Tests and summer holidays

July 31, 2008 / / 2 Comments

Very early this morning Sherlock and I met at the Careggi hospital where we had our blood tests done, the first tests we have had since April. I told her a couple of dumb jokes, so we had a good giggle before it was our turn. The entire process was incredibly fast, very few people in line before us (Italy is on holiday!), so we were at the hospital café having breakfast by 8 a.m. Marvellous! Thrilled at having finished so early, we looked at each other and exclaimed “from now on we will have our summer blood tests done on July 31^st!” Anyway, my test results will be ready in early September, hers in late August (I had more specific tests done, such as vitamin B12, and it takes longer to get those results).

Let’s see. Stefano and I are leaving for our summer holiday in about ten days, so I am busily planning our itinerary. We are driving to Bourgogne (Burgundy), France, where we will spend a couple of weeks. To break up the long (=nine hours) drive from Florence to Saulieu, we are going to stop in Mont Avic, the first natural park of the Valle d’Aosta (=Italy’s smallest region, by the way), where we will be able to enjoy a stunning mixture of mountains, lakes, forests, lakes and valleys (see for instance: http://tinyurl.com/5owxfe). We will spend a few days there, hiking and taking photos. It should be lovely. Ah, and cool!

This morning at the hospital Sherlock presented me with two sets of telescopic trekking poles that should help Stefano and me walk up, and down!, any steep mountain trails. That was so thoughtful of her. What a super friend! Grazie, fantastica Sherlock!!!

From Mont Avic we will then drive to Burgundy. We have rented a small cottage (=gîte) near the Morvan Regional Park (see: http://tinyurl.com/6kd5a4) and about an hour’s drive from the lovely city of Dijon (here is a Washington Post 2006 article titled “A little Dijon on the side”: http://tinyurl.com/zvuj5). Regrettably, there are no puffins in the Morvan Park, but we hope to see heaps of other birds and animals.

Anyway, there is a lot to see and do and eat in Burgundy, and it should also be cooler there than it is here, although I checked today’s temperature in Saulieu and almost fainted when I saw it was about the same as boiling Florence (yikes!)!

Well, I am not in the proper holiday mode yet…I have classes to prepare for tomorrow and confess to feeling a bit worn-out after having all that blood drawn from my arm this morning…so this is it for today. Take care, everyone!

Curcumin and pancreatic cancer trial results

July 24, 2008 / / 8 Comments

A few days ago Prof. Aggarwal’s senior administrative assistant sent me a message with an unexpected and very welcome attachment: the full report (yippee!) on the pancreatic cancer-curcumin clinical trial that has been taking place at MD Anderson in Texas. The report was published in the July 15 issue of “Clinical Cancer Research” (see abstract: http://tinyurl.com/6fjk59).

This was a Phase II study to determine whether oral curcumin has biological activity in patients with pancreatic cancer. Let’s skip all the introductory parts describing pancreatic cancer and then curcumin and go have a look at the “Results.”

The average age of the 25 patients enrolled in the study was 65. No treatment-related toxic effects were observed. To date, one patient remains stable for >18 months and another patient had a dramatic but brief tumor response. The former patient had previously undergone a failed Whipple’s surgery followed by gemcitabine and radiation for locally advanced disease. Curcumin decreased this particular patient’s CA125 level (CA125 is the abbreviation for Cancer Antigen 125, which is elevated in many types of cancer, but apparently and surprisingly not that common in myeloma), the size of his lesions remained stable, and indeed there has been a decrease in the standardized uptake value in those lesions from a baseline level of 10.6 to a level of 5.7 after 12 months of therapy.

The report continues: One patient had a brief but marked response (73% reduction in tumor size by Response Evaluation Criteria in Solid Tumors) that lasted 1 month […]. Interestingly, at the time of progression, the lesions that had regressed remained small, but other lesions grew larger. This patient also had a rapid and dramatic increase in cytokine levels (IL-6, IL-8, IL-1RA, and IL-10). When I read this last sentence, I confess to having felt slightly alarmed…Then I read the following: Conceivably, this occurred because of release of cytokines from the tumor associated with shrinkage. Oh, phew! Relief!

