IL-17 and medical day: stability!

February 6, 2008 / / 2 Comments

Well, the answer to yesterday’s question is as follows: yes, we can. Curcumin inhibits IL-17. Figures, huh? There are three (possibly more) studies that mention the IL-17-inhibiting role of curcumin. The abstracts can be viewed here: http://tinyurl.com/2rn3jy (a 2003 study), http://tinyurl.com/ynvkdj (a 2005 study). Thanks to Sherlock, I read the full study of the third abstract, a 2004 study published in “Cellular Signaling” and titled, get this: “Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes” (see abstract: http://tinyurl.com/2lfy7t).

All these studies tell us that curcumin inhibits IL-17. Simple as that.

Haematologist appointment. Stefano and I went to see my haematologist at noon today. I asked her outright to classify me. She said that I am definitely not MGUS, no way. My IgGs are too high, and let’s not forget the 40% bone marrow biopsy result (from last year). So it’s official: I’m "smouldering," which means, among other things: "to exist in a state of suppressed activity." Heh. She examined my tests more in detail and pronounced me stable. Stable as a rock. So, all good news.

I asked her what the half-life of a myeloma cell is. She replied that it depends on a variety of factors, such as the type of myeloma and its proliferation rate. It can be calculated using cells from a BMB. She told me that a myeloma cell can live up to several months. MONTHS? Drat, now I am almost sorry I asked!

She confirmed that I am taking the correct amount of vitamin D. She also told me NOT to stop taking curcumin when I get a cold or an infection of any sort. Even though it inhibits NF-kB, she said that stopping cold turkey (odd expression, that one, when you think of it) is not a good thing. Good to know.

Let’s see. I am going down my list of questions and scribbles right now, not necessarily in order of importance. Oh, speaking of importance, this is exciting: I gave her the myeloma stem cell study (she had read the abstract, not the full study) and the DMAPT study, and she is going to find out about the DMAPT trial that should be starting soon in the UK to see if I qualify for it. She is going to contact the researchers that she knows personally. I am at a loss for words. Can’t wait to hear back from her. Gulp!

She is going to push the lab technicians to get more details on my “old” bone marrow samples, which would be fantastic. And, last but not least, she is going to try to attend the upcoming presentation in Calenzano, where I will be giving a brief speech. She is leaving for a conference in Turkey that evening, so it’s iffy. Even if she isn’t able to make it, however, she is sending five people from her lab to the presentation. Five? Fabulous.

Last but not least. For the first time, she wrote that I am stable "perhaps" due to curcumin. And that I should continue with the same treatment. (When my GP read those two sentences this afternoon, he got very excited.)

As we stood up to leave at the end of the visit, she asked me to explain why there are cases of myeloma in India, if curcumin is so effective. I answered that there are only a handful of cases compared to the Western world, and besides, I managed to add with a straight face, those folks undoubtedly didn’t use turmeric in their diet. My husband let out a snort, and she gave me a big smile and shooed us out of her office. Hehe. I love my haematologist. Good sense of humour.

Yes, today was a good day.

Another pro-inflammatory cytokine: IL-17

February 5, 2008 / / Leave a comment

About a month ago I read a Science Daily article with an intriguing title: “Protein’s New Role Discovered In Autoimmune Disease.” (see: http://tinyurl.com/yrzaud). In a nutshell, University of Alabama researchers identified a previously unknown effect of a T cell-derived cytokine named interleukin-17, or IL-17 for short. This is an “immunity protein,” that helps induce and mediate pro-inflammatory responses, such as allergies, autoimmune diseases and whatnot. IL-17 also induces the production of many other cytokines, such as the infamous IL-6! Uh-oh!

Now, the news reported in Science Daily is that when the “messenger” signals from IL-17 were blocked, the disease-causing B cells dropped from 17 to 2 percent. Coincidence? Ah, no. As the articles states, “The drop was a clear sign that IL-17 plays a major role on shaping B cells’ ability to create more and more disease-causing antibodies.” So if IL-17 can be inhibited, B cells are slowed down in their efforts to create wacky antibodies. And here I thought B cells were the good guys, the cells that defend us against infections etc. Well, in autoimmune diseases they can go bonkers, as we can read in the Science Daily article.

