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LizM

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Reply with quote  #1 
Just read the below article on red wine and resveratrol.  I quit drinking red wine when diagnosed with breast cancer due to all negative information I read on breast cancer and alcohol.  I also thought that reservatrol was estrogenic and that those of us with hormone receptor positive breast cancer should avoid it.  Sure would love to drink a glass of red wine again.  Here's the article:

Prevention of estrogen-DNA adduct formation in MCF-10F cells by resveratrol.  Free Radical Biology and Medicine 45(2):136-145, 15 July 2008.

Muhammed Zahid, Nilesh W. Gaikwad, Mohamed F. Ali, Fang Lu, Muhammed Saeed, Li Yang, Eleanor G. Rogan, Ercole L. Cavalieri.  Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA.

"Resveratrol (Resv), a natural occurring phytolexin present in grapes and other foods, possesses chemopreventive effects revealed by its striking modulation of diverse cellular events associated with tumor initiation, promotion, and progression.  Catechol estrogens generated in the metabolism of estrogens are oxidized to catechol quinones that react with DNA to form predominantly depurinating estrogen-DNA adducts.  This event can generate the mutations responsible for cancer initiation.  In this regard, Resv acts as both an antioxidant and an inducer of the phase II enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1).  In this report, we present the effects of Resv on the metabolism of estrogens in normal breast epithelial cells (MCF-10F) treated with 4-hydroxyestradiol (4-OHE(2)) or estradiol-3,4-quinone (E(2)-3,4-Q).  Resv induced NQO1 in a dose- and time-dependentmanner, but did not affect the expression of catechol-O-methyltransferase.  Ultraperformance liquid chromatography/tandem mass spectrometry was used to determine the effects of Resv on estrogen metabolism.  Preincubation of the cells with Resv for 48 h decreased the formation of depurinating estrogen-DNA adducts from 4-OHE(2) or E(2)-3,4-Q and increased the formation of methoxycatechol estrogens.  When Resv was also present with the 4-OHE(2) or E(2)-3,4-Q, even greater increases in methoxycatechol estrogens were observed, and the DNA adducts were undetectable.  We conclude that Resv can protect breast cancer cells from carcinogenic estrogen metabolites, suggesting that it could be used in breast cancer prevention."

That abstract may give you a preview of what's in the article in this month's issue of Cancer Prevention Research.

nosurrender

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Reply with quote  #2 
Liz, I am going to tell you the first thing that came to my mind...
who the hell knows! They keep changing their minds!
I hope this means you can drink your wine again...
My onc always wants huge studies that have been backed up 15 ways from Sunday.

Hugs,
g


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muffy

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Reply with quote  #3 
Liz and Gina--
I thought the problem was never with the resveratrol but rather with the alcohol.  No problem with grape juice or the grapes.
I had some fettucine last night and had a glass of wine for the first time in months.  I felt sooooo guilty.

Here is Constantine's site info on this
http://home.earthlink.net/~ckaniklidis/brcaprev.htm#Alcohol

zschweeb

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Reply with quote  #4 
is it just me or is all that medical jargon extremely hard to understand ...i guess a simple yes or no isnt really possible though is it??...i just wish i could break the code lol


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Reply with quote  #5 

Liz and others:

The simple answer: NO.
The detailed answer, and associated explanation:

The facts on this issue are unchanged - indeed they, if anything, have only grown more negative - as I stated them in my now infamous and widely cited indictment of wine ("Why Wine is Irrelevant as a Source of Resveratrol"), for which I continue to have either high praise (very rare) or equally high, and sometimes virulent, abuse (common) heaped upon me. By now I have been "shot" as the "messenger" [of bad tidings] so often I am beginning to develop an immunity to it. Muffy got it dead on target, that the issue at stake is alcohol, not resveratrol which is decidedly on the side of the angels.