The discussion regarding this particular patient continues later on: Also, of potential importance in this patient is the observation that the tumors that originally regressed continued to show regression during the follow-up period on curcumin, whereas the tumors that grew were the ones that had been small originally. This observation suggests that there was a malignant clone responsive to curcumin, whereas another resistant clone emerged.

In contrast, the patient who has appeared to have benefited most from treatment with curcumin (patient 14) has had slow improvement over 1 year and a gradual decrease in cytokine levels […]. Of interest, patient 14 had the highest baseline levels of IL-1RA of any of the study patients. IL-1RA stands for “Interleukin 1 receptor antagonist” and is the natural antagonist of the pro-inflammatory cytokines interleukin-1alpha and interleukin-1beta (from Wikipedia).

Okay, in sum, this means that two patients appeared to have biological activity of curcumin after treatment. That sounds even less encouraging than the myeloma-curcumin study at first glance…BUT, after treatment with curcumin, a decline in NF-kB, STAT3 and COX-2 was observed, and that is important, methinks.

I was particularly interested in the test results of the patients taking 8 grams of curcumin/day: Although we found little, if any, free or unconjugated curcumin in these patients’ plasma, we easily detected levels of curcumin following digestion of plasma with combined glucuronidase and sulfatase enzymes. This is consistent with data suggesting that curcumin is present in plasma in conjugated (glucuronide and sulfate) forms. […] Plasma levels of drug released from conjugated derivatives of curcumin on day 1 of dosing decreased on average to 22 to 41 ng/mL from 2 to 6 h after the first dose of curcumin […]. This simply means that the curcumin that enters our body is transformed into conjugate forms, whose levels continue to decrease as time passes.

There is a lot of detail in this 9-page study. I couldn’t possibly summarize it or quote it all. But I think many of us are chiefly interested in the issue of bioavailability, which is dealt with on pages 7-8: only low levels of curcumin are detectable in plasma (steady-state level at day 3 is ~22-41 ng/mL). Nevertheless, some of the patients had biological activity of curcumin as evidenced by the antitumor effects noted above in two patients and by effects on cytokine levels and on NF-kB, COX-2, and pSTAT3 […]. Conceivably, the limited bioavailability of curcumin attenuated the response rate, because exposure to microgram amounts of curcumin is required to show antiproliferative effects in vitro. It is also possible that circulating curcumin levels do not reflect tumor tissue curcumin levels.

Ah, now this is what I have suspected (or hoped!) for quite some time: curcumin may be barely detectable in the bloodstream, but that doesn’t mean that it isn’t working on some different level…This thought seems to be confirmed by the following: It has been suggested previously that systemic levels of drug may not reflect drug levels actually present in tissues of interest. Although at least one study has examined curcumin levels in colon tissue of mice after oral administration, few, if any, studies have analyzed curcumin or curcumin metabolites in malignant human tissues. This is important: few, if any, studies have analyzed curcumin or curcumin metabolites in malignant human tissues.

The study continues with an unwelcome bit of news: However, the researchers add that even though the levels of NF-kB and COX-2 were decreased by curcumin, this did not translate into a clinical response. Bummer…

Conclusion: as we know, oral curcumin is well tolerated at doses for of 8 grams for up to 18 months (in my case, much longer than that!). And, even though our body doesn’t absorb it very well, biological activity is evident. This is an important statement.

The problem as far as pancreatic cancer is concerned is that higher levels of exposure need to be achieved. Curcumin is hydrophobic and therefore cannot be given i.v. However, because it is lypophilic, it can be encapsulated in a liposome, and such a preparation would allow i.v. administration, leading presumably to higher circulating levels of curcumin. Lipophilic…meaning that it dissolves in fats and oils. Okay, we already knew that, but read the following:

The researchers suggest that liposomal curcumin or other better formulations of curcumin may provide more consistent blood levels with better pharmacologic effect. And, (drum roll) they are developing liposomal curcumin for clinical trials.

Well, until liposomal curcumin is available, I will probably go back to my kitchen this fall and try to come up with another palatable fat-based concoction containing curcumin C3 Complex powder.

Blog-related “business”: I appreciate all the comments I have received recently. Thank you! I have been super busy these past few days, working hard and whatnot, and that is the reason why I haven’t gotten in touch with everyone privately, as I try to do (when I have more time). Sorry!

