Phase I trial of feverfew in cancer patients

May 16, 2009 / / 9 Comments

Those of you that who been following my blog in recent times know that I have been through a rather difficult period, emotionally speaking (in particular, the death of a close relative in Stefano’s family) and am only now getting my brain back on track…beginning to read studies again and so on. I have dozens of fascinating studies and Science Daily newsletters piled up on my desktop…plus interesting material and links that many of you have been sending to me. I should be finished by the year 2195…

Speaking of blog readers: Barry, I tried to send you TAB’s report, but I keep getting an “impossible-to-be-delivered” message. Sorry. I tried twice…failure both times. This happens now and again: I reply to a blog reader’s question, but my message doesn’t go through. So, if you have asked me a question and haven’t heard back from me, it may not be my fault (how’s that for a good excuse? hehe). Seriously, though, try writing to me again, using a different e-mail address if possible. Thanks!

Let’s get to today’s topic. In one of my posts on feverfew/parthenolide (PTL)/DMAPT, I mentioned en passant a 2004 Phase I feverfew trial…but I recall that I only glanced at the abstract and, back then, didn’t have access to the full study. Then I must have forgotten about it. Well, it just so happened that last week Sherlock (sei fantastica!) found and sent me a bunch of full studies on various topics, including, yippee, the 2004 feverfew trial study (abstract: http://tinyurl.com/qd7l85). Super!

Oh, before discussing the full study, I just wanted to say two more things. 1. I have planted two more feverfew plants in my front yard. The one that I planted last year barely made it through the summer and then died, much to my sorrow. It was my own bloody fault. It was a hot summer so I kept watering it…and I probably ended up drowning the poor thing. This just goes to show that too much love and attention and may not necessarily be a good thing. Anyway, this year I will do my best not to over-water the two plants that Stefano’s aunt sent to us from southern Italy. Fingers crossed. Actually, thus far they are doing fine…indeed, they are about to flower; as soon as that happens, I will post some photos.

2. In November 2008, soon after taking my first feverfew pill (not the Tanacet brand used in the 2004 clinical trial, by the way, but another brand containing a slightly higher PTL percentage), I felt a surge of heat on my upper lip. I checked in the mirror, and there it was: a small but rather angry cold sore. Stefano accompanied me to a pharmacy to buy some zovirax cream that I dabbed on the spot. The following day it had vanished. Other than that minor incident, I didn’t have any particular problems with feverfew.

Okay, now for the study. The abstract, which you can go read on your own, explains what feverfew is, gives the basic info about the trial and so on. As many as 4 mg of feverfew were given to a small group of cancer patients who experienced no significant toxicity. Interestingly, the maximum tolerated dose was not reached. I had to read the entire study to find out why.

On the down side, even at the highest dose—4 mg—there was no detectable concentration in the plasma. That means that feverfew is probably poorly bioavailable, as the researchers also suggest further on in the study. But, because of my initial reaction to the feverfew pill (the cold sore, I mean), I wonder if, like curcumin, feverfew might work on different areas in the body…other than the bloodstream, that is. These are the ramblings of a non-scientific mind, of course. Okay, let’s take a look at the full study.

The first paragraph makes the point that many chemo drugs derive from plant extracts: The taxanes, paclitaxel and docetaxel, are very important anti-cancer drugs derived from the yew plant family. Then we read a list of parthenolide’s properties…the main ones are potent in vitro anticancer and antiangiogenic properties, inhibition of NF-kB, IL-6, IL-8 and drug resistance.

The purpose of this clinical trial was to see if PTL would show up in cancer patients’ blood. It was administered daily for 28 days. Subsequent 28-day cycles were administered with an intervening break. No more than 4 mg/day were given because of drug supply issues…and financial considerations. Aha, that explains why the maximum tolerated dose wasn’t reached in this trial.

The patients took feverfew capsules (brand: Tanacet) containing 500 mcg of PTL, in the morning on an empty stomach (ahhh, how I loved all these details!). They were instructed not to eat for 1 hour after ingestion. More details: In cycle 1, blood samples were drawn on day 1 and 29 in the following fashion: pretreatment, and then 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 12, and 24 hours after the ingestion of the capsules.

Patient information: Twelve patients with advanced solid tumors were treated with feverfew. The median age was 73 years (range 48 to 80). There were 11 men and 1 women enrolled. The cancers treated included eleven prostate and one breast and all patients had metastatic disease and had received prior therapy.