As I noted there, most wines contain either no resveratrol whatsoever, or non-therapeutic wholly trace amounts (usually a few micrograms per glass). Thus, contrary to popular opinion, the amounts of resveratrol in wine are both widely variant, and therapeutically insignificant, with an average of 1.5 micrograms of resveratrol/ml, so that for a full glass of wine - which is about 5 fluid ounces (= 150 ml), total resveratrol content would be 225 micrograms, or just above two tenths of one milligram (0.2 mg), and similarly for grapes and grape juice. Yet the lowest potentially therapeutic dose ranges between a bare minimum of 10 mg., to about 32 mg. to 40 mg. for modest activity, to 100 mg (my current recommendation based on extrapolation from the aggregate evidence base to date) at typical optimal level, so to ingest just the lower range amount of 10 mg. (of minimal benefit) would require approximately 50 glasses of wine or a completely indigestible amount of grapes (multiple vanloads), and to consume the higher optimal level of antitumor benefit - 100 mg. - would require approximately five hundred glasses of wine daily which would of course be extremely non-salubrious, being lethal.

So lessons learned: in one of the largest studies to date, of a cohort of almost 3000 women diagnosed with breast cancer, reported out by Arthur Klatzky at the ECCO 2007 conference in Barcelona, it was found that breast cancer risk was significantly increased by:

(1) any amount of alcohol consumption, even less than half or a fourth of a glass, and by
(2) any form of alcohol consumption - beer, wine (white and red indifferently),

and all other forms were found equally risk-enhancing. And this and hundreds of other studies further established that

(3) each glass of alcoholic content contributed between 7 to 10% excess risk in a strictly linearly, never-terminating trajectory, with three drinks increasing risk by more than 30%, virtually the highest risk elevator ever recorded in breast cancer etiology and epidemiology,

an increase that may indeed exceed that of elemental estradiol / estrone itself, these results confirming again my own widely distributed conclusions made over a decade ago, and underlining that alcohol consumption in any amount whatsoever represents one of the most powerful exogenous / environmental carcinogens ever studied, and almost uniquely adverse, even catastrophic, to breast carcinomas, influencing negatively virtually every single molecular pathway - hundreds upon hundreds - ever implicated in the pathogenesis of cancer (and of course dozens of other major high-morbidity and/or -mortality diseases).

And from an even larger study of over 17,000 women published last year by Lina Morch with the Centre for Alcohol Research in Denmark, we learn that there is no lower threshold to significant risk increase via alcohol consumption, so that just two drinks a week on an average increase breast cancer risk by 4%, and with even one drink in a week (just one seventh of a glass daily) inducing a 2% risk increase. They also profoundly clarified the near-exponential risk associated with "compact drinking", that is, with drinking a number of glasses all at once or within the constraint of a single day, so that 2 to 3 glasses of wine (or anything alcoholic) in one day, just once in a week, would increase breast cancer risk by approximately 22.5%, and with weekend consumption and binge drinking further virtually doubling risk. And remember that Jasmine Lew's NCI-sponsored study of 184,000 women in April of this year, 2008, has already demonstrated that regular daily drinking of just one glass induces a 32% risk increase (contrary to the many irresponsible reports in the popular media claiming against the evidence that moderate, or less, drinking, is okay).

And the causal factors for this are not just simply estrogen, as often stated - several molecular pathways and biological mechanisms besides influence on sex hormone concentrations are involved, including the accumulation of carcinogen alcohol bi-products, and adverse influence on underlying insulin pathways, among many others, and so the adverse impact is not restricted solely to hormone-positive populations but cuts across all tumor biologies, of all known human cancers ever studied. (And mortality from breast cancer in high wine-consuming France is even higher than that in the United States (and over double that of curcumin-consuming India for example)).

So YES to resveratrol, NO to wine (and beer, and . . . ). Now I'm off to have a glass of O'Douls (non-alcoholic beer).

But save your artillery: I have acquired MBR (multi-bullet resistance).


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

LizM

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Reply with quote  #6 
Thank you Constantine. 