Personal note: I wrote this post in a bit of a hurry because Stefano and I are getting ready to leave for a brief holiday in the Apennine mountains. We will be back in Florence on Sunday. Have a great weekend, everyone!

Brain food

July 21, 2008 / / 4 Comments

This morning I took a bit of time off to go through a few of my piled-up Science Daily newsletters, and, after reading about the extraordinary discovery of a 700-year-old Mexican mummy suffering, when alive of course (an alive mummy…), from a Helicobacter pylori infection (remember my MGUS and H. pylori post?), I came across a study (see the Science Daily July 11^th issue: http://tinyurl.com/5qjf2f) on the importance of omega 3 and brain functioning: “Food is like a pharmaceutical compound that affects the brain,” said Fernando Gómez-Pinilla, a UCLA professor of neurosurgery and physiological science who has spent years studying the effects of food, exercise and sleep on the brain.

Omega 3 fatty acids can not only improve learning and memory, they can also combat brain disorders ranging from depression to dementia. Another excellent reason to take ‘em! And, if our diet doesn’t have enough of these fatty acids, we are in for trouble (oh bother, I wish I had eaten more fish in the past!).

The following excerpt reminded me of the post I wrote on Prof. Gang and curcumin, basil and ginger (July 16^th post): Getting omega-3 fatty acids from food rather than from capsule supplements can be more beneficial, providing additional nutrients, Gómez-Pinilla said. Food, not capsules, eh?…hmmm, I predict more fish in my future…but I will also continue to take my purified fish oil capsules.

And read this: Recent research also supports the hypothesis that health can be passed down through generations, and a number of innovative studies point to the possibility that the effects of diet on mental health can be transmitted across generations, Gómez-Pinilla said. Wowie.

So the saying “you are what you eat” should perhaps be modified to the rather more alarming “your grandchildren are what you eat.” Since Stefano and I don’t have children, that modified saying doesn’t worry me too much, but still…diet and DNA…who would have thought?!!!

Okay, that’s it! Before preparing my classes for tomorrow, I am going to snack on some salmon and blueberries. Then it will be time for my curcumin and some spinach washed down with orange juice (for the folic acid), a bit of exercise and, finally, a nap…okay, I confess…I am joshing a bit, but, seriously now!, all of these items are mentioned in the article, so please have a look. There is lots to be learned here. Interesting…

Double-edged sword

July 19, 2008 / / 2 Comments

The double-edged sword is iron. Our bodies need it in order to function normally, but too much iron can increase the risk of developing cancer by promoting free radicals, and let’s also not forget that, once you have cancer, your cancer cells eagerly gobble up this metal, which is essential to their growth and wellbeing.

But too little iron can lead us to develop anaemia, which is one of the markers of active myeloma. Anaemia, in fact, is the “A” in the acronym “CRAB.” Can’t have too much..can’t have too little…hence, the double-edged sword bit…

It just so happens that, according to my most recent (April) test results, my serum iron and ferritin (ferritin, by the way, is a protein that binds to and stores iron that the body can use when needed) are the lowest they have ever been, as far as I know. In May I went to see my fabulous family doctor who didn’t see that as a sign of the myeloma kicking up any dust. No worries. What is important, he remarked, is that my haemoglobin and haematocrit are normal (they are). By the way, he was very pleased with my overall results. So am I.

He told me to take an iron supplement to increase my serum iron levels, but, as stubborn as an Alpine goat, I decided to wait for my next test results (still haven’t taken them, by the way). The reason for my stubbornness will be clear at the end of this post.

I should mention that I have been intending to write about curcumin and its effect on body iron for quite some time now, but other things have been getting in the way. Today I was finally inspired to look over a draft that I wrote back in March (!), when an Italian blog reader (grazie!) left me a comment pointing to a study on curcumin that might provide an explanation for my low iron levels. Sherlock did not have access to that particular journal, but she was able to hunt down and send me a couple of other studies.

