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Arsenic (33As) is one of the most toxic heavy elements derived from the natural environment. The name 'arsenic' is derived from the Greek word 'arsenikon' meaning 'potent'.

Arsenicals (compounds that contain arsenic) have long been known as poisons and paradoxically used as therapeutic agents in the history of medi-cine.1 As early as 2000 BC, arsenic trioxide (As2O3), obtained from smelting copper, was used as a drug. Hippocrates (460 to 377 BC) used orpiment (As2S3) and realgar (As2S2) as escharotics (corrosive agents) to tumors or cancerous ulcers. Aristotle (384 to 322 BC) and Pliny the Elder (AD 23 to 79), documented the medicinal properties of arsenicals. Galen (AD 130 to 200) recommended a paste of arsenic sulfide for the treatment of ulcers. Paracelsus (1493 to 1541) used elemental arsenic extensively. He broke the rigid tradition of Galenic medicine and administered realgar internally to treat cancer-like tumors. Paracelsus gave cogency to the belief that there was a therapeutic window for toxic compounds in which clinical benefits can be achieved without extreme toxicity. In the eighteenth century, Fowler's solution (1% potassium arsenite) was used for the relief of various ailments. Arsenicals remained as the mainstay of medicine in the Materia Medica in the nineteenth century2 and were used as

Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine Edited by Gielen and Tiekink © 2005 John Wiley & Sons, Ltd the remedies for such diverse diseases or complaints as anorexia and other nutritional disturbances, neuralgia, rheumatism, asthma, tuberculosis, diabetes, intermittent fever, skin disorders, hematologic abnormalities, malaria and syphilis.2,3 At that time, Fowler's solution was so popular that it was mocked in cartoons. Fowler's solution was the primary therapy for chronic myelogenous leukemia (CML) until it was replaced by radiation and cytotoxic chemotherapy in the twentieth century.

In the early twentieth century, physicians still commonly used arsenicals to treat pellagra and malaria.1 In 1905, Fritz Swchaudinn proved the cause of syphilis to be Treponema pallidum. Soon later in 1910, Paul Ehrlich synthesized the arsenical compound Salvarsan or 606 (as the 606th compound tested in his laboratory) and its derivative that became the standard effective therapeutic agents for the treatment of syphilis for nearly 40 years until the introduction of penicillin.4

Arsenicals were also administered as vaginal inserts or powder for insufflation for treating vaginal discharge of any origin.1 They were apparently effective against Trichomonas, and were only subsequently replaced by metronidazole in the mid-twentieth century.

Although safer and more effective therapeutic agents have, over the years, replaced most medicinal uses of arsenicals, arsenicals remain important in the chemotherapy of trypanosomal infections.5 Melarsoprol is the arsenic drug currently approved for the treatment of late-stage African trypanosomiasis.

Arsenicals have been used in Chinese traditional medicine for more than 1000 years. Arsenic trioxide (As2O3), also called Pi shuang, was recorded in the Compendium of Materia Medica (edited by Li Shizhen, 1518-1593). Pi shuang and Xiong Huang (realgar, As2S2) have been used for the treatment of cancer and other conditions.6 Chinese physicians from Harbin led the revival in the medicinal use of arsenicals as anti-cancer agents in the early 1970s, when they used arsenic trioxide for treating cancers including esophageal carcinoma, malignant lymphoma and leukemia.7 In particular, notable success was observed in the treatment of acute promyelocytic leukemia (APL) with the characteristic chromosome translocation t(15;17).8,9 Long-term clinical trials showed that low plasma concentrations of As2O3 (1-2 mM) are effective in the treatment of APL,10 even in the patients resistant to all trans-retinoic acid (ATRA) or conventional chemotherapy.11 Complete remission rates (CRR) in the newly diagnosed and relapsed patients with APL were between 85 and 93%.9,11 13 More importantly, the side effects associated with arsenic were mild and responded to symptomatic treatment or resolved with dose reduction, while other severe toxic effects, such as myelosuppression commonly associated with conventional chemotherapy, were absent.9,11 13 After the successful clinical trials, the Food and Drug Administration (FDA) of USA approved arsenic trioxide injections (Trisenox®) in the year 2000 for the treatment of APL in adult patients who fail to respond to other chemotherapy or have relapsed disease.14 The success of using arsenic in the treatment of APL has prompted researchers to evaluate the potential of arsenic in treating other malignant disorders, including chronic lymphocytic leukemia (CLL),15 multiple myeloma (MM),15,16 and other solid tumors such as neuroblastoma,17 gastric18 and cervical tumors.19 This chapter focuses on the uses of arsenic for the treatment of malignancies.

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