After reading this article, I immediately checked out if IL-17 is involved in myeloma. Of course it is. Hah, figures! For instance, see the abstract of this 2006 study (http://tinyurl.com/2786gs), which shows that IL-17 “is a CD4 T-cell-derived mediator of angiogenesis that stimulates vascular endothelial cell migration and regulates the production of a variety of proangiogenic factors, such as tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial cell growth factor (VEGF).” Need I add more? Oh, ok, just this bit: the researchers conclude that “IL-17 plays a role in the promotion of angiogenesis and associated disease progression in MM.” Bad, bad IL-17!

I found an interesting bit of information on IL-17 in the MD Anderson October 31^st 2005 “Weekly News and Notes for Patients, Families and Visitors.” The article is titled “New immune cell found to be a key to inflammatory diseases” (see: http://tinyurl.com/2moorw). MD Anderson and other researchers discovered a new type of T-cell, called THi, produced IL-17, which they “linked to an immune system gone awry." An awry immune system? Well, if that doesn’t sound familiar…! Before this discovery, IL-17 was known to play a role in autoimmune and inflammatory diseases, but its origin was a mystery. The study’s lead investigator stated that “These findings suggest that shutting down the activity of these THi cells might stop chronic inflammatory diseases from developing in the first place.” How about that?

Okay, IL-17 is now officially on my list of evil pro-inflammatory cytokines. It is also connected, by the way, to NF-kB (I need to do more research on this topic; I may get to it, someday…). IL-17 also stimulates IL-8, which is an angiogenesis cytokine in myeloma. This reminds me that one of my future projects is to create a permanent page listing all of these pro-inflammatory cytokines and their role in myeloma progression. Eh.

I would like to end today with a question: is there anything that we can do to inhibit IL-17? Or could we already be doing something? The answer to this question will be in tomorrow’s post. Oh, and tomorrow is "medical day." I am seeing my haematologist at noon (with a list of questions as long as the highway between Florence and Bologna), then my family doctor in the afternoon (shorter list of questions). I imagine I will have quite a long post tomorrow!

Less IgA than a newborn…

February 3, 2008 / / 3 Comments

It’s a rainy day in Florence, and I am alone in the house (as “alone” as one can be with four cats, hah!…they are napping now, gathering up enough strength to totter downstairs for some lunch…), so it’s a perfect morning to do some research. I am working on at least four different topics that I find enthralling. But right now I would like to post about something different.

Yesterday I wrote a post to the MMA patient mailing list (by the way, you may sign up for it by clicking on the link in my Blogroll, just scroll down until you reach: "Join the MMA myeloma patients’ listserv") asking a question about my recent test results. I got many useful replies, some in private, some in public.

A very interesting reply was posted by one of my blog readers. This morning I wrote to him asking for permission to post his reply on my blog as well, and he kindly consented. So here goes:

“Immunoglobulins are produced by B-lymphocytes. The faulty ones produce monoclonal immunoglobulins or parts thereof. Immunoglobulin-G is the most prominent type. A molecule decays, after 21 days typically half will have been reabsorbed by the body. The IgG count is the total concentration of immunoglobulin-G in mg/dl, normal and monoclonal. The m-spike is a measure of only the monoclonal Ig. In normal individuals IgG counts are as given below.

Reference values for normal immunoglobulins

	in mg/dL
Age	IgA	IgG	IgM
newborn	1 – 50	200 – 1070	0 – 80
1 – 6 months	2 – 80	200 – 1070	25 – 150
7 – 12 months	8 – 90	200 – 1070	25 – 150
1 – 6 years	15 – 160	340 – 1240	45 – 250
7 – 12 years	35 – 250	650 – 1600	45 – 250
12 years and up	40 – 350	650 – 1600	50 – 300

A rise of the IgG may be caused by acute or chronic infections and does not necessarily mean increased MM. A change in m-spike may reflect a change in MM plasma cell concentration. Remember that the IgG number or m-spike is always somewhat inaccurate, so a small change may simply be due to a uncontrolled variation in the measurement procedure.”

Interesting. As for the issue of "molecule decay," I will be looking more deeply into it and will ask my haematologist about it on Wednesday. For now, I will leave it pending. Well, this has certainly been an interesting exchange. I now have plenty of fodder for thought. But it’s time for lunch so I am getting off the computer.

One last comment: thanks to this chart, I found out that I have less IgA than a newborn, and as much IgM as a newborn (barely)! Ahhhh, I feel so young, today…hmmm, almost…newly born!

