Encouraging EGCG data emerges from Mayo Clinic leukemia trials

By now I have a rather daunting backlog of Science Daily updates in my e-box…so, whenever I have a snippet of time, I try to go through a few. As I did yesterday, which is when I came upon a very promising article (http://tinyurl.com/qxcf96) on EGCG, extracted, as we know, from green tea.


A recently-published Mayo Clinic trial report tells us that EGCG (capsule form) is well-tolerated by CLL (chronic lymphocytic leukemia) patients, even at high doses….by the way, according to the Mayo researchers, even those who took as many as 2 grams twice a day did not reach the maximum tolerated dose…


A few exciting trial results: lymphocyte count was reduced in one-third of participants. Furthermore, The majority of individuals who entered the study with enlarged lymph nodes saw a 50 percent or greater decline in their lymph node size.


EGCG is currently being tested on CLL patients in Phase I and II trials. In fact, I just checked the Clinical Trials website and found that the Mayo Clinic study is still recruiting, so if you have CLL, you might be interested in seeing whether you might qualify: http://tinyurl.com/neld9s


Well, well. Good stuff. I have been thinking about adding EGCG to my intake (again). Since I have been so busy recently, though, I have been taking only my regular daily dose of curcumin, quercetin and fish oil…a mere 24 capsules a day…ah yes, I think it’s about time to add more capsules to my regimen… 

Ah, here is the link to the study abstract, published in the “Journal of Clinical Oncology” on May 26 2009: http://tinyurl.com/lz3ar5

Gossypol analogue

Remember my post on gossypin? Okay, well, today’s post has nothing at all to do with gossypin. (Hehe, sorry, couldn’t resist. ) But really, the word "gossypin" sounds like the substance I am about to discuss: "gossypol," which I thought was a derivative of gossypin, at first. But no, gossypin is a flavone extracted from the tropical rose mallow plant, whereas today’s protagonist, gossypol, is a polyphenol derived from the cotton plant. So, different compounds.
Gossypol, I read online, has been used for centuries against malaria and as a male contraceptive in China. The cotton plant produces gossypol to protect itself from the damage caused by pesky insects. It’s a toxin that inhibits the reproduction of insects and also of humans (mammals in general). Anyway, what I found interesting is that gossypol is now being studied for its anticancer properties. An all-too-familiar story!
The new edition of “Blood” (March 15 2008) has a study on a gossypol semi-synthetic analogue called "apogossypol" that apparently is more effective than gossypol against Bcl-2, an anti-apoptotic gene that almost certainly has a lot to do with the chemoresistance of myeloma cells. Brief aside: you can do a search here for Bcl-2, just scroll to the bottom of my Blogroll until you reach a "search" box; see in particular my August 27 2007 post titled “Survivin MM with curcumin.”
Sherlock (grazie!) sent me the full study; you can view the abstract here: http://tinyurl.com/ytsvdh The study begins with a look at the above-mentioned Bcl-2, which is overexpressed in many cancers and leukaemias and protects tumours and leukemic cells from kicking the bucket when exposed to chemotherapy, hormonal treatment or radiation. Bcl-2 has thus become a target for cancer treatment, especially where B-cell malignancies are concerned (non-Hodgkin lymphoma and CLL, in particular).
The study tells us that another gossypol analogue, AT-101, is being tested right now in Phase 1 and 2 clinical trials on patients with solid tumours, lymphomas and leukaemia. I checked to see what kind of clinical trials were testing gossypol, and there are twelve trials for different kinds of cancer ranging from brain to prostate cancer. And, of course, B-malignancies. The main problem of AT-101, though, appears to be the GI toxicity caused by its bothersome aldehydes; we don’t need to know what these are exactly, just that their removal eliminates any GI problems. The "Blood" study researchers did just that: they removed the aldehydes, thus creating apogossypol, which shows “superior blood concentrations over time […] compared with gossypol, due to slower clearance of the compound.”
Toxicity: the researchers tested the toxicity of gossypol and its analogue on normal female Balb/c mice (okay, I confess that I still shudder with horror when I think of all the suffering lab animals around the world…and to tell the truth, if someone told me, “it’s either you or that mouse,” it would be a tough choice for me to make, as silly as that probably sounds. If the choice were between me or a cat, well, you can imagine what my answer would be…now why can’t experiments be done on those maddening tiger mosquitoes??? ).
Back to the study. Well, apogossypol turned out to be less toxic than its parent compound. If you want to read more details, I will be happy to forward the study to you. Other results: unlike apogossypol, gossypol was toxic to the liver, caused GI problems and made the mice lose weight. Neither substance caused any kidney toxicity or heart trouble. Ok, I’ve read enough about the poor dear lab mice. Basta!
In vitro findings (phew, much better: I don’t have as much sympathy for cancer cells…). The researchers used “cultured B-cell lymphoma and CLL leukemia cells.” In both cell cultures, apogossypol was more lethal than gossypol.
The gist of the study: “The preclinical data presented here show superior efficacy and markedly reduced toxicity of apogossypol compared with gossypol, and thus indicate that further development of apogossypol for B-cell malignancies is warranted.” Well, interesting study. Another piece of the puzzle, perhaps. Only time will tell…

