Institute of Hematology and Blood Transfusion, Prague, Czechoslovakia
RA induces granulocytic differentiation in some of the human myeloid leukemia cell lines (HL-60, ML-1, -2, -3, NB4) and in cultures of fresh cells from patients with acute promyelocytic leukemia (APL). In human monoblastic leukemia cell lines (U-937, THP-1), monocytic/macrophage differentiation is induced. In optimal concentrations, both of the RA isomers, 13-cis (cRA) and all-trans RA (tRA), are equally potent in inducing differentiation. At suboptimal concentrations, tRA is the more potent inducer.
Physiologically, differentiation and maturation (especially in granulocytic cells) is accompanied by a concurrent cessation of cell multiplication. We have shown, however, that tRA may induce segmentation of ML-1 cell nuclei without the concomitant decrease of proliferative activity in the culture. Interestingly, nucleoli persist in all of the induced cells, including those with segmented nuclei. These findings -support the view that RA primarily induces cell differentiation and maturation and the cessation of cell multiplication is a result of the former.
cRA has been shown to induce complete remissions (CR's) in APL patients. More recently, remarkable results have been obtained with tRA. Of 106 APL patients reported so far (including chemotherapy resistant or relapsed ones, but excluding those that would not be eligible for chemotherapy), 78.7 % achieved a CR using tRA as a sole agent. In comparison to standard chemotherapy, tRA gives favorable CR rates, it is less toxic, it abolishes disseminated intravascular coagulation, but early relapses seem to be more frequent. In CR, the t (15; 17) translocation and derangements of the nuclear RA receptor alpha genes may persist. In our first patient treated by tRA, the normalization of myelogram occured only after increasing the ammount of dietary fats. However, atypical promyelocytic granules and a leukemic growth pattern of CFU-GM persisted.
Retinoic acid (RA) in the treatment of leukemia - Experimental background and clinical experience