The first study deals specifically with curcumin and iron. It’s titled Iron chelation in the biological activity of curcumin and was published in “Free Radical Biology & Medicine” in 2006. You can read the abstract here: http://tinyurl.com/3q9zzu

But first, what is iron chelation? The body cannot metabolize some heavy metals such as mercury and lead, and an accumulation of too much of this stuff can cause toxic effects, interfere with regular body functions etc. Heavy metals can be removed from the body using what are called chelating agents that bind to metals, hold on tightly to ‘em and finally expel them.

Apparently that is what curcumin does. As we can read in the above-mentioned abstract, ferritin protein levels decreased in cultured liver cells when curcumin was present. And Mice that were fed diets supplemented with curcumin exhibited a decline in levels of ferritin protein in the liver.

And now for a look at the full study, without overloading the post with details that I can barely grasp myself. The first part examines the well-known chemopreventive action of curcumin, so skip skip skip.

Then we get to the ferritin-iron-curcumin discussion. The jargon in this part is quite convoluted, hard to translate into simpler language. I did my best. Oh, before I forget: I skipped the part about the increase in GST, or glutathione S-transferase, in cultured liver cells, since that would have made this post way too long. But if you are interested in GST, let me know, and I will be glad to forward the entire study to you. Back to business, now.

The researchers suggest that iron chelation may be a novel mechanism that contributes to the potent cancer chemopreventive activity of curcumin. In their tests, curcumin activated IRPs, or iron regulatory proteins. These thingies get activated when iron levels decrease, for instance as a result of treatment with iron chelators. So far, so good.

The team examined the effect of curcumin on mice whose diet also contained some iron. One group was fed more curcumin, another less, and then there was the usual control (no curcumin) group: ferritin H and L proteins were both reduced to approximately 50% of control in mice receiving 2.0% dietary curcumin. (“H” stands for heavy, “L” for light.) I would like to mention that in no case were any adverse effects or toxicity observed as a result of the administration of curcumin to the mice.

The team also found that curcumin induced ferritin mRNA but reduced ferritin protein in cultured liver cells. Ehhh? I know, I know. But I found a rather simple (?) explanation (the link to this UC Berkeley study that I used in my March draft doesn’t work anymore, sorry about that!) that may help us figure out the difference between the two types of ferritin: iron accumulates in tissues in a solid, slow release form thanks to the ferritin protein. Ferritin protein manages iron and oxygen.

Ferritin mRNA instead has to do with genes, as the “mRNA” part suggests: A special structure in ferritin mRNA controls the synthesis rate of ferritin protein when iron has entered the cell. Okay, this is probably still not completely obvious to anybody without a scientific background, like yours truly. But the point is: curcumin’s ability to distinguish between the two types of ferritin—increasing the levels of the one (ferritin mRNA) but decreasing the levels of the other (ferritin protein)—suggests that it acts as an iron chelator, since iron chelators do the exact same thing.

Let’s have a look at the study results: One mechanism of action of synthetic chemopreventive agents is the induction of cytoprotective proteins. These include ferritin, a protein that functions as a cytoprotective protein by virtue of its ability to bind iron and reduce oxidative stress. And, just like chemotherapy, curcumin increases the levels of both subunits of mRNA ferritin, H (heavy) and L (light).

But, in contrast with chemo drugs, the levels of regular ferritin protein H and L declined to approximately 65% of control in cells treated with curcumin. That is quite a drop. The team demonstrated, however, that it is possible to reverse the trend, since iron depletion causes decreased levels of ferritin: If iron depletion underlies the curcumin-dependent decrease in levels of ferritin protein, then it should be possible to reverse the effect of curcumin on ferritin by repleting cells with iron. That is exactly what happened, and the researchers found that iron blocks curcumin-dependent ferritin repression.

At the end of the study we get to a very interesting bit of news. The researchers suggest that the intake of iron as a dietary supplement may bind to and interfere with the beneficial activity of curcumin. Aha! And, in fact, earlier in the study they write that iron was recently shown to attenuate the cytotoxic effects of curcumin in cultured squamous cell carcinoma. So iron renders curcumin less effective. Makes sense.

Well, after reading this study, I will not be taking an iron supplement…for now, at least. I cannot and indeed should not avoid iron completely (it’s in a lot of foods, of course), but I certainly don’t want to take anything extra that might interfere with curcumin’s anticancer activities…no way!

Margaret's Corner

Month: July 2008