Arsenic trioxide

Arsenic trioxide, also known as white arsenic, arsenic(III) oxide, arsenious oxide, or 砒霜, is a chemical compound. Its chemical formula is As₂O₃. It has arsenic and oxide ions in it. The arsenic is in its +3 oxidation state. It is very toxic. At very low dose it can be used to treat acute promyelocytic leukemia (APL), a type of blood cancer.

Properties

Arsenic trioxide is a white solid. It dissolves in water to make an acidic solution of arsenious acid. It dissolves easily in bases to make arsenites. It reacts with concentrated hydrochloric acid to make arsenic trichloride. It reacts with very strong oxidizing agents to make arsenic pentoxide. It reacts with reducing agents to make arsenic or arsine. It sublimes much easier than metal oxides, making it easy to separate by heating the mixture.

Occurrence and preparation

Arsenic trioxide is rarely found as a mineral. It is normally made from orpiment or realgar, arsenic sulfide minerals. About 50,000 tons of arsenic trioxide are made each year. Arsenic trioxide is made by burning arsenic in air, reacting arsenic with concentrated sulfuric acid, or the roasting of arsenic sulfide ores.

Safety

Arsenic trioxide is highly toxic when eaten. It also can be toxic if on the skin for long amounts of time. It affects the digestive system when eaten. Workers exposed to arsenic trioxide fumes in their job can be poisoned as well.

Uses

It is used to make elemental arsenic. It was used as a pigment (in Paris green) and as a wood preservative but was banned in many countries because it is so toxic.

Medical

Treatment of Acute promyelocytic leukemia

Arsenic trioxide is used to fight acute promyelocytic leukemia (APL).^[1]^[2]

Various forms of arsenic were used in China for over 2000 years.^[3]^[4] Arsenic first appeared in Western Medicine in the eighteenth century. In hematology, oral arsenic was first reported in the treatment of chronic myeloid leukemia from the 1860s to 1920s in Germany and Boston City. This treatment was phased out following World War II with the development of alkylating chemotherapy and radiotherapy. Intravenous pure As2O3 solution was first used in Harbin, China in 1973^[3] as discovered by Zhang Tingdong and colleagues.^[5]

In March 1971, Han Taiyun of the 1st Affiliated Hospital started to treat cancer patients with a formula he collected from traditional Chinese medicine doctors. It was presumably an oral formula, and contained a mixture of many ingredients, including arsenic chemicals, mercury chloride, and cinobufagin venom toad. Later, Han Taiyun turned the formula into an intramuscular injection called "713" or "cancer spirit". For certain tumors, it worked and became a local hit. But Han Taiyun gave that treatment up because the formula was too toxic for some patients.^[6]

Zhang Tingdong is a doctor of Traditional Chinese Medicine at First Clinical Hospital, affiliated with Harbin Medical University in Harbin, a city in the far north of China. He is also a hematologist (blood specialist).^[7]^[8]

In 1972, Zhang started to cooperate with Han Taiyun. Instead of working on many cancers, Zhang Tingdong focused mainly on leukemia. Also, instead of using a mixture of many ingredients, Zhang tested each individual component of the formula. He found that while the arsenic component is effective against leukemia, mercury chloride and cinobufagin venom toad were not, and caused renal toxicity and high blood pressure respectively. Their first paper was published in 1973, attributed to Zhang Tingdong, Pengfei Zhang, Wang Shouren, Han Taiyun at the Heilongjiang medical reports. They used "cancer injection" (also called "cancer spirit No. 1" or "Ailing-1")^[6]^[4] in the treatment of 6 cases of patients with chronic myeloid leukemia. They used arsenic trioxide as the main ingredient, with some trace "pink powder (mercury chloride)". After the treatment, the 6 patients, including a chronic-turned-acute leukemia patient, experienced improved symptoms. They also mentioned that arsenic trioxide is effective in treating acute leukemia.^[6]

The results were initially published on Chinese-language literature. In the 1990s, Zhang began to write in English, exposing this method to a broader scientific community. His work became widely known after 1996, when he co-authored a Blood article with Chen Zhu about this method.^[9]^[10] From 1994, the therapeutic value of intravenous pure ATO for the treatment of APL were further confirmed through clinical trials with the help of researchers from Shanghai, New York, etc.^[11]^[12] Intravenous pure As2O3 solution’s mechanism of action, pharmacokinetics and clinical efficacy of was extensively published^[3] and was later approved for leukemia treatment in the United States in 2000.^[13]

