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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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September 11, 2009

Antioxidants and Cancer: Backwards?

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Posted by Derek

Readers may remember a study from earlier this year that suggested that taking antioxidants canceled out some of the benefits of exercise. It seems that the reactive oxygen species themselves, which everyone's been assuming have to be fought, are actually being used to signal the body's metabolic changes.

Now there's another disturbing paper on a possible unintended effect of antioxidant therapy. Joan Brugge and her group at Harvard published last month on what happens to cells when they're detached from their normal environment. What's supposed to happen, everyone thought, is apoptosis, programmed cell death. Apoptosis, in fact, is supposed to be triggered most of the time when a cell detects that something has gone seriously wrong with its normal processes, and being detached from its normal signaling environment (and its normal blood supply) definitely qualifies. But cancer cells manage to dodge that difficulty, and since it's known that they also get around other apoptosis signals, it made sense that this was happening here, too.

But there have been some recent reports that cast doubt on apoptosis being the only route for detached cell death. This latest study confirms that, but goes on to a surprise. When this team blocked apoptotic processes, detached cells died anyway. A closer look suggested that the reason was, basically, starvation. The cells were deprived of nutrients after being dislocated, ran out of glucose, and that was that. This process could be stopped, though, if a known oncogene involved in glucose uptake (ERBB2) was activated, which suggests that one way a cancer cells survive their travels is by keeping their fuel supply going.

So far, so good - this all fits in well with what we already know about tumor cells. But this study found that there was another way to keep detached cells from dying: give them antioxidants. (They used either N-acetylcysteine or a water-soluble Vitamin E derivative). It appears that oxidative stress is one thing that's helping to kill off wandering cells. On top of this effect, reactive oxygen species also seem to be inhibiting another possible energy source, fatty acid oxidation. Take away the reactive oxygen species, and the cells are suddenly under less pressure and have access to a new food source. (Here's a commentary in Nature that goes over all this in more detail, and here's one from The Scientist).

They went on to use some good fluorescence microscopy techniques to show that these differences in reactive oxygen species are found in tumor cell cultures. There are notable metabolic differences between the outer cells of a cultured tumor growth and its inner cells (the ones that can't get so much glucose), but that difference can be smoothed out by. . .antioxidants. The normal process is for the central cells in such growths to eventually die off (luminal clearance), but antioxidant treatment kept this from happening. Even more alarmingly, they showed that tumor cells expressing various oncogenes colonized an in vitro cell growth matrix much more effectively in the presence of antioxidants as well.

This looks like a very strong paper to me; there's a lot of work in it and a lot of information. Taken together, these results suggest a number of immediate questions. Is there something that shuts down normal glucose uptake when a cell is detached, and is this another general cell-suicide mechanism? How exactly does oxidative stress keep these cells from using their fatty acid oxidation pathway? (And how does that relate to normally positioned cells, in which fatty acid oxidation is actually supposed to kick in when glucose supplies go down?)

The biggest questions, though, are the most immediate: first, does it make any sense at all to give antioxidants to cancer patients? Right now, I'd very much have to wonder. And second, could taking antioxidants actually have a long-term cancer-promoting effect under normal conditions? I'd very much like to know that one, and so would a lot of other people.

After this and that exercise study, I'm honestly starting to think that oxidative stress has been getting an undeserved bad press over the years. Have we had things totally turned around?

Comments (43) + TrackBacks (0) | Category: Biological News | Cancer


COMMENTS

1. processchemist on September 11, 2009 8:15 AM writes...

A friend of mine works on oxidative stress. The only thing I learned talking with him it's that's a minefield. Anyone remember this PNAS (in vivo antiproliferative effects of ascorbic acid)?

http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=18682554&nlmid=7505876&db=pubmed&url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18682554

The elesclomol fiasco it's maybe related to the mess of "paradox effects" of prooxidants and antioxidants...