Mayo EGCG study

Thanks to Don (see the link to his blog, Myeloma Hope, on the right), Sherlock and I found out about a 2005 Mayo Clinic study on EGCG (green tea extract, see my permanent page for more information). Sherlock looked it up and sent me the full study (abstract, 2006: http://tinyurl.com/29dyp5), which I read this morning. I almost cried with joy.

In a nutshell, after reading a Mayo in vitro report on EGCG’s annihilation of human CLL (chronic lymphocytic leukemia) cells, several Mayo (and probably non Mayo!) patients with CLL began taking this extract on their own. The researchers report that they became “aware of four patients with low-grade B malignancies,” who “appeared to have an objective clinical response.” Three of them achieved partial response (PR). I would like to note that their markers had been worsening before they began taking EGCG: “Several patients presented here had documented steady clinical, laboratory, and/or radiographic evidence of progression immediately prior to initiation of over-the-counter green tea products and then developed objective responses shortly after self-initiating this therapy.”

A "quick" parenthesis. During the discussion period at the NF-kB-curcumin-cancer conference on Saturday (see previous post), I was sitting up front with the other panel members, facing the audience. Next to me was a very nice doctor, I think a urologist (but wouldn’t bet my life on that). Well, in response to a question about why the Tuscan Regional Government doesn’t promote the use of curcumin, since it works for so many patients, scientific studies support its use in cancer treatment, AND it’s cheaper than many drugs, the good doctor answered, more or less, that science needs time, that anecdotal evidence is not scientific proof, that we have to wait until clinical trials are set up, the results published, blablabla. (I wish this cautious man had been on the Avastin committee, by the way!)
I waited until he had finished, took the microphone, and replied “you are right. Science needs time. But we are patients, cancer patients, and we don’t have that kind of time. If, for instance, I had waited for the results of the MD Anderson curcumin-myeloma clinical trial to be published, I don’t know how I would be doing right now. The first results from the trial were presented in December 2007, that is, almost two years after I began taking curcumin.” I forget what I added, but the tape should remind me (and perhaps slightly amend what I just wrote). At any rate, as I remember (!), he agreed that I was right.

Obviously, I am NOT suggesting that we (cancer patients) go out and try just ANYTHING. That would be absurd and dangerous. Beware of websites that tell you that they can cure your cancer! Avoid those like the plague.

But some substances, such as curcumin extracted from turmeric and EGCG from green tea, have been used for centuries to treat all sorts of ailments, as we know. So I am talking about "ancient" non toxic substances that have in recent years been studied in vitro and in vivo and have scientifically-proven anticancer and chemopreventive effects. These results are not anecdotal anymore. I am not the only myeloma patient to have had success with curcumin (sure, a few haven’t achieved similar results, but that is why we, patients, have to TRY it to see if it works in our particular situation).

My stance is, therefore: what’s the harm in trying a scientifically-proven, non toxic substance for eight weeks to see if your markers improve? If they do, then why not continue taking it? Unless, of course!, you have some health issue such as obstructed bile ducts in the case of curcumin (see my Warnings page).

