Interferon-alpha enhances the cytotoxic and cytostatic activities of chemotherapeutic drugs in human myeloid leukemia cells.

Abstract

In comparison with chemotherapeutic drugs, IFN-alpha showed a significantly better median survival rate in CML patients; therefore, current studies focus on the identification of the proper chemotherapeutic drug, with the most effective synergistic interaction with IFN-alpha for the elimination of the human myeloid leukemia cell clone. The cytostatic and cytotoxic effects of combining IFN-alpha with each of the three chemotherapeutic drugs carboplatin, daunorubicin, and cytarabine were evaluated in three human myeloid leukemia cell lines representing different stages of differentiation: MHH225 (CD34-positive multilineage), HL-60 (promyelocytic), and U937 (monoblastic) in both liquid suspension and agar clonogenic cultures. The ED90 (the concentrations of chemotherapeutic drugs required for 90% inhibition of colony formation or cell death) in human myeloid leukemia cells were in the following order: daunorubicin > carboplatin > cytarabine, with HL-60 the most sensitive and MHH225 the least sensitive. Whereas IFN-alpha failed to decrease significantly the ED90 of cytarabine in the three human myeloid leukemia cell lines, it significantly decreased the ED90 of carboplatin and to a lesser extent daunorubicin in both liquid suspension and agar clonogenic cultures. The present results are in line with the previous results of a negative interaction between IFN-alpha and cytarabine both in vitro in K562 human leukemia and in vivo in L1210 murine leukemia, and a synergistic cytostatic interaction between IFN-alpha and carboplatin in K562 cells. The significant synergism between IFN-alpha and carboplatin was observed in all four human myeloid leukemia cell lines with various stages of differentiation and confirmed in both serum-free and serum-supplemented cultures applying different in vitro assays: liquid suspension, agar clonogenic, and capillary agar microclonogenic cultures. Thus, given the in vitro profound synergism between IFN-alpha and carboplatin in all four human myeloid leukemia cells tested, together with the in vivo significant antileukemic activity of both IFN-alpha and carboplatin in several reported clinical studies for myeloid leukemia patients, the clinical use of the combination of IFN-alpha and carboplatin in the treatment of CML patients could prolong the complete hematologic and cytogenetic responses and consequently improve the survival rate. On the other hand, given the negative interaction between IFN-alpha and cytarabine observed in myeloid leukemia cells, together with the inferior cytogenetic responses observed in CML patients treated with the combination of IFN-alpha and cytarabine, caution should be exercised against the continuous clinical use of the combination of IFN-alpha and cytarabine in treating CML patients. In conclusion, the present results suggest the use of carboplatin and to a lesser extent daunorubicin instead of cytarabine in combination with IFN-alpha for the treatment of CML patients.