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2. Chemjobber on September 11, 2009 9:20 AM writes...

Will Reynolds link to this one? I predict not, but I could be wrong. McArdle will, if it's slow over there.

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3. Curious Wavefunction on September 11, 2009 9:28 AM writes...

Interesting study. So it seems that antioxidants could keep cancer cells going by gobbling up free radicals. Could this also be true for microbes? Are there examples where antioxidant intake made microbial infections worse?

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4. Sili on September 11, 2009 10:08 AM writes...

I know it's supposed to be sad, but I can't help but laugh myself silly.

Of course, the alties will decry this as being part of Teh Big Pharma Conspiracy and keep shilling ridiculously enormous doses of their own expensive brand vitamins for everything.

I hope Goldacre has seen this. I can really see him working himself into a righteous lather over this.

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5. RB Woodweird on September 11, 2009 10:11 AM writes...

How long until we see the first health and sports drinks "Rich In Oxidants!"?

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6. barry on September 11, 2009 10:31 AM writes...

The next experiments should involve adding oxidative stress. Artemisinin has been shown to kill the parasites of malaria through oxidative stress. If it can also enforce anoikis (death of detached cells), it may block or reduce cancer metastases.

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7. gyges on September 11, 2009 10:51 AM writes...

"And second, could taking antioxidants actually have a long-term cancer-promoting effect under normal conditions? "

Wasn't there a Finnish study that found that people who took vitamin supplements had a slightly higher incidence of cancer. The study was repeated by a group in California, the same result was found. All this is from memory; say, published within the last five years.

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8. Chemgeek on September 11, 2009 11:18 AM writes...

So, too much of a good thing may be bad? Wow, who'da thunk it.

I'm sure the altie spin will be some sort of oxidative/antioxidant/toxin/happy thoughts/water balance.

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9. MTK on September 11, 2009 11:54 AM writes...

Chemgeek,

Don't forget chelation.

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10. MTK on September 11, 2009 12:03 PM writes...

gyges,

I did a quick search and this may be what you are referring to.

http://www.nutraingredients.com/Research/Study-links-antioxidant-supplements-to-increased-mortality

It was a meta-study whose methodology, conclusions, and assertions you can read in the story. The irony is that the supplement groups sound strangely Big Pharma-like in their criticisms of the studies.

I also think there could be some parallels (not wrt to cancer obviously) to Omega 3 consumption.

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11. Kismet on September 11, 2009 12:07 PM writes...

RB Woodweird, I don't know if it will become mainstream, but alties in fact do already use *hydrogen peroxide* enemas.

We have a lot of data suggesting that antiox may increase mortality, but I haven't seen much about cancer incidence per se.

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12. CM on September 11, 2009 12:28 PM writes...

Clearly the antioxidants were not correctly potentized and diluted properly, thus the lack of benefit. ;)

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13. anon on September 11, 2009 1:16 PM writes...

Just out of curiosity, if barry is correct and Artemisinin were to block metastases would it be patentable? (For, now that the idea is in the public domain). I'm not sure, but I thought Big Pharma would lose some sort of patent rights which would not allow them to make enough profits to fund such multi-million dollar trials to test this hypothesis. Anyone know?

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14. Medical Toaster on September 11, 2009 1:20 PM writes...

Antioxidants reduce DNA damage that can result in the mutations required to develop cancer in the first place. Antioxidants will act to suppress cancer before it occurs. After cancer develops these studies suggest that antioxidants may enhance cancers ability to survive, proliferate and metastasize. So the key question is whether it is better to minimize mutation or attempt to minimize the chances that cancer will proliferate and metastasize. What should be clear to anyone with sense is that healthy cells do not need additional oxidative stress. Adding megadoses of antioxidants may not help much but the conclusion to be drawn is to not take the antioxidants not to add oxidants.

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15. Ed on September 11, 2009 1:33 PM writes...