The development of pure oral arsenic trioxide was invented and patented in Hong Kong, China. With memories of the Fowler’s solution, an oral As2O3 formulation or the “modern” liquor arsenicalis was revived.^[3] Oral arsenic trioxide was first used in the Queen Mary Hospital (QMH) to treat leukemia in the late 1940s and early 1950s. Its use was discontinued for almost half a century until 1998. That year, researchers at the QMH began to study the use of oral arsenic again. To figure out the safety and dosage, the team first checked the old medical records available from the Hong Kong Medical Museum. After two years of research, an oral formulation of arsenic was successfully developed and was granted a US patent^[14] in 2009.^[15]^[16] Oral preparation of As2O3 (oral-As2O3) was shown to be efficacious for APL in first relapse (R1), inducing second complete remission (CR2) in more than 90% of patients. Further, in an effort to prevent relapses, oral-As2O3 was used during induction and maintenance of CR1. This strategy resulted in favorable overall-survival (OS) and leukemia-free-survival (LFS). This 1mg/ml oral-As2O3 solution has a bioavailability comparable with that of i.v. As2O3.^[3]

Oral arsenic trioxide (Oral-ATO; ARSENOL^®) from Hong Kong was also the first oral preparation of pure arsenic trioxide produced under the Good Manufacturing Practice (GMP) standards.^[3] The formulation was developed by Professor Kwong Yok Lam and colleagues from the University of Hong Kong.^[17] As of 2024, only Hong Kong uses oral arsenic to combat relapsed APL. Intravenous arsenic trioxide is used in other parts of the world. The disadvantages of intravenous arsenic trioxide treatment includes high cost (around US$50,000 dollars per month, not including the high hospitalization cost involved) and serious cardiac toxicity.^[4] In 2025, it was reported that “Oral-ATO has obtained orphan drug designation from US Food and Drug Administration and the European Medicines Agency.”^[18]

Overdose

If arsenic poisoning occurs (with the person experiencing seizures, muscle weakness, confusion),^[19] the drug should not be given anymore and appropriate treatment should be started. Penicillamine is commonly used at a dose of up to 1 g/day.^[20] For patients unable to take medicine by mouth, dimercaprol can be given through muscle injection at a dose of 3 mg/kg body weight every 4 hours^[21] until life-threatening symptoms become less severe. In cases of coagulopathy,^[22] DMSA is used at a dose of 10 mg/kg body weight every 8 hours for 5 days, followed by every 12 hours for 2 weeks.^[23] Kidney dialysis may also be considered.^[24]

Research and development

Acute promyelocytic leukemia

On the other hand, Realgar/Indigo naturalis formula (RIF) was developed in the 1980s entirely based on traditional Chinese Medicine (TCM) concepts and comprises realgar, Indigo naturalis, Salvia miltiiorrhiza and Radix pseudostellariae. Tetraarsenic tetrasulphide (As4S4), indirubin and tanshinone IIA are the active ingredients of RIF with in-vitro synergism.^[3] All oral, chemotherapy-free model in the frontline management of APL highlighting the applications of RIF is being developed as of 2025. A major obstacle to cure in APL is early deaths. In addition, multi-centre clinical trials in patients treated with ATRA, arsenic trioxide and anthracyclines reported a relatively low incidence of early deaths of 3-10%. There is a trend of evolution of various therapeutic approaches from hospital-based induction and consolidation to home-based oral As2O3-based therapy especially during consolidation and maintenance. Other oral formulations of As2O3 are also being investigated with the hope of eventually developing an all oral, effective regimen in standard-risk APL.^[3]

Therapeutic application of intravenous arsenic trioxide is being developed in United Kingdom using the attenuated arsenic trioxide regimen in newly diagnosed APL. The treatment of “high-risk” APL remains a topic of contention as As2O3 is not yet approved for this indication. An exploratory study by the MD Anderson Cancer Center using ATRA-As2O3 with or without gemtuzumab ozogamacin (GO) suggested that an essentially chemotherapy-free regimen might be feasible for the upfront treatment of APL. The role of hematopoietic stem cell transplantation (HSCT) in the current era of arsenic trioxide was also reassessed. As2O3-based regimens are currently regarded as the first option for relapsed APL. The development of As2O3 –based therapy has improved the outcome of APL, from once the most fatal to currently the most curable leukemia.^[3]

Other types of cancer

As of 2009, animal studies have shown that the drug also affects ovarian,^[25] liver, stomach,^[26] prostate, and breast cancers,^[27] as well as gliomas^[28] and pancreatic cancer (in combination with parthenolide).^[29]

Arsenic trioxide also appears promising for treating autoimmune diseases (based on studies in mice).^[30]