Arsenic trioxide (medication)

Did You Know?

• In overdose, penicillamine up to 1 g/day is commonly used; for patients unable to take oral medications, dimercaprol is given intramuscularly at 3 mg/kg every 4 hours.
• Arsenic trioxide has shown efficacy against multiple myeloma in combination with ascorbic acid and bortezomib.
• The drug induces apoptosis in lung cancer cells, especially when combined with sulindac.

Medical uses

Arsenic trioxide is used for induction of remission and consolidation in adult patients with acute promyelocytic leukemia who have the t(15;17) translocation and/or the PML-RARα gene fusion, typically after prior retinoid and chemotherapy. For non-high-risk APL (white blood cell count ≤10,000/μL), a chemotherapy-free regimen combining all-trans retinoic acid (ATRA) and arsenic trioxide is preferred, showing superior efficacy and a favorable safety profile. High-risk patients (white blood cell count >10,000/μL) receive ATRA plus arsenic trioxide with added chemotherapy such as idarubicin during induction. The drug achieves high remission rates even in relapsed disease and is effective in pediatric and elderly populations. Oral formulations, including liquid and tablet forms, have been developed with comparable bioavailability to the intravenous form. Effectiveness appears similar to Realgar/Indigo naturalis, which is less expensive but less available. Arsenic trioxide works by encouraging proteosome breakdown of retinoic acid receptor alpha through nuclear matrix translocation and increased ubiquitination.

Pharmacology

Arsenic trioxide exerts toxicity through oxidative stress, disruption of energy production, and interference with protein functions. It generates reactive oxygen species, leading to organelle damage and cell death. The drug inhibits pyruvate dehydrogenase, disrupting mitochondrial ATP production and cellular respiration, which can trigger necrotic and apoptotic death. It interferes with DNA repair by inhibiting enzymes involved in base and nucleotide excision repair and interacting with zinc fingers in repair proteins. In cardiac tissues, it blocks the hERG potassium channel and alters calcium channel activity, causing QT prolongation and arrhythmias. Arsenic trioxide has broad-spectrum antimicrobial, antiviral, and antiparasitic properties, but its toxicity limits anti-infective use. Historically used for syphilis and trypanosomiasis, it shows potential against multidrug-resistant bacteria and inhibits hepatitis C virus replication. The anti-cancer mechanism involves inhibiting proliferation and inducing differentiation or apoptosis through multiple pathways.

Special warnings

Before treatment with arsenic trioxide begins, an ECG is required along with checks on potassium, calcium, magnesium, and creatinine levels. Any issues, especially a long QT interval, must be fixed first, and drugs that could lengthen the QT interval should be stopped if possible. Roughly 40% of patients will have a corrected QT interval over 500 ms at least once, raising the risk of ventricular arrhythmias like torsades de pointes. About a quarter of patients develop a leukocyte activation-like syndrome with high fever, breathlessness, weight gain, and lung infiltrates; high-dose dexamethasone (10 mg intravenously two to three times daily) often helps. During the induction phase, electrolyte levels, glucose, blood counts, and liver and kidney function are tested twice a week, then weekly during consolidation. If toxicity hits level 3 by National Cancer Institute standards, treatment is adjusted or stopped. Women who could become pregnant and men who could father children must use effective contraception.

History

In the 18th century, William Withering discovered that small doses of arsenic trioxide had therapeutic effects. Thomas Fowler prepared a 1% solution of arsenic and potassium carbonate used for skin diseases until the 20th century. Paul Ehrlich synthesized arsphenamine for syphilis, later replaced by penicillin. The first report of anticancer activity came in 1878 from Boston City Hospital, describing Fowler's solution lowering leukocyte levels. Arsenic trioxide was used for leukemia until radiotherapy emerged, then resurged in the 1930s for chronic myelogenous leukemia. In the late 1960s, physicians at Harbin Medical Academy in China used an arsenic-based melanoma ointment from traditional Chinese medicine. Early oral trials showed strong toxicity, but intravenous trials beginning in March 1971 showed lower toxicity. More than half of patients from the first Harbin trial survived five years, leading to further research and FDA approval in 2000.