A couple of lung cancer prevention trials have shown elevated cancer rates in groups taking vitamin E supplements IIRC.

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16. Beth Moell on September 11, 2009 1:33 PM writes...

Wow, I have seen first hand people with stage four cancer have amazing results with a high antioxidant's drink that deliver SOD, Glutathione, Resveratrol and Ellagic Acid. The key to not getting cancer is to nourish and protect the body.
I have watch 9 close family members die of cancer doing it the medical way. This is a bunch of B.S.
If we would get the horse ahead of the cart and learn how value nutrition, and protect our bodies we wouldn't get cancer.
Crap it makes me so mad that it could be as simple as that.

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17. VanillaBullshit on September 11, 2009 1:48 PM writes...

It's not as simple as that. Hope that helps.

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18. Kathy on September 11, 2009 1:53 PM writes...

This was very technical research, aimed at finding the WHY behind what observational studies of cancer patients have been telling them for years. The thing to keep in mind for practical purposes is that there is a huge different between antioxidant supplementation, and the antioxidants you get from food. They've known for ages, and recent research confirms, that eating antioxidant rich foods helps immune function and very slightly reduces cancer risk. Antioxidant supplements, on the other hand, have been shown in scads of studies to produce variable and often contradictory effects. This study doesn't change anything, it just sheds a little more light, at the biochemical level, on why this is so.

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19. speedwell on September 11, 2009 3:10 PM writes...

Beth Moell, I watched my mother die from breast cancer while following a "nutritionally based" cancer "treatment." We couldn't get her to go to an oncologist until it was too late. The doctor said if she had come in when they first discovered her simple, uncomplicated tumor, there would have been a good chance she could have survived. She frequently skipped chemo and radiation appointments, refused to take her prescriptions, and sucked noni juice like Kool-Aid. Thanks to morons like you who turned her against modern, effective medicine, I don't have a mom anymore. Thanks a whole f**king lot, moron.

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20. jaytee on September 11, 2009 3:21 PM writes...

Just eat and drink healthy and don't take anti-oxidant supplements. Sometimes you have to go back to basics. I asked my wife's oncologist what I thought was a stupid question 6 months ago. If vitamins tablets are good for normal cells why wouldn't they also be good for cancer cells? Looks like it wasn't so stupid.

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21. ryan on September 11, 2009 3:26 PM writes...

Chemjobber, one of the reasons I keep reading Glenn Reynold's blog is that he does link stuff that may not be politically incorrect. That is just because a scientific study comes up with results that differ from what he hoped they would show, it is still knowledge that is useful in figuring out what is really going on. Only when we truly understand something will we know how to control it. From the sound of this simple summary it sounds like may need to look into different defenses for different stages of cancers. Pre-cancer may like having more antioxidants whereas after the tumors start then switch to something else. Studies like this are great because they are looking at the actual mechanics of how these things happen. That is much more useful then some statistical study. "We found it more likely to die from taking this pill then that one" And a world of difference from the anecdotal "my sister fought off prostate cancer by only eating organic nuts" ... um sure dude whatever.

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22. David Govett on September 11, 2009 3:41 PM writes...

The only thing we discover is our ignorance.

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23. qetzal on September 11, 2009 3:58 PM writes...

Medical Toaster wrote:

Antioxidants reduce DNA damage that can result in the mutations required to develop cancer in the first place. Antioxidants will act to suppress cancer before it occurs.

It's nowhere near that simple. Consider the quintessential antioxidant sodium ascorbate (Vitamin C). Under some conditions, it actually causes DNA damage. (For example, see here.)

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24. David on September 11, 2009 5:25 PM writes...

About 4 years ago, there was a poster paper prsented at the AACR meeting regarding anti-oxident use and aggressiveness of breast cancer. The investigators looked at what antioxidents were taken by women in the 6 months (or so) prior to the diagnosis of breast cancer. Those who took antioxidents tended to have larger, higher grade tumors, if I recall correctly. Given the retrospective nature of the study one could not come to strong conclusions but it does provide the rational for more study.