I think I knew the answer but I needed to hear it so that I was not tempted to drink that glass of wine.  I absolutely love red wine.  I drank a glass daily before I was diagnosed and am convinced it played a role in my getting breast cancer, although my husband and friends think I'm nuts in thinking so.  It was my only vice before I was diagnosed.  I have replaced my evening glass of wine with green tea and now enjoy many different flavors of hot and cold green tea instead.  I do miss my wine sometimes but know that it is lethal for me.  I still have a glass on very very special occasions about once or twice a year but after I drink a glass of wine I feel guilty so it takes away the pleasure.  Thanks for keeping us on the straight and narrow.

Liz
LizM

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Reply with quote  #7 
Also, Constantine you said resveratrol is good even for hormone receptor positive breast cancer.  Should we be taking a supplement or can we get it from food.  If so, how much?

Thanks
edge

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Reply with quote  #8 

Liz:

You have the right rule: if the pattern of consumption is sporadic and rule-defying, and can only be summed up at the widest level of "x times in a year", say 7 or 8 or 9 times a year for example on special occasions (birthdays, promotions, anniversaries, etc. ) rather than "(x times) every week" or x times every month", then it is unlikely that there will be an appreciable cumulative adverse impact on elevated risk. I advise a woman in Greece who is just such a sporadic indulger and who furthermore is so committed to risk-reductive CAM, dietary and lifestyle / exercise interventions that it is implausible to believe the excess risk is not thereby substantially countervailed, if not overwhelmed handily.

As to potential benefit of resveratrol, the findings are not quite as mature as those on curcuminoids, EGCG and melatonin, but they are not that far behind either and I am even slowly aggregating some in vivo and clinical supporting data, much of it as yet unpublished. And although resveratrol appears to have some selectively as an anti-aromatase endocrine intervention, nonetheless it is not so narrowly circumscribed: researchers Carla Mangum, Joseph Cameron and Brittney-Shea Herbert at Jackson State and Indiana University in pending as yet unpublished research investigated the effects of resveratrol on triple negative cell lines, finding that it inhibits cell proliferation in a dose-dependent fashion, with in addition some special sensitivity in BRCA1 mutated cells. And although these results must still be critically appraised in peer-reviewed form, they are confirmative of my own research into the molecular pathways underlying triple negative, basal and BRCA-mutated breast cancer, and I have little doubt of further validation to appear.

As to optimal dosing, this is not wholly decided by the current evidence base, but the nearest extrapolation from the best evidence and some pending data would be higher than what was previously thought to be optimal, namely 25 to 50 mg / daily, but rather may be closer to 100 mg. daily for optimal antitumor / aromatase-inhibitory activity. Three high-quality suitably standardized formulations are:


(1) under the Now Foods label, from Vitacost.com:
http://www.iherb.com/ProductDetails.aspx?c=1&pid=1298809049621087047&at=0

(2) under the Enzymatic Therapy label, from iHerb.com:
http://www.iherb.com/ProductDetails.aspx?c=1&pid=7794831567434110542&at=0

(3) under the NSI label, from Vitacost.com:
http://www.vitacost.com/NSI-Resveratrol-Grape-Seed-Red-Wine-Extracts

and this is selective, as there may be others of comparable grade. However, avoid (1) Life Extension (LEF) Resveratrol Caps which failed quality-control testing (and which had formerly a formulation that passed) by the assay-standard ConsumerLab organiazation and were found to provided only about a quarter of the claimed 20 mg of resveratrol per capsule., (2) Resvert from Young Again Nutrients / Supplement Spot) which contained only a bit more than half of the claimed 25 mg per capsule, and (3) Revatrol from Renaissance Health Publishing, which claimed 400 milligrams of a "red wine grape complex" but contained a mere 2.2 milligrams of resveratrol per caplet.

On final warning: the triple negative study I referred to above found that low concentrations of resveratrol might adversely increase cell growth, so it is best to keep supplementation high, no lower than 25 mg daily. And although I am still not at the point that the threshold of robust data on resveratrol's antitumor benefit is sufficiently mature to definitively add to my strongly recommended CAM interventions, it is nonetheless without harm and the likelihood of substantial clinical benefit continues to increase with emerging evidence.