The dual nature of NF-kB

February 2, 2008 / / 2 Comments

This is the continuation of my January 22 post. From the Aggarwal (et al) NF-kB study, we know that when NF-kB “is found to persist in the nucleus, it is referred to as constitutive activation. […] The precise role of constitutive activation in tumors is not known but has been linked to resistance to apoptosis in human cutaneous T-cell lymphoma cells. It is tempting to believe that a similar mechanism accounts for the progression of all tumors that constitutively express NF-kB, but such a link has yet to be clearly identified.”

This entire section is interesting, actually, since it reports that another thing that has not been identified is the actual stimulus that renders NF-kB active all the time. What is clear, though, is that “Cells that express constitutively activated NF-kB are resistant to various chemotherapeutic agents and radiation treatment.”

And read this. In renal cell carcinoma (RCC) patients, “Serum C-reactive protein (CRP) elevation correlated with the increase in NF-kB activation; therefore, NF-kB may be a cause of the inflammatory paraneoplastic syndrome.” As we Myeloma Club members know, CRP reflects IL-6 activity and is thus an important marker for us. (My CRP, by the way, is within the normal range.) At any rate, I thought it interesting that this study reports a connection between high CRP and NF-kB. Well, well.

Another interesting quote: “Another virus that contributes to human cancer via NF-kB is the Epstein-Barr virus (EBV) implicated in Burkitt’s and Hodgkin’s lymphomas. The EBV nuclear antigen (EBNA)-2 and latent membrane protein (LMP)-1 enhance NF-kB activity thereby preventing apoptosis in EBV-transformed B cells.” While I was in grad school in Toronto, I tested positive for EBV. I was quite ill for about a month, tired all the time, etc., as I recall. Anyway, coincidentally (or…not?), a few years later I was diagnosed with MGUS. Well, I suppose it’s pointless to speculate, but this is not the first time I have read about the EBV-cancer link. Let’s proceed.

I found a fascinating study online (full study: http://tinyurl.com/2ntng6) titled “Good cop, bad cop: the different faces of NF-kB” that appeared in the January 2006 issue of “Cell Death and Differentiation.” It examines the different functions of this transcription factor, including that (drum roll!) of TUMOUR SUPPRESSOR. No kidding. NF-kB can promote both tumour growth and tumour suppression. Bad cop, good cop. How about that?

It is in this study that I read that NF-kB can be triggered by hundreds of “activators.” Hundreds? Parts of this study are barely intelligible, but I did manage to grasp a few basic concepts. The “classical” or “canonical” NF-kB pathway occurs when this transcription factor translocates, or moves, from the cytoplasm to the nucleus. This is when NF-kB gets activated by inflammatory cytokines such as tumour necrosis factor (TNF)-alpha and IL-1, in response, say, to a bacterial infection. The rest of that particular paragraph is not meant for non-scientific brains, for sure. So, skip, skip, skip! What matters is that at the end of this complicated process of activation, NF-kB ends up in the cell’s nucleus. This can occur in a matter of minutes. Amazing, eh? Then, once it has performed its good cop duties, under normal circumstances, NF-kB is escorted back (by a gene called IKB-alpha) to the cytoplasm, a process I mentioned briefly in my earlier post.

Then we have the “noncanonical” or “alternative” NF-kB pathway, which is activated by other kinases and, for instance, chemotherapy drugs. Some stimuli, such as UV-C (Short-wave ultraviolet radiation), activate NF-kB both by IKK-dependent and IKK-independent pathways. Ok, ok, my eyes are glazing over, too, and besides, I don’t want to get into too many details. Let’s stay focused on the main points.

Under certain conditions and in response to certain types of stimuli, it would appear that NF-kB can have proapoptotic effects. This “is consistent with the hypothesis that it is the mechanism of induction of NF-kB that determines its physiological function.” It’s all a matter of context, in other words. The important thing is that “If differences in the NF-kB response to a chemotherapeutic drug also occur in different tumors in patients or between patients with apparently the same type of cancer, the ability to more accurately diagnose NF-kB status could profoundly affect treatment choice and outcome.” (Apart from that unfortunate split infinitive, this is quite an interesting statement.)

