A cure in the toxin…

Coley [from Starnes, 1992, Nature 357: 11-12]THE year is 1892, and in a small ward of the Memorial Hospital in New York City, a male patient lies dying. He has a large sarcoma (a type of cancerous tumour) that originated on his right arm, and been feverish for 12 hours. His fever isn’t due to the cancer though – it’s a result of an infection his physician gave him. The physician’s name is William B. Coley, and he recently administered an injection of ‘Coley’s toxins’, a potent mix of bacterial toxins that may cure the man of his cancer, but equally may also kill him.

William Coley had for some time observed that his patients experienced a regression in their cancer as a result of infection with a bacterial pathogen. Indeed, Coley had read publications that supported this observation, most notably with sarcoma patients suffering from erysipelas infection – an acute skin infection caused by Streptococcus bacteria. Based on these observations Coley engaged in a system of treatment that would have modern day ethics committees in apoplexy – he set about deliberately inducing erysipelas in his cancer patients.

There was no guarantee that erysipelas would take hold, or that it wouldn’t actually kill the patient. However, by all accounts Coley achieved some definitive results that led to him to further develop his treatment. He set upon the idea of killing the Streptococcus by heat-treatment, and collecting the bacterial extract to inject into the patient – an approach akin to early forms of vaccination – however, the results weren’t so impressive. It wasn’t until he combined the extract of his heat-killed Streptococcus with extract of another heat-killed bacteria, Serratia marcescans (another common cause of wound infections) that he noted reproducible clinical successes. This toxic brew of bacteria extracts was called ‘Coley’s toxins’.

Coley’s toxins fell out of favour with the advent of radiotherapy and chemotherapies. Although these therapies might be thought of as being no less brutal, especially in the early days, they were more generally applicable to a range of cancers. The problem with Coley’s toxin was that it turned out to be specific for quite a small range of otherwise rare cancers, and so it was key to strictly select those patients who could expect to benefit from such treatment – and importantly, those for whom there was no other option due to the advanced stage of their cancer.

This is by no means quackery – it represented an early attempt to affect a treatment for a serious condition based upon the prevailing evidence. However, we would be remiss if we were to ever employ Coley’s toxin as it existed at the turn of the last century. In modern scientific approaches we would seek to identify the specific factor that has a causative link with regression of a sarcoma, whether this be the agent in Coley’s toxin, or the specific factor(s) that the body produces on exposure to Coley’s toxin. We would aim to elucidate its structure, the mechanism by which it functions, whether this can be improved upon, and whether it could be synthesised in a safe and reproducible manner.

Such observations are not limited to Coley’s toxins; other bacteria have been shown to result in regression of cancerous tumours, including Salmonella, Clostridium, and Pseudomonas. It is interesting to consider what extent this phenomenon might be explained in terms of competition between the infecting bacteria and the fast growing, resource-hungry cancerous tumour. The bacteria may do this directly, by secretion of cell-killing agents, or by enjoying the oxygen-depleted core of tumours. Alternatively, bacteria may act indirectly, by stimulating an immune response. It is perhaps unsurprising that bacterial species that have co-evolved with us over millions of years may be able to effectively manipulate our physiology to their own ends.

I first heard of the above historical account of bacterial-cancer interaction in a lecture given by Distinguished Professor Ananda Chakrabarty of the University of Illinois. His recent work has been on the purified product of one such anti-cancer agent, azurin, isolated from the opportunistic pathogen Pseudomonas aeruginosa. In animal models this blue coloured, copper-binding protein has been found to initiate cell death in melanoma and breast cancer cells by binding to, and stabilising, the tumour suppressor protein p53, enabling it to hang around long enough to initiate cell death. The protein is also interesting as it is one of the few bacterial proteins that have been found to cross the blood-brain barrier in man, thus making it useful as a means of targeting and treating deep brain tumours. Up to 50% of cancers have mutations in the p53 gene, thus the Chakrabarty lab is keen to identify any cytotoxic effects that azurin will have against such cancer cells.

Azuring also has also shown evidence of anti-HIV and anti-malarial activity, so it will be interesting to see where research with this protein leads.

Further information:

Starnes, C.O. (1992) Coley’s toxins in perspective. Nature 357: 11-12. [Access]

Yamada et al. (2002) Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer. PNAS 99: 14098-14103 [Access]
Chakrabarty A. (2003) Microorganisms and Cancer: Quest for a Therapy. Journal of Bacteriology, 185: 2683-2686 [Access]

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