DRUG STUDY AND INFORMATION FORM Generic Name: Tretinoin Trade Name: Vesanoid (Anti-cancer formulation) Drug Class:

Differentiating Agents (Retinoids) Structure/Chemistry: All-trans retinoic acid (ATRA); acidic form of Vitamin A

Pharmacodynamics

Mechanism of Action: Physiologic concentrations of ATRA are too low in APL (acute promyelocytic leukemia) cells to displace the repressor, so tretinoin provides enough ATRA to displace the repressor and thereby activates differentiation and promotes degradation of the PML-RAR- (a translocated-fusion gene that binds retinoic acid much less efficiently and does not promote myeloid differentiation). ATRA also binds and activates RAR- which promotes stem cell renewal that may possibly restore bone marrow. Background: RAR- receptor (critical for cell differentiation) dimerizes with retinoid X receptor to form a complex that binds ATRA tightly. Binding of ATRA displaces a repressor from the complex and promotes differentiation of cells. The PML gene encodes a transcription factor that inhibits cell proliferation and promotes myeloid differentiation. Many APL cells harbor a t(15;17) translocation that fuses RAR- with PML. Pharmacologic Effects: Prevents malignant tumors from blocking cells from normally undergoing differentiation and allows for more normal binding of retinoic acid by RAR-. Blocking differentiation is a hallmark of malignancy.

Drug Resistance or Tolerance: Further mutation of the fusion gene that abolishes ATRA binding, induction of CYP26A1 in liver or leukemic cells, or by loss of expression of PML-RAR-

Pharmacokinetics

Absorption: Oral dose of 45 mg/m2/day until 30 days after remission (90 days maximum usage). Should be given in combination with an anthracycline. Distribution:

Elimination: t1/2 of <1 hour. Eliminated by CYP3A4.

Metabolism:

Adverse Side Effects/Toxicity: Dry skin, cheilitis (inflammation of the lip), reversible hepatic enzyme abnormalities, bone tenderness, pseudotumor cerebri, hypercalcemia, hyperlipidemia, and retinoic acid syndrome (fever, dyspnea, weight gain, pulmonary infiltrates, and pleural or pericardial effusions). Drug Interactions: Give with anthracycline for complete remission of APL. Inducers of CYP3A4 speed up metabolism of tretinoin while inhibitors delay metabolism which may lead to hypercalcemia and renal failure. Retinoic acid syndrome decreased by corticosteroids and chemotherapy. Therapeutic uses: APL (acute promyelocytic leukemia)

Miscellaneous: