History of Medicine

Arsenic: medicinal double-edged sword

Despite its proven therapeutic benefits, concerns of toxicity and carcinogenicity caused a decline in the medicinal use of arsenic.

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 as enemas.

Arsenic
For over 2,000 years the role of arsenic as a curative compound has been analyzed and questioned.

© 2008/Custom Medical Stock Photo

Arsenic as materia medica

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 and leukemia.

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.

New uses for medicinal arsenic

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 over.

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.

Current role in cancer treatment

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 days.

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 therapy.

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="" stable="" disease.="">

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.

PERSPECTIVE

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
HemOnc Today Chief Medical Editor

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 as enemas.

Arsenic
For over 2,000 years the role of arsenic as a curative compound has been analyzed and questioned.

© 2008/Custom Medical Stock Photo

Arsenic as materia medica

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 and leukemia.

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.

New uses for medicinal arsenic

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 over.

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.

Current role in cancer treatment

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 days.

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 therapy.

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="" stable="" disease.="">

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.

PERSPECTIVE

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
HemOnc Today Chief Medical Editor