells in 'S' phase of cell cycle caused by methotrexate is enhanced in the presence of interferons. These results suggest that specially gamma-interferon changes the cellular environment of HL-60 cells in such a way as to make methotrexate more potent cytotoxic agent to HL-60 cells causing cell death. This study also clearly indicates the biochemical role of thymidine in modulating the activity of methotrexate in combination with interferons.
Sur
P
P
Fujisaki Cell Center, Hayashibara Biochemical Laboratories, Inc., Okayama, Japan.
Matsuo
Y
Y
Otani
T
T
Minowada
J
J
D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute; D008727:Methotrexate / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D013763:Tetrahydrofolates / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D016898:Interferon-alpha; D013763:Tetrahydrofolates; D007371:Interferon-gamma; D013936:Thymidine; D008727:Methotrexate