But I agree that it is one of life's more devilish cruelties to interfere with the otherwise incredibly rich and seductive world of wine.; fortunately there are other pleasures, like the many many kind and caring users of these forums, and their creator (small "c", for Gina).


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

PineHouse

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Reply with quote  #9 
Hi Constantine,

I'm already on your curcumin+EGCG+vitD3+melatonin regimen, and I suspect that a lot of others are too.  I assume you soon are going to add this resveratrol into the regimen?

Would there be any concern in the future that some of the supplements may adversely impact each other?  I assume each of the supplements have been studied individually and not necessarily with each other.

Just playing devil's advocate, I guess, kind of "borrowing" the attitude of some oncologists when I ask about certain chemo combos "that have not been studied" as such combos.

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Stage IV (lung 6/08; brain 12/08), ER-/PR-/AR-/HER2-, BRCA1 mutated, normal p53
Avastin+Taxol; Carboplatin; PARP Inhibitor; Navelbine+Xeloda; Avastin+Ixempra; Doxil+Cytoxan; currently on Abraxane+Gemzar
Early stage BC occurences: 1996,1999,2003 tx AC->T,CMF,Taxotere
ShirleyHughes

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Reply with quote  #10 
Hey, Constantine.  Long time no see (or should I say, post?). 
 
I received the same information via email about wine.  I thought, what the heck...I wish they'd make up their minds!
 
Ya know, drinking as much wine as you say we would need in order to get the resveratrol we needed sounds, uh, kinda fun IF it wouldn't kill us!  However, I don't drink any alcohol.  One reason...I'm on too many "brain" drugs, and I'd fear it might make me a bit more loopy.  So, I can't blame alcohol on my breast cancer, but I can blame HRT that had progesterone added to it.  Feels good to blame something besides myself.  Yeah, it was the drug company's fault.  I did hear on the news the other day that a couple of women won a bunch of money after suing because they took Prempro and had bc.  One has died, and the other lady will probably never see the money.
 
I just wanted to drop in to say, HI  , and thank for clearing up the subject on red wine.  I'll tell any friends who drink it and think they're getting bc prevention benefit...WRONG...and that they'd have to drink 500 glasses a day to get the amount of resveratrol they needed.
 
Shirley
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Reply with quote  #11 

Pinehouse:

The data supporting resveratrol, boswellic acids, and certain other CAM agents I am currently reviewing is continuing to mature, and in this interim they have provisional status in my antitumor CAM regimen, being designated as of potential value even in this pre-final stage in the specialized context of elevated risk disease, which I consider to be:

  1. triple negative disease (TN)
  2. inflammatory breast cancer (IBC)
  3. metastatic breast cancer (MBC)
  4. HER2-positive disease (HER2+)

and for most patients outside of these elevated risk groups, deployment of these agents is not as compelling, although some with greater concerns or anxiety over either the optimality of their current or past treatments, or over the pattern of their future risk, may still opt to pursue these provisional interventions. As the status of these or any other agent being evaluated change and the supporting data appreciably matures, the core antitumor CAM regimen will be expanded or refined as appropriate.

As to the concern about the cross-agent safety and lack of interaction-based compromise, nothing of course is ever proposed or put forward by me without such sufficient evidentiary foundation, based on rigorous principles of evidence-based methodology.

However, that said, let me clarify a misunderstanding about DDI (drug-drug interactions), construed as I do, broadly as inclusive also of vitamins, herbals, nutraceuticals and dietary / nutritional food substances. As I estimated elsewhere, there may be a DDI set of roughly 10,000 agents (roughly 7000 of which are prescription drugs), and it is not the case that safety and lack of adverse interaction is based on direct head-to-head data of any arbitrary two of these, say X and Y, since the number of combinations is a staggeringly large number, computed as all combinations are, as 10,000!, signifying

10,000 x 9,999 x 9, 998 x 9997 . . . down to one,

a number so vast that it is safe to say that after even several thousand years from now, we may have data only on approximately one trillionth of 1% of all the potential combinations, from 2 drugs at a time, to three drugs at a time, up to whatever we view as a reasonable upper limit to the number of agents the average human may coadminister at the same time.

