All-Trans-Retinoic Acid Pharmacology and Its Impact on the Treatment of Acute Promyelocytic Leukemia.

The approach to the treatment of acute promyelocytic leukemia (APL) has changed dramatically over the past decade and, as a result, the long-term event-free survival for patients has improved significantly. The addition of the vitamin A derivative, all-trans-retinoic acid (ATRA), to treatment regimens has been responsible for this improvement in survival. Although ATRA is a potent remission induction agent in APL, continuous administration of ATRA as a single agent does not maintain patients in remission. Although lower plasma concentrations were initially noted at the time of relapse in patients with APL, subsequent studies have demonstrated that the decline in plasma drug concentrations occurs within one to two weeks of initiation of treatment, and possibly as early as three days. The inability to maintain adequate plasma concentrations of ATRA because of rapid upregulation of its catabolism is an attractive hypothesis to explain the inevitable recurrences in patients with initially responsive disease, but more recent data suggest that this mechanism alone is unlikely to be responsible for drug resistance. Cellular retinoic acid binding proteins (CRABPs) play a critical role in regulating the amount of free retinoic acid capable of reaching and activating nuclear receptors. Recent studies using leukemic blasts obtained at the time of relapse have demonstrated a shift in the ATRA dose-response curve in vitro. In addition, there is an upregulation in the expression of CRABP in leukemic blasts obtained at relapse. These observations suggest that ATRA resistance is not simply an inability to maintain therapeutic plasma concentrations of drug, but rather may be linked to the intracellular regulation of drug. The intricate nature of the homeostatic mechanisms that maintain tight control over retinoids, combined with the multiplicity of retinoid receptors and signaling pathways, leave open the possibility of a yet-to-be-defined mechanism of resistance that is independent of the clinical pharmacology of ATRA.