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25. steve on September 11, 2009 5:27 PM writes...

There have been some "alternative" suggestions over the years suggesting the health benefits of hydrogen peroxide. These suggestions have been disregarded by the antioxidant crowd. I wonder if there is something to it?

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26. Mary on September 11, 2009 5:41 PM writes...

Very interesting.
My money is on the health benefits of gin.

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27. Gateway1 on September 11, 2009 5:47 PM writes...

Derek, the data you cite as somehow new has been part of the discussion on the effects of anti-oxidants for over twenty five years.

So Yawn. But you never fail to latch onto anything, however tenuous, which promotes your industry. I suppose if Merck patented vitamin E and sold it at $100 per dose, you'd be all for them.

You are a willing foot-soldier for the Pfizers of the world.

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28. Chemjobber on September 11, 2009 7:32 PM writes...

Ryan -- I like and read his blog, too. It's just that I suspect this wasn't Reynolds' brand of counter-intuitive. As I said, maybe I'm wrong. (It's really hard to know what the dude links, as many as he puts out a day.)

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29. anon on September 11, 2009 8:54 PM writes...

Hunch alert: my guess is that large doses of E and C in healthy people is not a good idea. Insufficient info to make a real judgment, but that's how I'm voting "with my mouth", as it were.

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30. metaphysician on September 12, 2009 10:08 AM writes...

Maybe this should also go under "Snake Oil". . .

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31. Rich on September 12, 2009 12:05 PM writes...

On Artemenisene and cancer:
http://seattlepi.nwsource.com/local/...cerherb14.html

And a pubmed abstract:
1: Cancer Lett. 2008 Oct 4. [Epub ahead of print] Links
Synthesis and anti-cancer activity of covalent conjugates of artemisinin and a transferrin-receptor targeting peptide.

Oh S, Kim BJ, Singh NP, Lai H, Sasaki T.
Department of Chemistry, University of Washington, Box 351700, Seattle, WA 98195-1700, USA.
Artemisinin, a natural product isolated from Artemisia annua L., shows a unique anti-cancer activity by an iron dependent mechanism. Artemisinin was covalently conjugated to a transferrin-receptor targeting peptide, HAIYPRH that binds to a cavity on the surface of transferrin receptor. This enables artemisinin to be co-internalized with receptor-bound transferrin. The iron released from transferrin can activate artemisinin to generate toxic radical species to kill cells. The artemisinin-peptide conjugates showed potent anti-cancer activity against Molt-4 leukemia cells with a significantly improved cancer/normal cells selectivity.
---------------

When taking most chemotherapy regimens, it is well established that antioxidant supps should be avoided. The thinking is that eth supps protect the cancer cells. Maybe they protect cancer cells from the body's killing mechanisms too.

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32. Bill Sardi on September 12, 2009 1:23 PM writes...

Cell dish studies mislead. Toxic cancer treatments (radiation, chemo) generate free radicals, which is why there are so many side effects associated with cancer treatment, and mortality itself emanating from cancer treatment. Cancer treatment is horribly non-selective -- it damages healthy tissue too. Available data suggests use of antioxidant therapy following treatment to limit damage to the brain (chemo brain) and tissues surrounding the area of treatment, particularly the heart. Cancer patients who die of heart failure while under treatment for cancer, the doctor says "we got the cancer, but unfortunately he had a weak heart." It was the cancer treatment that irrepairably damaged the heart and caused early death. Do not fear antioxidant therapy during cancer treatment if you want to survive.

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33. Kismet on September 12, 2009 4:00 PM writes...

Gateway1, but his industry *does* look good. Despite its fucked up ethics, despite all those problems, the pharma biz has provided actual cures and will hopefully continue to do so. The future lies in biomedical research and pharma, not supplements, not diet or any such crap.