We already know that NF-kB has pro-inflammatory effects. But the study shows that “NF-kB activity can also be required for the resolution of an inflammatory response. NF-kB activity in the later stages of inflammation has been associated with induction of anti-inflammatory genes and the induction of cell death. Moreover, inhibition of this late-stage NF-kB activity extended the length of the inflammatory response, inhibited the expression of p53 and Bax, and prevented apoptosis.” So sometimes NF-kB can reduce inflammation. I am not sure what late-stage NF-kB activity means, but the inhibition of the tumour-suppressing p53 gene is certainly not a good thing. More research needed.

Now read this shocker: “Because NF-B can perform a tumor suppressor function in some tissues, will its inhibition actually promote cancer in some situations?” Ouch!

The answer is: probably not, since treatment is “relatively short term,” and thus its inhibition of NF-kB would not have enough time to give rise to cancer. So the inhibition of NF-kB, the study states, seems to be the best approach to treating cancer. If the treatment were long-term, though, such as in the treatment of chronic inflammatory diseases, the “continuous suppression of NF-kB activity over a number of years could manifest itself in, for example, squamous cell carcinoma.”

This is a real head-scratcher. A "damned if you do, damned if you don’t" situation. I’d better stop here before my brain melts. But I have not finished with this topic. Not at all.

A quick update before I sign off to go feed the cats: since my so-so test results, I have introduced flaxseed oil capsules into my protocol, also because Sherlock is taking them, too. A slight change. I will update my protocol soon. Have a great weekend, everyone!

Be happy, but not TOO happy…(oh, and my test results…)

January 31, 2008 / / 8 Comments

The first part of my post title refers to a Science Daily article I read this morning while waiting, or fidgeting is more like it!, to drive to the hospital to pick up my blood test results: these refer to the tests that Sherlock and I took before beginning our biocurcumax experiment. More precisely, to the November-January period of my CMC (cocoa mass curcumin) experiment, when I was also taking a low dose, no more than the daily recommended dose, of Scutellaria baicalensis and Zyflamend.

A quick aside: you can read this rather interesting Science Daily "happiness" article here: http://tinyurl.com/2l38re In a few words, a new study suggests that "moderate happiness may be preferable to full-fledged elation." The “don’t be too elated” study seems quite appropriate in view of my current test results: yep, more seesaw results. I am getting used to going a bit up then down, so it’s no big deal, now that I have had time, a few hours, to process and digest the numbers. Ready? Ok, here goes.

My IgG went up from 27,80 to 31,90 g/L. Now, that’s not a huge jump in the wrong direction, but it’s still a jump, 12% or so. However (!), my m-spike went down slightly, from 2,20 to 2,17, and my monoclonal component decreased from 25,7 to 25 %. These aren’t huge changes compared to my previous tests, but I think the two itsy bitsy decreases are interesting. From what I understand, in fact, the m-spike and IgG count go down together, hand in hand, and vice versa. Perhaps I was fighting a cold or some sort of infection during those two months, so my good immunoglobulins increased. It’s very possible. Well, I won’t say any more on the matter until I speak with my hematologist next Wednesday.

Ok, first let’s get the negative stuff out of the way:

Ferritin ( = iron stores) is back to 7, down from last test’s 10 ng/mL. No worries, it has been that low. It will go back up.

My albumin is down from 49,5 to 48,2 %. Oh well. It’s been lower.

Beta-2 microglobulin went up to 1,9 from 1,6 mg/L. Still way within normal range, though.

Hematocrit went down a bit, from 39,5 to 37,4 g/dL. Hmmm. Well, it, too, has been lower.

Now for the good stuff:

My serum iron jumped from 62 (barely within the normal range) to 81 microg/dL. Guess all those steaks and spinach with lemon juice made a difference, after all!

Bence Jones is negative. For the blog readers who are not members of the very exclusive Myeloma Club: that’s good.

Total protein went down a teeny bit, from 8,8 to 8,7, creeping back toward the normal range (high end of the normal range is 8,6 g/dL). Good.

LDH, or lactate dehydrogenase, decreased from 158 to 146 U/L. Also good, since high levels of the LDH enzyme are associated with aggressive disease, which we do not want!

Creatinine is stable at 0,7, no change.

Calcium went down from 9,6 to 9,2 mg/dL. Still way within the normal range. Nice to see it go down a fraction.

CRP is still within the normal range. I hate it that I don’t get a number but only a “less than” value.