Problems. Even though the patients experienced no significant toxicities, the trial was stopped at the dose level of 4 mg daily once it was determined that no parthenolide was identified in the plasma of any of the patients. By the way, side effects included: fever, gastrointestinal side effects, chills, fatigue, and blurred vision. The blurred vision and fever were experienced by a diabetic patient, therefore causes other than the feverfew were considered more likely.

The ominous statement, “No patients responded to therapy,” certainly did not bode well for my own recent experiment with feverfew. You see, I took one 600 mcg PTL pill, that is, quite a bit less than the 4 mg/day dose…it seems that I should have been taking 5 or 6 pills. Well, live and learn. But the researchers had also written that, while some patients requested to leave the study and others left because of disease progression, some (no details given) had responding or stable disease, with no appearance of new lesions, and were thus allowed to stay in the study for six cycles. Furthermore, If a patient had evidence of continued response after 6 cycles, treatment was to be continued for two more cycles beyond the best response. Okay, there is no question that this part is more than a tad confusing. Perhaps I should write directly to the researchers. In any case, as far as my own experience is concerned, I have been taking feverfew since November 2008…so perhaps, uhm, the temporal effect added to my wishful thinking and positive attitude will make a difference. Realistically, though, I won’t be surprised if my next test results don’t change one whit.

Toward the end of the study, the researchers state that their efforts will now focus on purifying parthenolide and identifying causes for the inability to deliver systemic levels with low doses such as 4 mg of parthenolide per day. And, further on, The data from our trial supports the need to purify parthenolide and administer higher doses. I wish them success!

Another anti-myeloma compound: pristimerin

May 15, 2009 / / 1 Comment

Remember my post/page on celastrol (from the thunder of god vine)? Well, for a memory refresher, you can scroll down my Pages to the one titled: Other anti-myeloma/cancer substances.

At any rate, a few weeks ago, looking through the table of contents for the April 23 edition of “Blood,” I came across a study discussing a related compound (Sherlock, grazieee!, sent me the full study): pristimerin, a naturally-occuring substance that has strong anti-myeloma activity. See abstract: http://tinyurl.com/dbr36b

Since one of the proliferation factors involved in myeloma is cyclin D, a group of researchers from different cancer institutions conducted high-throughput chemical library screens for compounds that induce suppression of cyclin D2 promoter transcription. The top-ranked compound was a natural triterpenoid, pristimerin.

A natural triter…huh? No worries, I looked it up. Triterpenoids (hehe, try saying “triterpenoid” ten times FAST!) are biologically active, anti-inflammatory, anticancer and antioxidant compounds extracted from many plants, e.g. from the Celastrus and Maytenus species. Remember my posts/pages on glycyrrhizin, ursolic acid, betulinic acid, celastrol and oleanolic acid? Well, these substances are triterthingies, too. Okay, with that matter cleared up, let’s give this thing a go.

From the abstract we learn that pristimerin strongly inhibits proteasomes. (Ah, just like bortezomib and, ta-da!, curcumin.) In fact, I found a 2008 study on that very topic: http://tinyurl.com/pct6y7 The abstract tells us that pristimerin has been used for ages in folk medicine as an anti-inflammatory remedy. Now, where have I heard THAT before…? Anyway, in addition to killing breast cancer cells, pristimerin also targets proteasomes in prostate cancer cells. Well, well…

Okay, back to the April 2009 “Blood” study. Interesting titbit: pristimerin’s anti-proteasome activity occurs even at low concentrations. Furthermore, this substance inhibits our old enemy, hyperactive NF-kappaB, as well as cyclin D expression. In fact, it does such a good inhibiting job that the researchers make the following statement: As a consequence, pristimerin induces selective myeloma cell apoptosis in vitro and in vivo with greater potency than that described for other antineoplastic triterpenoids such as celastrol or CDDO, which are currently in clinical trials. Not bad, eh…

Okay, let’s get to the good stuff. In lab tests, pristimerin caused substantial suppression of all the cyclin D proteins. Even myeloma-friendly cytokines such as IL-6 could not protect myeloma cells from certain death. Hah!

Pristimerin was tested in vivo, too…specifically, on…gee, one guess!…nude mice with implanted plasmacytomas. The first experiment showed that high doses of pristimerin were too toxic…the mice had to be put out of their misery. So the researchers developed a liposomal formulation, which turned out to be less toxic and better tolerated in a second mice-based experiment. Result: Statistically significant tumor growth inhibition occurred at pristimerin doses of 2 to 3 mg/kg intravenously twice weekly, compared with vehicle-treated mice.

Pristimerin also worked in synergy with bortezomib. The two substances alone were less effective than when combined.

