RETINOID RESISTANCE IN LEUKEMIC-CELLS

Recent studies have shown that a high proportion of patients with acut e promyelocytic leukemia (APL) achieve complete remission after treatm ent with all-trans retinoic acid (RA). Nevertheless, despite an initia l good response, most patients who received continuous treatment with all-traits RA relapsed and develop RA-resistant disease. The detailed mechanisms for this development of RA resistance by APL cells are stil l unclear. Several possible mechanisms have been considered to explain irt vitro resistance to RA, One obvious explanation is the generation of new mutations in the retinoid receptors, However, UF-1 cells (the first permanent APL cell line with RA-resistant features) had no point mutations in the ligand-binding domain of the RAR-alpha gene. Another potential mechanism for clinical RA resistance is the pharmacologic a lteration in the metabolism of all-traits RA. Continuous treatment wit h all-trans RA in APL is associated with a progressive reduction of th e plasma concentrations of RA. Induction of cytochrome P-450, cellular RA-binding protein (CRABP) and P-glycoprotein resulted in lower plasm a and cellular levels of active retinoids. Thus, acquired resistance t o RA may be explained at least in part by drug metabolism in leukemic cells.