Control of proliferating potential of myeloid leukemia cells during long-term treatment with vitamin D₃ analogues and other differentiation inducers in combination with antileukemic drugs: In vitro and in vivo studies

Growth inhibition of murine and human myeloid leukemia cells by differentiation inducers during long-term culture was examined to improve the strategy for therapy of myeloid leukemia by differentiation inducers. When the effect of 1α,25-dihydroxyvitamin D₃, a typical differentiation inducer, on proliferation of mouse myeloid leukemia M1 cells was examined at a constant product of time and concentration (480 nM in 20 days), the continuous treatment with 24 nM 1α,25-dihydroxyvitamin D₃ was the most effective for inhibition of cell proliferation. After 20 days, the cumulative cell number was reduced about 3 x 10⁵ times by continuous treatment with 24 nM 1α,25-dihydroxyvitamin D₃. Similar results were obtained when M1 cells were treated continuously with dexamethasone. M1 cells resistant to 1α,25-dihydroxyvitamin D₃ appeared about 25 days after the start of continuous treatment with 24 nM 1α,25-dihydroxyvitamin D₃. On the other hand, when M1 cells were treated continuously with 1α,25-dihydroxyvitamin D₃ and noncytotoxic doses of antileukemic drugs such as 1-β-D-arabinofuranosylcytosine and daunomycin, resistant cells did not appear for at least 35 days. A similar effect of 1α,25-dihydroxyvitamin D₃ and antileukemic drugs on cell proliferation was observed with the human monoblast-like cell line U937. The survival of syngeneic SL mice inoculated with M1 cells was prolonged more by treatment with both 1α-hydroxyvitamin D₃ and daunomycin than by treatment with either drug alone. These results suggest that continuous treatment with both differentiation inducers and certain antileukemic drugs may be more effective therapeutically than treatment with a differentiation inducer alone.