Oh, I almost forgot. All of my celiac disease tests were negative, and you know what that means: pasta for lunch!

Well, even though I know that the myeloma is still stable (Sherlock, whose mind is much more analytical than mine, confirmed my feeling), I admit that I am not the happiest camper in the world right now. I would have liked to have seen a drop in my IgG count, a substantial drop. But it’s true that my m-spike dropped a wee bit, and besides, the above-mentioned happiness study shows that, compared to blissfully happy folks, people who are only mildly happy have room for improvement. I like that. Furthermore, if you are completely happy and satisfied, you have nothing to wish for, as Sherlock wisely pointed out to me earlier today. And that is no fun. So, hey, every so-so test result has a silver lining, isn’t that the saying?

My questions, for now:

1. Did the Scutellaria baicalensis clash with the curcumin cocoa mix, even though I took them at different times of the day?

2. Did I take enough Scutellaria to make a difference? (Off the top of my head: probably not.)

3. Do tests taken in certain periods of the year yield similar results? (Work in progress.)

4. When I am testing one supplement, should I quit taking curcumin for a month or so, to see if said supplement really works by itself? Now there is a scary thought. It’s like asking the Peanuts character Linus to give up his security blanket for a month or so. Tremble tremble ! But, in the interest of science…who knows…I might consider it.

Sherlock and I agreed earlier that I should change over to the…atomic bomb, i.e. take biocurcumax the way she is: once a day, all in one gulp. Forget about tickling my myeloma cells with a half dose twice a day. My gut feeling right now is that I want to blast the blasted myeloma cells with the entire arsenal, i.e. the full dose. At this point, I should mention that I am a pacifist in real life, but when it comes to myeloma cells, well, I feel like crawling down my bone marrow with a bow and curcumin-containing arrow and hunt the malignant cells down one by one.

I am going to look over my tests this weekend, and Sherlock and I will come up with a plan for March. Tomorrow Stefano is driving to southern Italy with his parents and brother to make sausages and whatnot out of a poor dead pig (I tried to save the pig’s life, but was outnumbered…this is a long-standing family tradition), so I will be “alone” in Florence with the four kitties. Plenty of time to study this issue. And go play cards with my girlfriends. Life is good.

PERSONAL SUCCESS STORIES

January 30, 2008 / / 4 Comments

A couple of days ago a blog reader privately suggested that I create a permanent page listing all the personal stories that have been published on my blog and the ones that may get posted (in the comment section only) in the future. This will ensure that they won’t get "lost." It’s true, I have more than 250 posts now, so yes, blog readers’ stories will eventually be impossible to find again, even for me! So this is a brilliant idea, thank you!

Below I list only the three stories published in the comment section of my January 27 post, but there are a few "older" stories listed on the permanent page (right-hand side of my homepage). Yesterday, in fact, I took off some time to go through some of the older post comments searching for personal stories (I will post only the ones that have been published on my blog; I will NOT publish any personal exchanges, of course, no worries), but I may have missed someone, so please remind me if you don’t see your story posted here. I have taken the liberty of editing out the parts that I thought less important, but feel free to scold me if I took out too much.

And by the way, I will be happy to post any stories concerning supplement-taking and dietary changes, so please don’t hesitate to send me the details. Now and in the future. And you can also send me updates as your story progresses. They don’t have to be success stories, necessarily, of course.

The following is not paraphrased, but is in your (blog readers) own words.

January 25 2008 post. Sherlock’s story: "I’ll just say how I took my curcumin capsules (8 gr./d). I took them all together (I follow a personal theory of the ‘atomic bomb’), late in the afternoon or late at night. I’ve not been very regular in the way I took them because I work out of town and sometimes is really difficolt for me to get hot milk and melt there 16 capsules of curcumin. So I used different systems, according to the situation:

– capsules melted into hot milk
– capsules taken drinking hot milk
– capsules taken drinking cold milk (not so often)
– capsules taken with just water

sometimes my stomach was empty, somethimes was full.
When I melted the capsules into hot milk I added either some olive oil, or some butter or some chocolate. Most of the time I did not add anything. My protocol also included 1.5 gr of quercetin and 1 gr. of fish oil every day. That’s all. I’m very happy that curcumin worked even if I changed the method of assumption according to my daily schedule. I think the most important thing has been to take all the 8 gr. together. My body knew that once a day a big dose of curcumin was going to cause apoptosis where it was needed."

