INTERFERON-ALPHA ENHANCES THE CYTOTOXIC AND CYTOSTATIC ACTIVITIES OF CHEMOTHERAPEUTIC DRUGS IN HUMAN MYELOID-LEUKEMIA CELLS

In comparison with chemotherapeutic drugs, IFN-alpha showed a signific antly better median survival rate in CML patients; therefore, current studies focus on the identification of the proper chemotherapeutic dru g, with the most effective synergistic interaction with IFN-alpha for the elimination of the human myeloid leukemia cell clone. The cytostat ic 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 dif ferent stages of differentiation: MHH225 (CD34-positive multilineage), HL-60 (promyelocytic), and U937 (monoblastic) in both liquid suspensi on and agar clonogenic cultures. The ED(90) (the concentrations of che motherapeutic drugs required for 90% inhibition of colony formation or cell death) in human myeloid leukemia cells were in the following ord er: daunorubicin > carboplatin > cytarabine, with HL-60 the most sensi tive and MHH225 the least sensitive. Whereas IFN-alpha failed to decre ase significantly the E(90) of cytarabine in the three human myeloid l eukemia cell lines, it significantly decreased the ED(90) of carboplat in and to a lesser extent daunorubicin in both liquid suspension and a gar clonogenic cultures. The present results are in line with the prev ious results of a negative interaction between IFN-alpha and cytarabin e both in vitro in K562 human leukemia and in vivo in L1210 murine leu kemia, 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 ser um-free and serum-supplemented cultures applying different in vitro as says: liquid suspension, agar clonogenic, and capillary agar microclon ogenic cultures. Thus, given the in vitro profound synergism between I FN-alpha and carboplatin in all four human myeloid leukemia cells test ed, together with the in vivo significant antileukemic activity of bot h IFN-alpha and carboplatin in several reported clinical studies for m yeloid leukemia patients, the clinical use of the combination of IFN-a lpha and carboplatin in the treatment of CML patients could prolong th e complete hematologic and cytogenetic responses and consequently impr ove the survival rate. On the other hand, given the negative interacti on between IFN-alpha and cytarabine observed in myeloid leukemia cells , together with the inferior cytogenetic responses observed in CML pat ients treated with the combination of IFN-alpha and cytarabine, cautio n should be exercised against the continuous clinical use of the combi nation of IFN-alpha and cytarabine in treating CML patients. In conclu sion, the present results suggest the use of carboplatin and to a less er extent daunorubicin instead of cytarabine in combination with IFN-a lpha for the treatment of CML patients.