The analogs of vitamin D₃ named PRI-2201, PRI-2202, PRI-2205 were previously tested for their antiproliferative activity against different cancer cell lines. In general, all compounds have revealed similar or higher activity in cancer cell growth inhibition compared to calcitriol or PRI-2191.
In this paper, the effect in vitro of pretreatment with calcitriol or its above mentioned analogs on antiproliferative activity of cisplatin or doxorubicin on HL-60 cells has been evaluated.
The cells were exposed to various concentrations of calcitriol, PRI-2191, PRI-2201, PRI-2202 or PRI-2205 and cisplatin or doxorubicin. The cytostatic effect was measured by the MTT assay and then the results were calculated as an IC50 (inhibitory concentration 50%). The studies of combined treatment with vitamin D₃ analogs and cisplatin on HL-60 cell line in vitro showed an increase in cell proliferation inhibition when compared to cisplatin alone. This effect was obtained by using lower doses of analogs (10, 1 or 0,1nM) and cisplatin in the dose 1µg/ml.
Calcitriol, PRI-2191, PRI-2201, PRI-2202, PRI-2205 used in 1nM concentration showed synergy or an additive effect in proliferation inhibition when combined with cisplatin (up to 40% of proliferation inhibition in combination than with cisplatin alone) on HL-60 leukemia cells. Analogs PRI-2191 and PRI-2201 used at the dose 1nM in combination with cisplatin showed an synergistic effect, analogs PRI-2202 and PRI-2205 used at concentrations showed a significant proliferation inhibition of HL-60 cells when combined with cisplatin. Comparing the IC50 results for these combined treatment to results for all of these compounds used alone, we can conclude that calcitriol analogs allow to decrease the dose of cisplatin from 1,7 to 6,4 times. In the case of combined treatment with vitamin D₃ analogs and doxorubicin synergistic or a subadditive effect in profliferation inhibition was observed. Especially, lower doses of doxorubicin (0,1 and 0,01µg/ml) combined with lower doses of analogs (10 or 1nM) causes synergy in proliferation inhibition. Even 0,001 µg/ml of doxorubicin combined with PRI-2191, PRI-2201 or PRI-2205 increases the inhibition of cell growth significantly. Using vitamin D₃ analogs we can decrease the dose of doxorubicin for inhibition of cancer cell growth. PRI-2191 allows to decrease the doxorubicin dose up to 12 times, PRI-2201 up to 4 times, PRI-2202 and PRI-2205 up to 3,5 times. We have previously demonstrated synergistic antiproliferative activity of PRI-2191 with some known antitumor drugs in the HL-60 cells. The antitumor effect of PRI-2191, PRI-2202 and PRI-2205 combined with cytostatics in mice mammary and lung cancer models was also evaluated. The results presented suggest that the improved therapeutic effect may be achieved in vivo by the combined application of the analogues (without calcemic activity) of calcitriol with antitumour agents also on human promyelocytic leukemia cell line.

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