Okay, so the parenthesis wasn’t "quick" at all!  Let’s have a close look at the Mayo EGCG study. The full study.
According to the Mayo researchers, “EGCG also reduced levels of the protein Mcl-1, an anti-apoptotic protein of known importance in CLL B-cell resistance to apoptosis,” at very very low doses. As usual, I looked up this protein in reference to multiple myeloma, and DUH!, wouldn’t you know it!, the blasted thing turns out to be “essential” for the survival of human myeloma cells in vitro, see abstract: http://tinyurl.com/yuhlku. Essential! 
The study provides a detailed description of four CLL cases. Patient number 1 is a 58-year-old woman diagnosed with the “small lymphocytic lymphoma (SLL) variant of CLL/SLL,” whose BMB in 2003, 20 months after diagnosis, showed a “20–25% marrow involvement by CLL/SLL B-cells.” She began taking an OTC (over the counter) green tea supplement containing 315 mg of tea polyphenols. Twice a day. Within a year, “she demonstrated a steady clinical and radiographic decline in her lymphadenopathy with >50% reduction in bilateral axillary nodes and near normalization in the size of all other areas of adenopathy. The patient’s reduction in lymph node size met the NCI criteria for a partial response (PR).” She is doing well (this report was written at 44 months after her diagnosis) and “has not required conventional therapy.”
Patient number 2, a woman, 55 years old, was diagnosed with stage IV disease, asymptomatic. She began drinking a cup of green tea every day ( = two tea bags). Result, 20 months after her initial diagnosis: “>50% decrease in the sum of the products of the six largest lymph node areas consistent with a PR according to the International Working Group criteria for non-Hodgkins lymphoma.”
Patient 3, woman, 50 years old. Five years after being diagnosed with Rai stage 0 CLL (see here for info on CLL staging: http://tinyurl.com/yo2u8m), her absolute lymphocyte count (or ALC) increased, and she developed night sweats and fatigue (that sounds so familiar to me: back in the pre-curcumin era, in 2005, I had both of those symptoms). After reading the Mayo report, she began using a green tea patch, “labeled as containing 300 mg polyphenols,” and drinking three green tea packets a day (300 mg polyphenols per packet). Just one month later her markers had improved. At the time of the report, 77 months after her diagnosis, even though she discontinued the patch and was drinking only one packet of green tea per day, she was classified as stable. No conventional therapy.
The last patient mentioned in the Mayo report is a 60-year-old woman diagnosed with Rai stage 0 CLL in 1995. In 2004 her WBC (white blood count) and ALC increased. This concerned her, so (again, after reading the Mayo in vitro report) she began drinking eight cups of green tea per day. After just one week (ONE WEEK!) her markers had improved. She continued drinking green tea, and her ALC decreased by 50%. 120 months from diagnosis, she “is still asymptomatic from her CLL.”
The discussion part of the study tells us that “In total, our report on these patients with low grade B-cell malignancies adds to the growing evidence that food products that contain polyphenols have anti-tumor activity. In fact, the polyphenol containing agents have not only been shown to have anti-tumor activity but have been linked to chemoprevention of human tumors. A number of epidemiologic studies have linked consumption of green tea to a decreased risk of cancer. A wide range of animal models has also supported green tea’s ability to prevent tumorigenesis. Multiple mechanisms have been proposed as the explanation of the effect of green tea, including anti-angiogenic properties, DNA damage, and inhibition of telomerase. More recent studies of EGCG suggest this agent may affect folate metabolism, suppress transcription factors leading to cell-cycle arrest, and induce oxidative stress through generation of ROS. In vitro studies have also shown EGCG decreases levels of anti-apoptotic proteins at drug levels which are achieved in the serum of tea drinkers in vivo.” Sorry for this tremendously long quote, but there was really no way to summarize or shorten it.

The Mayo report is about CLL patients, of course, but let’s not forget that EGCG has been shown to work against myeloma cells, too. And in fact I am in touch with quite a number of MGUS and SMM folks who take this supplement or drink green tea. Successfully. So now I am more curious than ever to find out how Sherlock and I will do on one gram of EGCG combined with our eight grams of curcumin.

Oh, another important note: the study points out that EGCG should be taken on an empty stomach: “The plasma concentration of free EGCG could be increased five-fold when taken in fasting conditions rather than with food.” If you choose to drink green tea (té verde, in Italian) rather than take an EGCG supplement, by the way, well, in this photo Priscilla, my two-year-old cat, demonstrates how to drink it properly (raise your cup to your mouth…just like this). Sorry, couldn’t resist, she is TOO cute.

The Mayo researchers’ final words, which echo the above-mentioned Italian conference doctor’s thoughts: “These anecdotes cannot determine the effectiveness of tea polyphenols, and highlight the need for clinical trials to define the optimal dosing, schedule, toxicities, and clinical benefits before widespread use can be recommended.” The Mayo EGCG clinical trial is currently recruiting CLL patients, by the way: http://tinyurl.com/2p5l8q.
Well, in my opinion, the Mayo report shows that sometimes we patients just have to jump the gun…proceeding, of course, with well-informed, scientifically-based caution, as always.

The myeloma tap: part I

This post was way too long so I decided to cut it in half. I will post the second part tomorrow. Only then will today’s title make complete sense.