In the study’s Discussion, the researchers declare that pristimerin possesses substantial antimyeloma cytotoxic activity […] with a potency more than 10-fold that of CDDO or betulinic acid for solid organ malignancies, and more than 2- to 3-fold that of CDDO for multiple myeloma,39 and that pristimerin is synergistically cytotoxic with bortezomib, perhaps the most active antimyeloma agent in the clinic today.

Further on, they add that Uniquely, we find that pristimerin induces significant proteasome inhibition, which likely contributes to both its inhibition of NF-kB pathway signaling and specific cytotoxicity in myeloma. To our knowledge, no other triterpenoid has been demonstrated to inhibit proteosome function, although such activity could perhaps account for some of the activities of cytotoxic triterpenoids. Using in vitro and in vivo studies, we demonstrate that pristimerin causes selective antimyeloma cytotoxicity, within a therapeutic window, identifying it as a lead compound for the development of enhanced triterpenoid-derived anticancer pharmaceuticals.

They also raise the possibility that pristimerin might be able to overcome myeloma’s well-known ability to become resistant to conventional treatments.

Well, this is simply an introductory report on yet another promising anti-myeloma substance extracted from plants. Clearly, more research and testing are needed…and no, I am not ready to fly to China, hunt down and munch on the roots of Celastrus hypoleucus, a pristimerin-containing plant…nope, not yet!

A few links to pristimerin studies

1. “Antiproliferative activity of pristimerin isolated from Maytenus ilicifolia (Celastraceae) in human HL-60 cells,” 2008: http://tinyurl.com/rbukj5

2. Triterpenoids and doxorubicin, 2006: http://tinyurl.com/qzahub

3. Anti-cytomegalovirus activity of pristimerin, 2007: http://tinyurl.com/q83kmy

4. Antifungal properties of pristimerin and celastrol, 2005: http://tinyurl.com/o99rrg

5. More information on triterpenoids, 1986: http://tinyurl.com/db8cde

Oasi Stagni di Focognano

May 9, 2009 / / 8 Comments

Yesterday my computer decided it needed a rest and refused even to boot…unfortunately Stefano couldn’t fix it until today…which reminds me how lucky I am to be married to a computer genius…oh, and speaking of being married to a genius (not just in the field of computers, by the way) and whatnot, yesterday was our 10th wedding anniversary. WOW! 10 years…already…

I have to say, though, that we were so tired last night that we didn’t do anything much out of the ordinary…but since cheesecake is one of Stefano’s favourite sweets, day before yesterday I prepared a scrumptious New York style cheesecake, and last night we brought pizzas home for dinner (I usually make my own pizza with herbs…but not on my anniversary!).

Then, this morning, while my computer was mulling things over (Stefano launched a “get-your-act-together-or-else!” program that needed to run for hours), we went to a WWF oasis right outside of Florence, in the municipality of Campi Bisenzio: Oasi Stagni di Focognano. It’s a swampy area that hosts quite a variety of migrating bird species at different times of the year. Who would have thought…so close to Florence…! See: http://it.wikipedia.org/wiki/Oasi_di_Focognano (in Italian)

We were quite lucky this morning. We saw and took photos of white herons, black-winged stilts (in Italian, they have a nobler name: cavalieri d’Italia, or Italian knights), grey herons (aironi cenerino), common coots (folaghe) and great crested grebes (svassi). We actually spotted more birds, but these are the main ones.

Apparently, though, the best time of year to visit the oasis is in the autumn and the early spring. When birds are migrating, of course. Last fall we were told that a few storks landed in the main lake, and as late as last week a kingfisher (martin pescatore) was spotted. Too bad we missed it! So this morning Stefano and I registered at the oasis as “photographers,” which means that next time we won’t need to be accompanied by a guide but can go off on our own and stay as long as we want. Excellent.

These are some of the photos I took. Stefano’s photos are much better (he has a BIG camera with a super-long lens), but he is still looking through them, and I didn’t want to wait…oops, it’s late, time for dinner…and, uhm, for some more cheesecake! Ciao!

Curcumin beats chemoresistance and helps thalidomide and bortezomib fight myeloma

April 30, 2009 / / 14 Comments

A new study, carried out by a group of MD Anderson researchers and published this month in “Molecular Cancer Therapeutics” (see abstract: http://tinyurl.com/c2hlfx) confirms what we already knew about curcumin’s synergy with bortezomib.*

The researchers performed experiments on myeloma cells and also on nude mice. Now, since I frequently read about “nude mice,” some time ago I gathered the courage to do a bit of research… almost wish I hadn’t!…at any rate, these mice are simply hairless (hence their nickname “nude”), not in need of a new set of clothes. Most importantly, though, due to a genetic mutation, they are born without a thymus and thus have an inhibited immune system, which means that they are not able to reject tissue or tumour grafts (they also have little or no defence against viruses and all sorts of nasty stuff, poor dears). Therein lies their usefulness.

