DIFFERENT COMBINATIONS OF RETINOIDS AND VITAMIN-D3 ANALOGS EFFICIENTLY PROMOTE GROWTH-INHIBITION AND DIFFERENTIATION OF MYELOMONOCYTIC LEUKEMIA-CELL LINES

The efficacy of all-trans retinoic acid (RA) in the treatment of acute promyelocytic leukemia results from the ability of RA to differentiat e these peculiar leukemic cells. The efficacy of differentiation thera py could be improved and extended to other forms of leukemia by associ ating retinoids with other differentiating agents. Here we have compar ed the effects of different combinations of retinoids with 1 alpha,25- dihydroxyvitamin D3 (VD3) analogs on myelomonocytic cell lines HL-60, U937 and THP-1. All-trans RA, its natural isomer 9-cis RA and the arot inoid TTNPB, which differ by their respective specificities for the RA receptor families (retinoic acid receptor and retinoid X receptor), w ere found to cooperate with VD3 in inhibiting cell growth of the leuke mic cell lines. Although the three cell lines displayed different susc eptibilites to retinoids, each molecule was able to cooperate with VD3 in inducing U937 cell differentiation. Because the effects of VD3 on calcium metabolism limit its therapeutic use, we studied the effects o f two synthetic analogs, MC903 and KH1060. Both agents cooperate with RA, acting more efficiently than the natural molecule in inhibiting ce ll growth and inducing some parameters of U937 cell differentiation. T hese results extend our previous data demonstrating that RA and VD3 ex ert synergistic effects on the differentiation of the myelomonocytic c ell line U937. They demonstrate that combinations of agents able to in hibit leukemia cell growth with limited side effects may be found amon g a wide array of retinoids and vitamin D3 analogs.