But yeah, the old hypotheses of oxidative damage & disease have been crumbling for some time...

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34. RTW on September 12, 2009 9:45 PM writes...

Back in the mid 1980's I was interested in looking at Artemenisene derivatives in anticancer screens. I was starting my career in Anti-Cancer research at the time, and many such drugs where reactive, or DNA binding type materials. My rational was that the stabilized peroxide moety of Artemenisene might have interesting anti-cancer properties. We all know afterall that peroxides are toxic to all sorts of living things.

Also since the compounds where already used in folk medicine, and being taken seriously as anti-malerials they where apparently relatively non toxic to healthy cells. My director thought it a crazy idea, and besides what did I know - I didn't hold a PhD!

So - it will probably take someone with the will to buck the status quo to really investigate this. Good luck to them....

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35. Vader on September 14, 2009 10:07 AM writes...

A lot of people act like morbidity and mortality is somehow unnatural, the result of biology gone awry, with diet a favorite culprit.

All of us have a probability of death of 1.000. Sooner or later we're going to die of *something.*

This is not to condemn stuff that measurably extends quality years of living. Statins *good*. But it strikes me that things like antioxidants and vitamin supplements are right down in the noise level, at best.

Something pretty weird I ran across lately is a fad for taking metformin off-label as a "life prolongation" drug. Metformin is a pretty good drug, but I suspect it will do squat to prolong the lives the majority of people who do not suffer from metabolic disorder. And no drug is completely safe; if you work at it hard enough, you can kill yourself with metformin by going into lactic acidosis, a fairly nasty way to go.

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36. Kismet on September 14, 2009 10:40 AM writes...

Well, Vader I think you should read up on Vitamin D and K2 then. Those are vitamins. They likely extend (healthy) life span of the elderly, it's not noise.

Furthermore, it doesn't matter whether morbidity and mortality is natural or not (do not commit the natural fallacy), BUT morbidity and mortality is pretty darn bad, so there's no reason not to prevent death. Diet also is not just a "favouritge", hypothetical cuplrit, diet IS demonstrably one of the main culprits apart from our own biochemistry.

Interestingly Metformin has no or only a smal risk of lactic acidosis. In fact most cases were likely mis-attributions. However, there's no data in long lived mice, let-alone healthy humans suggesting that metformin could work for life-extension. So at the moment, it's not prudent to take metformin to extend life span.

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37. qetzal on September 14, 2009 5:14 PM writes...

Well, Vader I think you should read up on Vitamin D and K2 then. Those are vitamins. They likely extend (healthy) life span of the elderly, it's not noise.

[citation needed]

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38. Kismet on September 16, 2009 1:37 PM writes...

Maybe I shouldn't have included a link to ORAC's blog. Damn auto-moderation. To find the post you can search science blogs with the term: kismet "vitamin D"

So to keep it short, strong epidemiology and a recent meta-analysis of RCTs supports the role of vitamin D in preventing premature mortality (RCTs were done mostly in middle-aged and elderly people; I consider the effect of 6% from *sub-optimal* doses *much* better than noise).
And besides it's role in preventing fractures is well established (frature -> increase in mortality & morbidity).

Arch Intern Med. 2007 Sep 10;167(16):1730-7.
Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials.
Autier P, Gandini S.

Arch Intern Med. 2008 Aug 11;168(15):1629-37.
25-hydroxyvitamin D levels and the risk of mortality in the general population.
Melamed ML, Michos ED, Post W, Astor B.

Arch Intern Med. 2008 Jun 23;168(12):1340-9.
Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality.

Bone. 2009 Jan;44(1):168-72. Epub 2008 Apr 10.
Contributions of 25-hydroxyvitamin D, co-morbidities and bone mass to mortality in Japanese postmenopausal women.
Kuroda T, Shiraki M, Tanaka S, Ohta H.