Now, let me state that, after reading about nude mice, not to speak of other lab animals!, I finally stopped regretting that I didn’t choose science as my major in college and grad school. Ah yes, I’d have been the crazy student taking all the nude mice home, wrapping them in warm shawls and keeping them as pets…hmmm, something tells me that my brilliant scientific career wouldn’t have lasted very long…

Okay, now that that is all cleared up, and I have admitted publicly to how silly I am, let’s proceed. An important result of this new study is that curcumin inhibited the proliferation of human multiple myeloma cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. The wonderful orange powder also helped bortezomib and thalidomide kill myeloma cells by reducing NF-kappaB’s incessant hyperactivity (=a bad BAD thing!), which also affected the gene products under its control (cyclin D1, etc.).

Going on to the full study, now (grazieeee, Sherlock!). After a paragraph dealing with the usual dire myeloma statistics, blablabla, we find out that the researchers used C3 Complex, the curcumin that I (and many others) take. Good to know.

And then we get to the actual experiment, which I will try to summarize. The nude mice were divided into four groups: 1. the control group, which was treated just with corn oil and saline; 2. the curcumin alone group (1 gram of curcumin per kilogram…holy cats, that seems like a LOT! Ah no, wait, see my footnote**); 3. the bortezomib alone group, and 4. the curcumin and bortezomib combo group.

25 days after the treatment start date, the mice were killed, and their tumours examined. Skipping the long and detailed explanation of how this process was carried out, let’s get to the results. Compared with the other three groups, the biggest tumours were in the control group, as to be expected. There was instead a significant decrease in tumour volume in both the curcumin and bortezomib groups, i.e., 2 and 3. But in group 4, the combo group, the tumours were even smaller: When examined for tumor volume on different days, we found that curcumin + bortezomib combination was much more effective in reducing the tumor volume compared with either agent alone.

As for thalidomide, the researchers used myeloma cells treated with curcumin in combination either with bortezomib or thalidomide and found that Curcumin potentiated the apoptotic effect of bortezomib from 25% to 85% and thalidomide from 10% to 75%. Not bad at all…

Another interesting titbit, for those who remember my PARP cleavage post: When we examined the poly(ADP-ribose) polymerase cleavage, which indicates caspase-3 activation, a well-known characteristic of apoptosis, we found that curcumin potentiated the effect of bortezomib and thalidomide. In this particular case, curcumin worked better with thalidomide.

Now for the Discussion part: First, cells resistant to chemotherapeutic agents have been shown to express increased activation of NF-kB and suppression of this NF-kB can sensitize the cells to the drug. Second, multiple myeloma cells and mantel cell lymphoma are known to express constitutive active NF-kB that is resistant to bortezomib. Fairly clear, no?

Then we get to an interesting titbit concerning CRP: C-reactive protein, whose expression is regulated by NF-kB, has been shown to enhance the proliferation of myeloma cells and protect myeloma cells from chemotherapy-induced apoptosis both in vitro and in vivo. Among other things, CRP also increases the production of IL-6 with which it works synergistically to protect myeloma cells from chemotherapy-induced apoptosis. Bad stuff…!

Other proteins that help myeloma cells become resistant to the attacks of chemo drugs are cyclin D1, the members of the infamous Bcl family and survivin. I have posted about all of these buggers. At any rate, the study confirms that curcumin down-regulates all of them…as we already knew from previous posts.

Like curcumin, bortezomib inhibits the activation of NF-kappaB, but through different mechanisms. As follows: Bortezomib inhibits the proteasome, resulting in the accumulation of IkBa, whereas curcumin prevents IkB phosphorylation, thus blocking its subsequent ubiquitination and degradation through suppression of upstream kinase IKK. Thus, these different mechanisms of NF-kB suppression provide the rationale for combining these agents to effectively inhibit NF-kB activation. Now, even if we don’t understand the meaning of all this, what is clear is that curcumin and bortezomib attack myeloma cells and reduce NF-kB activity in different ways. And that is exactly why, when combined, they work better than when they are used alone.