But of course that is not how DDIs are evaluated. When the FDA mandates a warning of potential adverse interaction for a label agent, say the benzodiazepine agent diazepam (Valium), it may in some instances note as it does in fact in this case that, at present, we have at least some direct data - typically in vivo or better - of potentially adverse interaction with cimetidine (Tagamet), ketoconazole (Nizoral), fluvoxamine (Luvox), fluoxetine (Prozac), and omeprazole (Prilosec), but since Valium metabolism is CYP3A4 and CYP2C19-mediated, as are all the agent just enumerated, then we do not have to also test Valium with each of erythromycin, clarithromycin, itraconazole, telithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, voriconazole, grapefruit juice, and the approximately 4000 other prescription drugs - to say nothing of non-drugs, foods, etc. - that are known to be CYP3A4-mediated (and a lesser number of those that are CYP2C19-mediated).

We therefore use not direct data of in vitro, in vivo, or human clinical interaction between any 2, 3 or more arbitrary agents that might be co-consumed, but rather use fundamental principles of pharmacokinetics to deduce the potential for adverse interaction across classes of similarly hepatic metabolized agents.

So, no, for the 7-tuple set of agents in my antitumor CAM regimen:

curcuminoids, EGCG, melatonin, HD-D3, CoQ10, boswellic acids, resveratrol

we do not have direct data of their pairwise, then triple-wise, etc. lack of adverse interaction and nor do we need this - and yes, we know them to lack such adverse potential, knowing the ways of all entities involved in the cytochrome P450 hepatic enzyme system. This is not significantly different in degree, if not in kind, from many of the doublet, triplet, and other combinations of chemotherapeutic and biological agents daily used by oncologists typically for second-line and later stage treatment of advanced / metastatic disease, where for most of these no supporting single, let alone several, confirming RCTs exists to founded the deployment, and for which no FDA approval of such combination has ever been issued (or ever likely to be).

As to devil's advocate from the oncologist's perspective, this is a bit hard to swallow, and I have parodied it often:

Patient:
Doctor Z, I am taking Lipitor, Klonopin, Soma, Ambien, Nexium, Lopressor, Meclizine, Synthroid, Glugophage, Plavix, Singular, Voltaren, and Flexeril along with my Xeloda, Avastin and Carboplatin.

Doctor Z
:
[Eyes glazed, head tumbled unto chest, with low-pitch buzz saw snoring emitted intermittently]
Whazz that? Lipiklop, Nexipress, Glucoplav, Flex-a-who? Zzzz. Hm, no problem . . . [head slumps heavily] Zzzz.

Patient
:
I also drink a quart of Gin daily with my lard-fried bangers and grapefruit juice, but I jog at least 20 minutes every ten days or so, so that can't . . .

Doctor Z
:
Wha? grapes? and you log? Logging's good, fine, good fo you
[declines radpily into semi-stupor].
ZZZZZZZZZZZZZZZZZZZZ

Patient
:
I'm also taking Vitamin C and ginseng . . .

Doctor Z
:
WHAT!!! VITAMINS!!! HERBS!!! Discontinue those immediately!!! And don't come back here till your clean! $@!*+(%#={:|@^


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

Fancy

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Reply with quote  #12 
Oh, Edge, I'm laughing and crying at the same time!  I think I'm at the only hospital in the universe that prescribes vitamins and herbs to patients.  The one time I asked my onc about vitamins and herbs he told me to talk to the CAMs--it's not his area of expertise but THEY know all!  And by golly, they do!

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edge

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Reply with quote  #13 

Fancy:

It is very rare, but you've provided an invaluable service to all users of these forums by exemplifying how open-minded an enlightened health professional should be, and by also keeping the issue of CAM interventions in such prominent place in dealing with a patient with truly integrative medicine.


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

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