Effects of retinoic acid steroidal analogs on human leukemic HL60 cell proliferation in vitro and on angiogenesis in vivo.

Retinoic acid (RA) can be regarded as a pharmacological agent commonly used for its ability to affect growth and differentiation of a variety of cell types, such as acute promyelocytic leukemic and endothelial cells. In the present work we studied the effect of all-trans-RA (ATRA) and its steroidal analogs EA-4, EA-136 and EA-137 on the growth of human promyelocytic HL-60 cells in vitro. The specific steroidal substrates were chosen in order to further investigate their ability to improve the pharmacological properties of conjugated antileukemic agents. ATRA decreased the number of HL60 cells from the first 24 h after its addition to the cell culture medium. The decrease was significant at concentrations higher than 10(-5) M. All the analogs tested also decreased the number of HL60 cells with an IC50 similar to that of ATRA, except for EA-4 whose IC50 was almost two orders of magnitude lower than that of ATRA, 72 h after its addition to the cell culture medium. Since angiogenesis is important for the growth of hematological malignancies, we furthermore studied the effect of ATRA and its analogs on the formation of new capillaries in the in vivo chicken embryo chorioallantoic membrane (CAM). ATRA, EA-136 and EA-137 induced angiogenesis in the CAM, increased the layer of CAM keratinocytes, and resulted in a significant degree of extravasation. EA-4 had no effect on either angiogenesis or tissue structure in general. It seems that the retinoid EA-4 is a promising agent for the inhibition of human leukemia cell growth.