Thursday, February 08, 2007

Cheap, safe drug kills most cancers -- but being held up by the need for regulatory approval

New Scientist has received an unprecedented amount of interest in this story from readers. If you would like up-to-date information on any plans for clinical trials of DCA in patients with cancer, or would like to donate towards a fund for such trials, please visit the site set up by the University of Alberta and the Alberta Cancer Board. We will also follow events closely and will report any progress as it happens.

It sounds almost too good to be true: a cheap and simple drug that kills almost all cancers by switching off their "immortality". The drug, dichloroacetate (DCA), has already been used for years to treat rare metabolic disorders and so is known to be relatively safe. It also has no patent, meaning it could be manufactured for a fraction of the cost of newly developed drugs.

Evangelos Michelakis of the University of Alberta in Edmonton, Canada, and his colleagues tested DCA on human cells cultured outside the body and found that it killed lung, breast and brain cancer cells, but not healthy cells. Tumours in rats deliberately infected with human cancer also shrank drastically when they were fed DCA-laced water for several weeks.

DCA attacks a unique feature of cancer cells: the fact that they make their energy throughout the main body of the cell, rather than in distinct organelles called mitochondria. This process, called glycolysis, is inefficient and uses up vast amounts of sugar.

Until now it had been assumed that cancer cells used glycolysis because their mitochondria were irreparably damaged. However, Michelakis's experiments prove this is not the case, because DCA reawakened the mitochondria in cancer cells. The cells then withered and died (Cancer Cell, DOI: 10.1016/j.ccr.2006.10.020).

Michelakis suggests that the switch to glycolysis as an energy source occurs when cells in the middle of an abnormal but benign lump don't get enough oxygen for their mitochondria to work properly (see diagram). In order to survive, they switch off their mitochondria and start producing energy through glycolysis.

Crucially, though, mitochondria do another job in cells: they activate apoptosis, the process by which abnormal cells self-destruct. When cells switch mitochondria off, they become "immortal", outliving other cells in the tumour and so becoming dominant. Once reawakened by DCA, mitochondria reactivate apoptosis and order the abnormal cells to die.

"The results are intriguing because they point to a critical role that mitochondria play: they impart a unique trait to cancer cells that can be exploited for cancer therapy," says Dario Altieri, director of the University of Massachusetts Cancer Center in Worcester.

The phenomenon might also explain how secondary cancers form. Glycolysis generates lactic acid, which can break down the collagen matrix holding cells together. This means abnormal cells can be released and float to other parts of the body, where they seed new tumours.

DCA can cause pain, numbness and gait disturbances in some patients, but this may be a price worth paying if it turns out to be effective against all cancers. The next step is to run clinical trials of DCA in people with cancer. These may have to be funded by charities, universities and governments: pharmaceutical companies are unlikely to pay because they can't make money on unpatented medicines. The pay-off is that if DCA does work, it will be easy to manufacture and dirt cheap.

Paul Clarke, a cancer cell biologist at the University of Dundee in the UK, says the findings challenge the current assumption that mutations, not metabolism, spark off cancers. "The question is: which comes first?" he says.


A Clarion Call for Health Independence

Lorenzo's Oil (1992) is one of the best movies you've never seen. This incredible drama hit the big screen for two seconds before skidding into rental stores, where it failed to find the wider audience it deserves. Lorenzo's Oil is a compelling reality-based story of parental devotion and the triumph of truth over authority. It is a beautifully acted and skillfully directed tribute to the power of love to prevail, it seems, over death itself.

The movie opens in 1983. Augusto (Nick Nolte) and Michaela (Susan Sarandon) Odone watch in horror as their only son, Lorenzo, rapidly degenerates from a disease so rare that no one is pursuing a cure. Indeed, at first, no one knows what is happening to the five-year-old. Lorenzo is ultimately diagnosed with adrenoleukodystrophy. ALD is an inherited, sex-specific genetic disorder passed from mother to son in which the myelin sheaths - the fatty coverings that surround and protect nerve cells in the brain - deteriorate, resulting in physical and mental breakdown. (As a disease, it is related to multiple sclerosis.) In more practical terms, the breakdown means that Lorenzo dissolves from being a precocious and delightful child into a violently disturbed boy who is finally unable to perform simple biological functions such as swallowing.

The boy is going to die and soon; that is the consensus of every doctor and scientist whom the Odones consult. Lorenzo is going to live; that is the quest of his parents. They have no medical or scientific training. Augusto is an Italian economist; Michaela is an Irish-American linguist. Nevertheless, as Augusto states, "When you are in a strange country, you learn the language." At first, the Odones speak the language (medicine) in a conventional manner. Because ALD is both a newly discovered disease and a rare one, there is little hard data or funding available. At first, they accept the experimental treatments, the need for control-group research, and other standard slow-moving approaches. But Lorenzo does not have the luxury of time.

Soon the Odones are ransacking medical libraries and pursuing every footnote on human or animal research that bears even remotely upon ALD. They pursue information from doctors and researchers with a passion commonly associated with stalkers. Eventually, the Odones organize an international symposium to discuss ALD. A division of labor emerges through which Augusto becomes the primary researcher and Michaela the caregiver, but each participates equally in the crusade to save Lorenzo.

