One of the main problems in chemotherapy of patients with cancer is administration of drugs in high doses usually resulting in side effects. Drug administration protocols include different cytotoxic drugs used in various combinations. Consequently, it is of major interest to identify compounds combinations that can enhance their individual activity. The purpose of the work was to analyze the influence of imatinib, PRI-2191 (analog of calcitriol) and cytostatics (cisplatin, idarubicin and docetaxel) combination on the inhibition of proliferation of human leukemia cell line HL-60.This compounds take action by means of different mechanisms. Thereforewe carried out simultaneous treatment of HL-60 cells with these drugs. We observed that PRI-2191 strengthened the effect of imatinib and cytostatics. Imatinib combined with cytostatics had an antagonistic effect (combination with cisplatin or idarubicin) or additive effect (combination with docetaxel). Moreover, we observed the synergistic effect of interaction in triple combinations of cytostatics used together with imatinib and PRI-2191. Many anti-cancer therapies exert their therapeutic effect by inducing apoptosis in some tumor cells. Therefore we studied the influence of compounds combination on the cell cycle and apoptosis of HL-60 cells. Imatinib and cytostatics alone increased the number of cells in apoptosis. While PRI-2191 alone stopped the cells in G0/G1 phase and decreased the number of cells in S phase. Imatinib, cisplatin or idarubicin in combination with PRI-2191 increased number of cells in G0/G1 phase and decreased number of cells in S phase and in apoptosis in comparison with cytostatic alone. The combination of docetaxel and PRI-2191 decreased number of cells in G2/M and S phase and stopped the cells in G0/G1 phase and in apoptosis. The triple combination of imatinib and PRI-2191 together with cisplatin or together with idarubicin decreased number of cells in S phase and increase in G0/G1 phase. Imatinib with PRI-2191 and docetaxel stopped cells in G0/G1 phase and in apoptosis, and decreased number of cells in G2/M and S phase. In summary, applied combinations act on the cell cycle stronger than compounds used individually. Moreover, the calcitriol analog- PRI-2191 proved to be able to abolish the antagonistic interaction between imatinib and cytostatics. We suppose, that calcitriol analogs may be of potential use in anti-cancer therapy when are combined with different types of drugs.

This work was supported by the Foundation for Development of Pharmaceutical Sciences(grant 9/FB/2004, Poland)

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