Retinoids

tretinoin The biology and pharmacology of retinoids are discussed in detail in Chapter 62. The most important of these for cancer treatment is tretinoin (all-trans retinoic acid; ATRA), which induces a high rate of complete remission in acute promyelocytic leukemia (APL) as a single agent, and in combination with anthracyclines, has become part of a curative regimen for this disease. Under physiologic conditions, the RAR-a receptor dimerizes with the retinoid X receptor (RXR) to form a complex that binds ATRA tightly, displacing a repressor of differentiation. In APL cells, there is a t(15;17) translocation that results in a fusion protein (PML-RAR-a) that binds retinoids with much decreased affinity, lacks PML transcription factor function (i.e., inhibition of proliferation and promotion of myeloid differentiation), and blocks the function of transcription factors such as C/EBP, which promote myeloid differentiation. Physiologic concentrations of retinoid are inadequate but pharmacologic concentrations displace the repressor from the fusion protein, activating the differentiation program and promoting degradation of the PML-RAR-a fusion protein. Resistance to ATRA arises by further mutation of the fusion gene that abolishes ATRA binding or by loss of expression of the fusion gene.

The usual dosing regimen of orally administered ATRA is 45 mg/m2/day until remission is achieved. ATRA as a single agent reverses the hemorrhagic diathesis associated with APL and induces a high rate of temporary remission. In combination with an anthracycline, ATRA achieves >70% relapse-free, long-term survival. ATRA reaches a plasma concentration of 400 ng/ml and is cleared by CYP-mediated elimination with a t/2 of <1 hour. Treatment with CYP inducers increases drug metabolism and may result in resistance to ATRA. Remission rate and time to remission induction improve with the inclusion of other chemotherapy. When used as a single agent, especially in patients with >5000 leukemic cells per mm3 in the peripheral blood, ATRA induces an outpouring of cytokines and mature appearing neutrophils of leukemic origin. These cells can clog small vessels in the pulmonary circulation and elsewhere, resulting in the "retinoic acid syndrome" characterized by fever, respiratory distress, pulmonary infiltrates, pleural or peri-cardial effusions, and mental status changes. Glucocorticoids and chemotherapy decrease the occurrence of the retinoic acid syndrome. Retinoids as a class, including ATRA, cause dry skin, cheilitis, reversible hepatic enzyme abnormalities, bone tenderness, and hyperlipidemia.

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