Many doctors are hostile, not helpful. Clearly, they are annoyed and offended by aggressive lay people who do not accept their authority but, instead, have the audacity to seek a cure. Even some members of a support group for parents of ALD boys condemn the Odones for not facing the reality of their son's impending death. Alone and racing against death, the Odones persist for three years before finding the clue that leads them not to a cure but to a treatment; oleic acid can destroy the fatty acids that are destroying Lorenzo's brain. Augusto develops a formula he calls "Lorenzo's Oil" - a combination of two fats extracted from olive oil and rapeseed oil. The formula proves remarkably effective in presymptomatic boys with the ALD gene because of its ability to halt the body's production of the specific acids that attack the myelin sheaths.

Dr. Hugo Moser, the world's foremost authority on ALD, subsequently conducted a 10-year study in which 120 presymtomatic boys with the gene for ALD were given Lorenzo's Oil. Eighty-three of them remained disease-free. From the data, Moser concluded Lorenzo's Oil reduced the onset of disease by half. Augusto later received an honorary Ph.D. for his work.

For Lorenzo himself, however, the discovery came too late. The treatment could not repair the extensive damage to his brain. The real life Augusto shifted his attention to research on the regeneration of brain tissue. The movie ends with a 12-year-old Lorenzo who has improved significantly enough to be able to communicate through sign language. Today, Lorenzo is 28 years old. Although he has little body function, his mind is alert and he is reported to enjoy music and listening to books.

Several factors combine to make Lorenzo's Oil a superb film. The acting is exquisite. Saradon, of whom I am generally not a fan, received a well-deserved Oscar nomination for her role. The director and co-author, George Miller, whose credits include Mad Max and The Witches of Eastwick, produces a near-flawless movie that is brilliantly edited. He also provides a fine emotional balance. A medical doctor himself, Miller does not demonize the experts who obstruct the Odones' quest. He condemns the mechanistic approach now prevalent in medicine without condemning the people who employ it. To this end, Peter Ustinov is perfectly cast as a sympathetic, well-meaning doctor who simply cannot help as long as he stays within protocol. Miller's background also imbues the movie with a medical accuracy that is disturbing and difficult to watch but never gratuitously so. You hate to see Lorenzo suffer but his suffering, after all, is the crux of the film.

The movie's themes are haunting. Perhaps the most obvious one is the power of parental love. This theme is best captured by Sarandon's fierce portrayal of Michaela, which reveals a maternal devotion that is literally frightening in its intensity. The power of marriage is an equally strong theme. It is inconceivable that the Odones could have endured Lorenzo's illness, their financial difficulties, and the scorn of the world without having each other. Especially today when marriage (or partnership) is often viewed as disposable, it is heartening to view a family who will never abandon or give up on itself.

On a more political level, the overriding theme is "Question Authority." Early in Lorenzo's Oil, Augusto requests medical material to better understand what is happening to his son. Without meaning offense, a doctor assures Augusto that he could not make possibly make sense of the studies. The Odones do not stop questioning even when the responses are openly hostile. Their willingness to tolerate both unlikely theories and the skepticism those theories elicit is precisely what leads them to the source of an effective treatment: olive oil. It is not merely that experts are shown to be fallible and constrained by narrow thinking. It is that ordinary people are shown to be capable of realizing their own self-interest even in "expert only" areas.

Finally, Lorenzo's Oil is a counterargument to the assumed need for government funding and law to regulate all things medical in order to ensure progress and quality care. The movie is a clarion call for individuals to take control of their own bodies and their own medical well being. It is the triumph of personal responsibility over bureaucracy, the individual over the system.



Just some problems with the "Obesity" war:

1). It tries to impose behavior change on everybody -- when most of those targeted are not obese and hence have no reason to change their behaviour. It is a form of punishing the innocent and the guilty alike. (It is also typical of Leftist thinking: Scorning the individual and capable of dealing with large groups only).

2). The longevity research all leads to the conclusion that it is people of MIDDLING weight who live longest -- not slim people. So the "epidemic" of obesity is in fact largely an "epidemic" of living longer.

3). It is total calorie intake that makes you fat -- not where you get your calories. Policies that attack only the source of the calories (e.g. "junk food") without addressing total calorie intake are hence pissing into the wind. People involuntarily deprived of their preferred calorie intake from one source are highly likely to seek and find their calories elsewhere.

4). So-called junk food is perfectly nutritious. A big Mac meal comprises meat, bread, salad and potatoes -- which is a mainstream Western diet. If that is bad then we are all in big trouble.

5). Food warriors demonize salt and fat. But we need a daily salt intake to counter salt-loss through perspiration and the research shows that people on salt-restricted diets die SOONER. And Eskimos eat huge amounts of fat with no apparent ill-effects. And the average home-cooked roast dinner has LOTS of fat. Will we ban roast dinners?

6). The foods restricted are often no more calorific than those permitted -- such as milk and fruit-juice drinks.

7). Tendency to weight is mostly genetic and is therefore not readily susceptible to voluntary behaviour change.

8). And when are we going to ban cheese? Cheese is a concentrated calorie bomb and has lots of that wicked animal fat in it too. Wouldn't we all be better off without it? And what about butter and margarine? They are just about pure fat. Surely they should be treated as contraband in kids' lunchboxes! [/sarcasm].

Trans fats:

For one summary of the weak science behind the "trans-fat" hysteria, see here. Trans fats have only a temporary effect on blood chemistry and the evidence of lasting harm from them is dubious. By taking extreme groups in trans fats intake, some weak association with coronary heart disease has at times been shown in some sub-populations but extreme group studies are inherently at risk of confounding with other factors and are intrinsically of little interest to the average person.

The use of extreme quintiles (fifths) to examine effects is in fact so common as to be almost universal but suggests to the experienced observer that the differences between the mean scores of the experimental and control groups were not statistically significant -- thus making the article concerned little more than an exercise in deception


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