JHope (she has been taking curcumin for more than two years, as I recall): "I have been taken curcumin – approximately 10 grams/day in podwer form (with bioperine) dissolved in hot milk. I also add fish oil (lemon flavor). I have been doing this for 2 years. My IgA marker has improved to the point that last test in December it was only 63 points above normal. This week I went to see a multiple myeloma specialist and shared with him what I was doing and he said to continue taking it that he has another patient that is doing the same and his numbers have improved tremendously. He also suggested to drink green tea.

Earl: "I have comments that could be helpful to others. My wife passed away 10 years ago due to MM. Five years ago I got a “pre-cancerous” prostate called high grade PIN. The doctor said there is nothing you can do except watch it……..I said, ” I think not.” I came up with a plan after checkng the internet extensively. I was able to REVERSE the pre-cancerous cells; as of August 13, 2008, they became non-existent. It was the last of three biopsies. Big picture: I went to an ALL organic diet; got a vita mix and drank approx 48 ounces a day of vegetables (Kale, broccli, red cabbage,parsley,carrots, and apples)…it tasted awful but I didn’t care. Also took “ground” flaxseed, cod liver oil, Aloe Vera, Vit c, N acyetal cysteine (NAC), Saw Polmento, Zinc, and selenium. Walked 45 minutes every day, lost 25 lbs and never regained the weight, stopped smoking and drinking. I stopped eating red meat and went to free range chicken and wild catch fish. BIG PICTURE: I placed all good things in my body and kept out the bad. The doctor reluctantly said I have changed the cell structure back to normal again. I have added curcumin the last 2 months: result, my triglycerides went down to 71 and my CRP, C-reactive protein is .2 The inflammation in my system is about 0…..a very good indicator of no cancer. If this article helps someone I will be happy. I too watched test results for 12 years and know the fear and excitement with bad and good results. I was VERY disciplined…..I realize that. But I made a choice to live and it worked. Sincerely Earl"

The dandelion phenomenon, part II

January 28, 2008 / / 3 Comments

Picking up from where I left off yesterday, the first type of cancer to be linked to stem cells was chronic myeloid leukaemia, or CML. The Johns Hopkins researchers proceed with a lengthy discussion on a drug called imatinib, which is used in CML, but without much success in the long-term. CML patients relapse if they discontinue imatinib (which, the researchers tell us, is currently being used more than interferon-alpha or IFN), or their cancer progresses even while they are on it. There appears to be no survival advantage in taking imatinib. The explanation, the researchers suggest, may lie in the CML stem cell resistance to this drug.

They use the dandelion analogy: “This pattern of activity is analogous to cutting a dandelion off at ground level. Although this will eliminate the visible portion of the weed, the unseen root also needs to be eliminated to prevent regrowth of the weed.”

Contrary to what happens with imatinib, CML patients’ response to the above-mentioned IFN is slow and gradual, “but can be durable.” So IFN would appear to act against the CML stem cells. Then we read “Thus, treatments that selectively attack cancer stem cells will not immediately eliminate the differentiated tumor cells. In this situation, cure (elimination of the cancer stem cells) in effect precedes the clinical demonstration of complete remission (clearance of the differentiated cancer cells) and could occur without actual disease shrinkage.”

This explains why these researchers took such a strong stance against the above-mentioned theory of complete remission. Complete remission may last months or years, but the cancer will return, eventually, unless the cancer stem cells are targeted. A treatment that targets cancer stem cells, however, won’t necessarily affect the circulating non-stem cancer cells. Hence, in this scenario, cure occurs before complete remission. This is contrary to everything I have read on the myeloma patient listservs (where a lot of the focus is on complete remission, or CR as we write it) and in the official myeloma literature. There are heaps of studies on the importance of complete remission in myeloma, in fact.

The researchers go on to discuss bortezomib (marketed as Velcade), a proteasome inhibitor, and lenalidomide (marketed as Revlimid, a derivative of thalidomide) commonly used in the conventional treatment of myeloma. These two drugs “can inhibit myeloma plasma cells but appear to have little activity against myeloma stem cells in vitro,” which means that they are pruning only the visible part of the dandelion, whereas rituximab, a monoclonal antibody, targets myeloma stem cells, i.e., the dandelion’s roots, according to the Johns Hopkins team.