Anyway, I have it, I have it! Yes, the FULL recently published Johns Hopkins myeloma stem cell study that I mentioned a couple of days ago. Okay, I confess that I have had it in my possession since last Sunday, when a very kind blog reader (thank you thank you thank you!) sent it to me, but just haven’t gotten around to writing a post about it. The study, by the way, was conducted by a team led by Dr. William Matsui and published in the January 1 2008 issue of “Cancer Research.” You can view the abstract here: http://tinyurl.com/2yuru9.

Before I go on, though, I wanted to mention that another blog reader posted an interesting New York Times article on the controversy surrounding the cancer stem cell theory and other interesting info, so if the issue of stem cells is your cup of tea, please go read Carla’s comment on my “Stem cells and myeloma” post, Jan 12th.

Back to us. I have to admit, reading this stem cell study was not exactly as fun and easy as reading one of the Harry Potter books, but I found it almost as engrossing. The study begins by providing a bit of background, including this: “Early studies examining a murine model of multiple myeloma suggested only a minority of cells were capable of clonogenic growth.” Hmmm, so only a tiny percentage of myeloma cells can clone themselves…I didn’t know that. I thought they were all capable of creating clones. Live and learn.

Myeloma stem cells are mentioned in a 1977 study (full text: http://tinyurl.com/2d8z3n), which, by the way, shows black and white photos of myeloma cells for those who might be interested. Anyway, according to the Johns Hopkins investigators, this early study showed that “the cloning efficiency of primary multiple myeloma specimens was 1 in 1,000 to 100,000 cells. To date, it has remained unclear whether these clonogenic cells are distinct from the plasma cells that constitute the majority of tumor cells.”

Then, in 2004, Dr. Matsui et al published a study (full text: http://tinyurl.com/2233wp) in “Blood” on clonogenic myeloma cells. Clonogenic, by the way, has two meanings: 1. “giving rise to a clone of cells” and 2. “arising from or consisting of a clone.” I went through the 2004 study, which reported that “highly clonogenic cells from both human MM cell lines and primary patient samples do not express CD138, but rather markers that are characteristic of B cells.” This rather baffling sentence will, I hope, become clearer after the upcoming section on CD138 (and part II, which I will post tomorrow, should also help in that sense). The 2004 study also suggested that, like chronic myeloid leukaemia or CML, “MM is another example in which cancer stem cells are a rare cell population that is distinct from the differentiated cells that comprise the bulk of the disease.”

CD138. Now I am going to delve into some rather difficult material that has to do with this thing called CD138. Also known as syndecan-1, CD138 “is “a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells.” I know, I know…Let’s see if this will clarify matters: proteoglycans are “glycoproteins but consist of much more carbohydrate than protein; that is, they are huge clusters of carbohydrate chains often attached to a protein backbone,” according to Prof. Kimball’s Biology Pages. (Hmmm, lots of carbs plus some protein…pasta with meat sauce! )

Seriously though, it doesn’t really matter if we don’t completely grasp what CD138 is. What’s important is that we understand the following excerpt from the 2004 Johns Hopkins study. CD138 “is the most specific marker for normal and MM plasma cells. However, normal CD138+ plasma cells appear to be terminally differentiated and unable to proliferate, and there have been few studies using this marker to study the proliferative capacity of MM cells.”

Not the easiest stuff to digest, eh! Well, let’s see if I can explain what CD138 is in a few simple words (if I make any mistakes, please let me know): in sum, CD138 is a thingie (ok, a proteoglycan) sticking to the surface of regular myeloma cells—the ones, that is, that are NOT able to clone themselves. These are the CD138 "plus" myeloma cells. Patients whose myeloma cells release, or "shed," CD138 (CD138 "negative" cells) into the serum have a worse prognosis than those whose myeloma cells still have it. Hence it is a helpful prognostic marker (for more info, see this 2002 “Blood” study: http://tinyurl.com/2h26uq). CD138 levels can be measured in MGUS patients, too (see this 2006 "Neoplasma" abstract: http://tinyurl.com/yr9vzd).

A September 2007 “Blood” study (see abstract: http://tinyurl.com/2slg3t) confirms that “High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis.” So again we see that if CD138 is shed into the myeloma “microenvironment,” this is bad news for us (poor prognosis etc.). Interesting aside: this is true for CLL patients as well (see this January 2008 abstract: http://tinyurl.com/3ap8ba). Connections, connections.

Ok, that’s it for today! Phew.