Another useful characteristic of curcumin: it can help alleviate fatigue and peripheral neuropathy, which are common side effects of the conventional chemo drugs used to treat myeloma. Indeed, the study states that these effects can be REVERSED by curcumin. No comment needed here, methinks…

The study ends with a very strong statement: In conclusion, the chemoresistance remains a major challenge in the treatment of patients with multiple myeloma as well as other cancers. Multiple myeloma patients who have relapsed after conventional dose chemotherapy or stem cell transplantation are typically treated with high-dose corticosteroids, thalidomide, or bortezomib. However, a large number of these patients do not respond to treatment with these agents. Moreover, prolonged exposure leads to the development of resistance and toxicity, and progression-free and overall survival times for multiple myeloma patients are short. The ability of curcumin to suppress NF-kB activation, down-regulate the expression of cyclin D1 and Bcl-xL, inhibit cell proliferation, potentiate the effects of bortezomib and thalidomide, and overcome chemoresistance provides a sound basis for conducting clinical trials with curcumin, alone or in combination with other agents, to enhance treatment efficacy, reduce toxicity, and overcome chemoresistance of relapsed or refractory multiple myeloma.

*Probably based on the fact that I mention chemo treatments from time to time, especially bortezomib (Velcade), more than a few readers have asked me if I have ever had any conventional treatments. The answer is no. For more on that, please see “My Discovery of Curcumin” page, which, er, needs some updating, for instance I have been taking curcumin for more than three years now, not just two…but anyway, the basic info is there.

**When I first saw that 1 g/kg (or 1000 mg/kg) of curcumin was the daily dose administered to the nude mice in group 2 and 4, I thought that that would translate into a massive amount of curcumin for humans. But then I vaguely recalled that there were differences between mice and humans, other than the, uhm, rather obvious ones. And I remembered that there was a way to convert doses from mice to humans. A bit of research led me to a 2008 study (http://tinyurl.com/cv6opy) dealing with this very topic and providing, yay!, the converting formula. So, unless my math is even worse than I thought (!), based on this formula and a 60 kg human being, 1000 mg/kg x 3 = 3000; 3000 : 37 = 81 x 60 = 4860 mg/daily dose. That means: less than 5 grams of curcumin a day in human terms. So for the past three years plus I have been taking a larger dose of curcumin than was used in this study. Interesting. And finally, an appeal to all my blog-reading math whizzes: would you mind checking my calculations? Thanks! It just seems way too simple, that’s all…

The “swine” flu virus

April 29, 2009 / / 13 Comments

Today I would like to comment on what is going on in Mexico and, by now, several other countries, including Spain, the UK and Germany. I am concerned mainly about my family in the U.S. and my buddy Sherlock and her husband (currently in southern California), but my thoughts are also with those of you who live in the affected areas.

According to the reports I have read, the main symptoms of this new strain of the influenza virus are: coughing, sore throat, aches, fever, chills, general malaise and then, after about a week, respiratory problems. Can we take any precautions? Sure we can. Let’s have a look at a few of the standard flu season recommendations (sorry if I forget anything)…

Flu viruses can survive up to two hours (or even more!) on surfaces such as doorknobs, countertops, phones, toys, shopping cart handles and computer keyboards. I read that these dangerous buggers live longer on plastic, metal or wood surfaces (i.e., non porous) than they do on fabrics, skin or paper. Based on that bit of information, here is a suggestion list:

avoid shaking hands with people.
don’t cough or sneeze into your hands (never!) but rather onto your sleeve.
never touch your eyes, nose or mouth unless you have washed your hands. Speaking of which…
the most important thing is to wash your hands thoroughly and frequently, especially after returning home from an errand or whatnot.

Some time ago, I read a very useful suggestion posted by a myeloma list member: as you wash your hands, sing “Happy Birthday” to yourself. That silly little song lasts exactly the amount of time recommended for a thorough hand-washing. I have been using this technique for quite some time, now, regardless of the season: “Happy Birthday to me, Happy Birthday to me, Happy Birthday dear meeeee, Happy Birthday to meeee, and Many moreeeeee.” Depending on my mood, I sing it (to myself) in Italian, too…since the language is irrelevant, of course.

Italy is not an at-risk country (thus far), so I am not concerned for myself or Stefano. Hmmm, a thought just occurred to me…I haven’t had any tests now in about six months and am finally running out of my feverfew pill supply. For the past several weeks I had been planning to go up to the hospital for my tests…but every time I decided on a particular day, something happened, and I had to postpone. Well, I guess I had better go have my tests done before the virus reaches Italy (as it may or may not). Okay, off to the hospital next week. I will wear a mask…just to be on the safe side.

In conclusion, all I can say to all of you who are currently in areas at risk is: please be careful, stay informed (see: http://en.wikipedia.org/wiki/2009_swine_flu_outbreak), wash your hands, laugh to enhance your immunity and, above all, please stay well!