Clin Endocrinol (Oxf). 2009 Feb 18. [Epub ahead of print]
Vitamin D and mortality in older men and women.
Pilz S, Dobnig H, Nijpels G, Heine RJ, Stehouwer CD, Snijder MB, van Dam RM, Dekker JM.Department of Internal Medicine, Division of Endocrinology and Nuclear Medicine, Medical University of Graz, Austria.

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39. Amy Alkon on September 20, 2009 8:40 AM writes...

This is not to condemn stuff that measurably extends quality years of living. Statins *good*.

Um, not quite.

From Dr. Michael Eades, who takes an evidence-based look at what to eat on his blog:

http://www.proteinpower.com/drmike/statins/more-statin-madness/

In the last paragraph in the quote above, the authors confess that the data from actual randomized control trials show that statins confer no all-cause mortality benefits to women of any age and to men over 69. They are playing a little fast and loose with the truth here because as I have posted before, the gold standard trials have shown no benefit for women and no benefit to men over 65 or to men under 65 who have never had heart disease. The only improvement in all-cause mortality has been in men under 65 who have been diagnosed with heart disease, and even that benefit is so small that many people question if the extra cost and side effects of the statins are worth it.

So the authors of this study acknowledge that there has never been a randomized control trial that has shown any benefit to taking statins, but that doesn’t stop them. They forge ahead trying to figure a reason that all these clinical trials haven’t shown an advantage.

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40. Beth Moell on October 13, 2009 7:39 PM writes...

This is to Speedwell,
First off I'm not a hateful person like you.
My sister was diagnosed with brain cancer after her second child was born at the age of 26. I watch her go through 4 brain surgery's chemotherapy and radiation. When she decided to die she was put in a senior hospital and it took her 9 months to die. I watch my niece and nephew go through hell. My Mom took her death really hard. She was pump up with steroids and had grow hair all over her face. My sister was amazing MOM. She did it the doctors way! Right after my sister died my grandmother died of ovarian cancer. She also did everything the doctors told her too. Gosh, I'm so made that you think I'm apart of the problem!!!
My Dad is a cancer survivor but has lose 5 brother and sister to cancer, doing it the doctors way.
So you tell me, would you want to find other ways to help fight cancer if you had it? 1500 people die everyday to cancer related death. Do you think the doctors way is always the right way? People are dieing!!!! And if they make it through the cancer at what price did they have to pay! We live in a disease care symtem, and we need to take control of are health before it to late and the doctor tell us we have cancer.
Protecting our bodies is key to staying healthy.
I'm sorry you lose your Mom to cancer. My prayers go out to you.
God Bless
PS Why can't we work together and find a solution.
Yes Doctors save people from cancer, but what about the 1500 today that died?

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41. Dr. R.M. Howes on June 7, 2010 10:53 AM writes...

Antioxidant studies have been based on the free radical theory, which has been invalidated because of its lack of predictability over the past 50 years and it failure to meet the requirements of the scientific method. If you wish detailed free information please visit www.iwillfindthecure.org or www.medi.philica.com. Actually, oxygen free radicals are proving to be essential for energy production and secondary cellular signaling. R.M. Howes MD, PhD

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42. Dr. R.M. Howes on June 7, 2010 10:54 AM writes...

Antioxidant studies have been based on the free radical theory, which has been invalidated because of its lack of predictability over the past 50 years and it failure to meet the requirements of the scientific method. If you wish detailed free information please visit www.iwillfindthecure.org or www.medi.philica.com. Actually, oxygen free radicals are proving to be essential for energy production and secondary cellular signaling. R.M. Howes MD, PhD

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43. Tim Dunn on August 17, 2010 1:38 PM writes...

Lumping all anti-oxidants together doesn't strike me as being very scientific. Beta-carotine is bad when mixed with alcohol; Vitamin E supplementation seems harmful, but many others seem more positive, such as curcumin, resveratrol, EGCG, etc. - and are helpful with rheumatoid arthritis and related conditions.

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