The danger, the researchers point out, is that “As with IFN in CML and rituximab in myeloma, therapy directed against cancer stem cells might be prematurely abandoned if clinical activity is judged solely by criteria that reflect the effects of treatment on the bulk of the cancer.” And in fact, they add,“Not surprisingly, rituximab was found to have limited activity against myeloma in a short-term clinical trial. Rituximab’s activity against myeloma stem cells probably could not have manifested as immediate clinical responses in this trial because of the persistence of the long-lived, but terminally differentiated, myeloma plasma cells.” There you go.

So when we target stem cells, we must be patient. Unfortunately, nowadays, patience is no longer a virtue. We want to see immediate results. Overnight.

The researchers suggest setting up a clinical trial using bortezomib against the bulk of the cancer cells and then rituximab against the myeloma stem cells. Almost two years and a half have passed since this study was published. I went to have a look at the clinical trials being conducted right now. There are 591 trials (!) testing rituximab. I narrowed my search to myeloma, and found that there are 18 trials using rituximab alone or in combination with other drugs, such as lenalidomide or melphalan. Only one study, at the Dana-Farber Cancer Institute, is being conducted with rituximab and bortezomib, but for patients with Waldenstrom’s macroglobulinemia.

Well, these are certainly interesting times. I am all in favour of the dandelion theory, and it is for that reason that I am monitoring the DMAPT clinical trial, which should be beginning soon. (I admit to being more interested in substances such as DMAPT than in rituximab.)

The trees that are slow to grow bear the best fruit. (Molière)

The dandelion phenomenon

January 27, 2008 / / Leave a comment

This post turned out to be way too long, so I decided, as I have done with a few other posts that got out of hand (!), to divide it into two parts. I will post the second, longer "chapter" tomorrow.

Yesterday I read, and was spellbound by, a study on stem cells conducted by Dr. Matsui et al, and published in “Blood” in September 2005. The full study is available online: http://tinyurl.com/2539p7 An extraordinary study that makes some interesting points concerning “current methodologies used to develop new cancer therapies.” I thought I would highlight some of them (conventional methodologies only are discussed, by the way), even though you can go read the full text for yourselves: it’s easy to read, unlike most scientific texts. A real pleasure!

The abstract starts out with the following statement: “Although most cancer patients respond to therapy, few are cured. Moreover, objective clinical responses to treatment often do not even translate into substantial improvements in overall survival.” As various studies have shown, they write, the response of myeloma patients to chemotherapy does not lengthen their survival. An explanation for this could lie in the cancerous stem cells: “a rare population of cells that exclusively maintain the ability to self-renew and sustain the tumor.”

Now let’s have a look at the full study. The researchers immediately take a strong stance on the issue of "clinical response": “More than 30 new anti-cancer drugs have been approved over the past two decades. Approval required all of these drugs to show a clinical benefit, which can be documented by objective measurements of tumor response, improvements in quality of life as assessed by questionnaires, or a delay in the time to recurrence. However, these benefits have led to only modest increments in survival for the majority of cancer patients. Emerging laboratory and clinical data are beginning to point out potential flaws in the current methodologies used to develop new cancer therapies.”

What happens today is that when patients respond to a drug in a clinical trial, that drug is developed and made available as quickly as possible, with the idea that it will have an impact on the patients’ survival. If clinical trial designers, however, had to take into account “recurrence or an improvement in overall survival,” they would have to deal with very complex issues, such as large numbers of patients and allowing enough time, probably a lot of time, for follow-up.

The researchers do add that “objective responses” to chemotherapy may decrease side effects and improve quality of life. The issue at hand, though, is survival, for which “there is surprisingly little evidence.” As far as multiple myeloma is concerned, for instance, “neither the magnitude nor the kinetics of clinical response has an impact on survival.”

The researchers strongly criticize the concept of complete remission: “In actuality, the major rationale for the use of objective clinical response as a surrogate for biologic activity is the premise that a complete remission must precede cure.” They declare instead that “a complete remission by standard criteria may be neither a prerequisite nor a requirement for the actual generation of a cure.” This will become clearer as we proceed through the text.

Before signing off, I would like to urge everyone to read Earl’s story, in case you haven’t already done so (Beth posted his story on her blog, and I posted about her…post in early January). See his comment on my January 25^th post. Have a great Sunday!