Friday, 11 June 2010

Traditional Chinese Arsenic for Cancer

Arsenic is another favourite poison of crime writers and has a long history of medical use. As usual, it’s a bit difficult to imagine how it could ever have been considered a medicine, considering the effects of a toxic dose:

“Soon after taking it the suffer experiences faintness, nausea, sickness, epigastric pain and tenderness. The symptoms quickly increase. The vomit is brown, and often streaked with blood; the pain is very severe; there is profuse diarrhoea, with much tenesemus [painful straining]; and there are cramps in the calves and legs. The vomiting becomes violent and incessant; there is a burning sensation in the throat, with intense thirst. Soon collapse sets in; the skin is cold, the pulse small and feeble, and the patient dies collapsed.”

- W. Hale White, Material Medica (1892).

Understandably, Agatha Christie and her ilk tended to omit the more propulsive effects of arsenic on the upper and lower gastrointestinal tract, but they otherwise describe fatal arsenic poisoning pretty well. It’s violent, nasty and painful.

It’s difficult to keep an account of the use of arsenic in medicine short, but thought-provoking (generally the aim), so interesting is the long history of the use of this poison. Where ever you turn, another fascinating connection pops up. Composing a pithy post is further complicated by the number of arsenic-containing compounds (“arsenicals” rather than simple arsenic oxides and sulfides) which have also been used as therapeutics, and provide a springboard for an adventurous dive in a completely different direction.

Arsenic is a metal (technically, a metalloid) that occurs in nature, mainly in two sulphur-containing forms, red arsenic (realgar) and yellow arsenic (orpiment); if either is burned in air the trioxide form, white arsenic, is the result. It’s not hard to imagine that when the ancients found such a rare, colourful and mysterious material that they would have thought it was a gift from the gods. Hippocrates described how to find arsenic, and how it could be used as a medicine in his view (earlier uses are entirely feasible though). Various later Greek physicians that found it killed lice and caused skin growths to slough off. Around the same time arsenic entered recorded use in far eastern Asian folk remedies, usually in mixtures with other herbal or animal components. TCM remedies are rightly treated with caution by “western” clinicians, since they frequently contain arsenic and long term exposure to low doses of arsenic is known to lead to a variety of tumours. In contrast to the arsenic that may naturally occur in soil and our water supplies, arsenic in TCM isn't a contaminant but rather purposeful ingredients, and has been for hundreds of years.

Although the use of arsenic in medicine has a long history in Europe, it was during the 18th century that the use of arsenic flourished, as the self-administration of poisons as therapeutics became fashionable. Most famously, physician Thomas Fowler produced a solution of arsenic (in conjunction with Withering of digitalis fame) which although initially indicated for "periodic fevers" and "agues" (malaria) inevitably became a popular panacea. As with so many poisonous preparations of the age, Fowler's Solution soon became a popular nerve and stomach tonic, a treatment for hysteria, dropsy, ulcers, and cancer. It was used externally to kill parasites, to treat skin conditions (eg psoriasis) and as an antiseptic. Every well-to-do home would have had a bottle, and felt safer for it. Physicians' recommendations for dosage varied widely from a few drops to spoonfuls several times a day. This was the era of theatrical pharmacology: drugs that had a violent effect on the body were held to have equally potent effects on disease. Arsenic became known as "the mule", not only because it's effects on the body were unpredictable and dangerous, but also because of the perception that it could perform in all diseases, under all circumstances. Amongst its other actions on the body, arsenic produced generalised swelling of tissues, creating the illusion of weight gain and a general improvement in health; many diabetics’ lives were shortened as a result.

Towards the end of the 19th century, the use of heroic dosing in general had declined and Fowler's Solution was used more cautiously. However, it was still held to be efficacious in a variety of clinical settings. Slowly, the use of such tonics declined as more clearly efficacious drugs came into use. There was one notable exception: arsenic remained in use for the treatment of leukaemia well into the 1930s, until chemotherapeutics and radiotherapy came to the fore. The 1936 edition of W. Hale White's Materia Medica notes that arsenic had been replaced by diathermy for skin conditions, while preparations of liver had surpassed it in the treatment of anemia. In contrast to earlier editions, no other conditions rate a mention. Arsenic had finally had it's day.

Or had it?

Chinese physicians began investigating TCM preparations as cancer treatments in the 1970s and reported their results to the world. One such remedy - Ailing-1 - appeared to be beneficial in a subgroup of patients who all had acute promelocytic leukaemia (APL). Patients were followed for long periods, and survival rates were impressive. Ailing-1 is a typical TCM remedy composed of several ingredients, but the 1% arsenic stood out as a likely active ingredient (the next likely would probably be the mercury). This was indeed found to be the case, and arsenic has now been the subject of several trials worldwide for APL, the consensus being that it has efficacy in this cancer. In all cases, arsenic has been used in patients who have relapsed after successful treatment with, or have developed resistance to conventional treatments. There is now ongoing interest in using arsenic again as an adjunct to existing therapies in other malignancies.

How does it work? As with any chemotherapy, selective toxicity is probably the simplest explanation. Different cells respond to poisons at different doses; APL cells are sensitive to low doses of arsenic. The molecular jiggery-pokery is a little to complex to describe here (there’s a link at the end for those who think they can stomach it.)

While it easy to retort that TCM simply reignited interest in a known use for arsenic in this case, it’s not the first time that elements of a TCM remedy have been purified and employed by medicine. That said, there aren’t many such examples and most of TCM is probably dangerous nonsense.

More on the mechanism of action of arsenic in APL

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