DRUG STUDY AND INFORMATION FORM Generic Name: Arsenic Trioxide Trade Name: Trisenox Drug Class: Differentiating

Agents Structure/Chemistry: As2O3

Pharmacodynamics

Mechanism of Action: Inhibits thioredoxin reductase and thereby generates ROS while inactivating glutathione and other sulfhydryls that scavenge ROS. Arsenic trioxide also upregulates p53, JUN kinase, and caspases associated with the intrinsic pathway of apoptosis and downregulates anti-apoptotic proteins such as bcl-2. It promotes degradation of the APL fusion gene and NF-B (dampens apoptotic response due to genomic damage). It also induces differentiation of leukemic cell lines.

Pharmacologic Effects: Promotes leukemic cell differentiation and creates ROS that contribute to genomic damage.

Drug Resistance or Tolerance:

Pharmacokinetics

Absorption: Well absorbed orally but usually given IV (0.15 mg/kg/day over a 2 hour period for 60 days) Distribution:

Elimination: Eliminated through enzymatic methylation and then excreted in the urine.

Metabolism:

Adverse Side Effects/Toxicity: May experience reversible side effects including hyperglycemia, hepatic enzyme elevations, fatigue, dysesthesias (unpleasant abnormal sense of touch), and lightheadedness. A leukocyte maturation syndrome may develop in 10% of patients that present with pulmonary distress, effusions, and mental status changes (reversed by oxygen, corticosteroids, and temporary discontinuation of arsenic trioxide). May lengthen QT interval because arsenic trioxide inhibits the rapid K+ efflux channels in the myocardium. Drug Interactions: Avoid drugs that lengthen the QT interval such as macrolide antibiotics, quinidine, or methadone.

Therapeutic uses: Given to patients with relapsed APL (acute promyelocytic leukemia) after failed courses of ATRA (tretinoin).

Miscellaneous: