For over 2,400 years, arsenic — from the Greek word
arsenikon, meaning “potent” — has been used as both a
therapeutic agent and a poison. During their time, Hippocrates used the arsenic
sulfides realgar and orpiment to treat ulcers, and Dioscorides used orpiment as
a depilatory. Since then, arsenic and its derivatives have been found to be
useful in treating diseases such as cancer and syphilis.
In the 19th century, arsenides and arsenic salts were used in the form
of external pastes to treat ulcers and cancer. They were also prescribed as
antiperiodics, antipyretics, antiseptics, antispasmodics, caustics,
cholagogues, depilatories, hemantinics, sedatives and tonics. The drugs were
used to treat systemic illnesses and could be prescribed in liquid or solid
form, could be inhaled as vapor, injected, administered intravenously or given
For over 2,000 years the role of arsenic as a curative compound
has been analyzed and questioned.
© 2008/Custom Medical Stock Photo
In the 1700s, English inventor Thomas Fowler developed a solution of
arsenic trioxide in potassium bicarbonate (1% w/v) that was used to treat
asthma, chorea, eczema, pemphigus, psoriasis, anemia, Hodgkin’s lymphoma
In 1878, the compound, aptly named “Fowler’s solution,”
was discovered to lower white blood cell counts in normal individuals, with a
more significant decrease occurring in those with chronic myelogenous leukemia
treated for 10 weeks. After this finding, Fowler’s solution was used as a
mainstay in the treatment of leukemia until it was succeeded by radiation in
the 20th century.
However, treatment with arsenic trioxide made a brief reappearance in
1931 after a report that nine patients with CML responded to the treatment at
Boston City Hospital. The patients’ white blood cell counts dropped from
several hundred thousand per cubic millimeter to about normal; their livers and
spleens reduced in size. Bone marrow biopsy specimens revealed apparent normal
hematopoieses and patients had a general sense of well being.
The treatment’s re-use was short-lived after researchers reported
chronic arsenic poisoning in five of six patients treated for CML. Based on
these findings, the researchers recommended careful patient observation with
the use of the solution. In time, the use of arsenic trioxide lessened and was
again replaced — this time by radiotherapy and cytotoxic chemotherapy.
Salvarsan, an organic arsenical, was introduced in 1910 by Nobel
laureate, physician and founder of chemotherapy, Paul Ehrlich. His compound,
which was one of 500 organic arsenic compounds, cured syphilis. Today, the
compound is still used in the treatment of trypanosomiasis.
In the 1960s, researchers continued to examine the role of arsenic in
medicine. The efficacy of potassium arsenite was tested on various animal
malignancies. Researchers tested on tumors due to their known response to
certain antitumor therapies. They found that animals with Ehrlich ascites
tumors, one of eight tumor models tested, was the only type of tumor that
responded to arsenic therapy.
Cancer-selective cytotoxics were continually sought after, and a group
of sulfhydryl inhibitors, including oxophenarsine, were evaluated for
anticancer activity. Researchers reported arsenic’s preferential
selectivity for malignant cancer cells in both clinical and radioactive tracer
studies; however, anticancer agents replaced the sulfhydryl inhibitors in the
early 1970s. But the role of arsenic as a therapeutic cancer agent was not
By analyzing traditional cancer treatment preparations, a group of
Chinese physicians discovered a common agent among them —
As2O3. On account of their finding, the group studied
arsenic oxide in a number of cancer types and achieved 90% remission rates in
relapsed acute promyelocytic leukemia. Further studies conducted in Europe and
North America reported similar results.
Despite these advancements, the toxicity of arsenic was once again a
concern. Adverse effects, including carcinogenicity and skin cancer, caused a
decline in the compound’s use in medicine. In 1979, the International
Agency for Research on Cancer classified arsenic and certain arsenic compounds
as agents carcinogenic to humans in their carcinogen classification system.
At the time, arsenic had not been proven to be carcinogenic in animal
models or responsible for an increase in human solid tumors. Today, however,
documentation exists on the effects long-term inorganic arsenic has on humans:
an increase in the risk for cancer, especially of the lungs and skin.
On Sept. 25, 2000, injectable arsenic trioxide (Trisenox, Cell
Therapeutics Inc.) received FDA approval for the treatment of relapsed APL.
According to an FDA press release, approval was based on multicenter
clinical trial results. The study included 40 patients with relapsed or
refractory APL who were assigned to arsenic trioxide transfusions.
Twenty-eight patients in the study population (70%) reached remission
and met the “response” criteria. Median time to remission was 51
The compound works by converting immature cancerous white blood cells
into normal white blood cells, which at times can lead to a sudden increase in
white blood cell count. This increase can be accompanied by the “APL
differentiation syndrome,” which presents with inflammation and fluid
accumulation in the lining of the heart and lungs. The syndrome occurred in
eight of 40 patients in the study (20%), but was not severe enough to interrupt
Additionally in 2001, researchers from the University of Arkansas for
Medical Sciences conducted an efficacy study that demonstrated arsenic
trioxide’s activity in end-stage, high-risk multiple myeloma.
The evaluation included nine patients with advanced refractory multiple
myeloma. Patients were assigned to a fixed-dose of intravenous infusion given
daily for up to 60 days. Four patients completed more than 30 days of infusion;
two experienced >50% reduction in myeloma paraprotein, one had stable
disease and one progressed.
Five patients had <30 days infusion; three progressed and two had
For over 2,000 years the role of arsenic as a curative compound has been
analyzed and questioned. Despite its carcinogenicity and the toxic effects
associated with long-term exposure, scientists and physicians have used the
poison successfully in practice to treat numerous ailments and diseases.
Currently, arsenic trioxide is approved only to treat relapsed or refractory
APL. – by Stacey L. Adams
For more information:
- Antman KH. Introduction: The history of arsenic trioxide in cancer
therapy. Oncologist. 2001;6:1-2.
- Munshi NC. Arsenic trioxide: An emerging therapy for multiple
myeloma. Oncologist. 2001;6:17-21.
- Scheindlin S. The duplicitous nature of inorganic arsenic.
Mol Interv. 2005;60-64.
- Waxman S, Anderson KC. History of the development of arsenic
derivatives in cancer therapy. Oncologist. 2001;6:3-10.
For those who wish a good read that extolls the extraordinary
contributions of Chinese science back to 2000 B.C., I recommend The Man Who
Loved China by Simon Winchester.
– Harry S. Jacob, MD
Today Chief Medical Editor