Tag: myeloma

Genistein and signalling pathways

/ / 4 Comments

Yesterday I went through the 2006 “International Journal of Cancer” study (abstract: http://tinyurl.com/7eady3), which discusses how genistein affects the transcription factor NF-kappaB and the Notch-1 signalling pathway in pancreatic cancer cells.

 

[Note 1: Notch signalling is crucial for the growth and survival of multiple myeloma cells, not just pancreatic cancer cells…see, for instance, these two “Blood” 2004 abstracts: http://tinyurl.com/9p7k5e and http://tinyurl.com/7f9vzw. So this discussion is relevant to us myeloma folks, too.]

 

The abstract informs us that Notch signalling helps maintain the balance between cell proliferation, differentiation and apoptosis, and thereby may contribute to the development of pancreatic cancer…this process is, however, blocked by genistein. And, by inhibiting Notch-1, genistein also blocks NF-kappaB, which mediates survival signals that inhibit apoptosis and promote cancer cell growth. This process also affects the genes controlled by NF-kappaB, as we will see in a sec.

 

The cancer cells have no way out…except death.

 

[Note 2: the implications of inhibiting the Notch/NF-kappaB signalling process gave another push to my idea of gathering in one place (say, an Excel spreadsheet) all the data I have collected in the past year or so…if only I had more free time, had a scientifically-oriented brain, and were more organized…eh. Well, my rambling all over the place will simply have to do for now. But I have to admit that even I get overwhelmed by all the info contained in my own blog!!! If I could condense it somehow…]

 

The full study begins with the usual cancer statistics…in this case, of course, those concerning pancreatic cancer, which has the worst prognosis among all major cancers. Apparently, though, people whose diets are high in soy are less likely to get this type of cancer, suggesting that a high intake of soy products may protect people against pancreatic cancer.

 

Basically, as anticipated in the abstract, the study demonstrates that the inhibition of Notch-1 blocks NF-kappaB, at least in part. And this process also hinders genes that are regulated by NF-kappaB, such as COX-2, cyclin D1, MMP-9, Bcl-2, Bcl-xL and survivin. Well, well, we meet again…these are all genes implicated in the survival and merrymaking of myeloma cells, so this is a very important point.

 

In conclusion, the study demonstrates that the administration of genistein leads to the death of pancreatic cancer cells. The researchers speculate that one possible mechanism by which genistein induces apoptosis is due to down-regulation of Notch-1, a gene that is abnormally activated in many human malignancies and keeps pancreatic cancer cells alive and well, as it does with other types of cancer cells (erythroleukemia and cervical cancer are mentioned here).

 

And, as we know from my December 29 post, genistein also kills myeloma cells AND increases bone formation…

 

Toxicity issues. I was actually somewhat reassured after perusing a report carried out by the National Toxicology Program (U.S. Dept of Health and Human Services) in 2006, see http://tinyurl.com/9voc22 Incidentally, it answers Chris’ question concerning chickpeas. Even though the main source of genistein is soy, much smaller amounts can also be found in Lentils, peas, kidney beans, peanuts, chickpeas, broccoli, cauliflower, and barley meal. The report concludes that genistein is safe for human (adult) consumption. In order to reach possibly harmful levels of genistein, we would have to swallow huge quantities of the stuff, more than 35 mg/kg a day. Yep, that’s a lot. In any event, the main potential toxicity has to do with reproductive issues, which is not a concern for me.

 

I also took a look at a more recent (=2008) NTP report (see: http://tinyurl.com/7z3gnd) that confirms that although genistein did show adverse effects with dietary exposures of 100 or 500 ppm, there were no clear adverse effects on the reproductive or developmental parameters measured at genistein concentrations ranging from less than 1 ppm (control diet) to 100 ppm, a range of doses producing serum concentrations achievable from the phytoestrogen content of human diets.

 

Well, the more I read, the more I am tempted to try genistein (only from a certified non-GMO source), but I have other things to test first…in the meantime, I will (try to) keep an eye on this substance, too…

Genistein and myeloma, part II

/ / 4 Comments

A blogging friend sent me the full genistein study (thanks!!!) recently published in “Phytotherapy Research” (abstract: http://tinyurl.com/7wwnku), a study that I mentioned in my December 29th post. It starts out with the usual dismal information about multiple myeloma, which is a B-cell malignancy characterized by the latent accumulation in bone marrow of secretory plasma cells with a low proliferative index and an extended life span and accounts for 1% of all cancers and more than 10% of all blood cancers…oh, and it remains incurable…

 

There follows a description of what happens when the transcription factor NF-kappaB gets constitutively activated (that simply means that it is activated all the time)…this is not good, as far as we myeloma folks are concerned, since it means that our myeloma cells are protected from apoptosis (=from kicking the bucket). Reading on…blablablabla…okay, the upshot: NF-kappaB is an important target for myeloma treatment. So far, we have learned nothing new.

 

The research team chose to test genistein, a predominant isoflavone found in soybeans, which has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. Genistein suppresses NF-kappaB and many of the genes that it regulates. And humans can consume it safely, so they say.

 

Results. The team tested two different myeloma cell lines that expressed a hyperactive NF-kappaB. The cells were treated with different amounts of genistein and doxorubicin. A very small amount of genistein was sufficient to suppress the activation of NF-kappaB. It also worked synergistically with doxorubicin, leading to greater antitumor activity in vitro. Good.

 

For the more technically-oriented, genistein also inhibited Akt phosphorylation (when this happens, NF-kappaB doesn’t travel to the nucleus, which is a GOOD thing, take my word for it) and down-regulated ICAM-1, cyclin D, bcl-2 and bcl-xL (=four wicked genes).

 

Okay, but does genistein kill myeloma cells? Yes. How? Well, The precise molecular mechanism is not clear, the researchers admit. But wowie zowie, check this out: like curcumin, zerumbone and cyclopamine, genistein inhibits the Notch-1 pathway…does anyone remember what that pathway is? Right, it has to do with STEM cells…well, this might tip the balance in genistein’s favour, as far as I am concerned…yes, this is good news indeedie! I am so glad I read the full study!

 

Thanks to my big-hearted blogging friend, I have in my possession the 2006 genistein-Notch full study, which is next on my reading list…in the meantime, scribble scribble, a mental note: make more chickpea curries for dinner…

Genistein and myeloma

/ / 3 Comments

A blog reader/myeloma list friend (thank you!) sent me the link to a newly published study on genistein and multiple myeloma: http://tinyurl.com/a3qezp

 

Sherlock is abroad for the holidays, so I can’t get my hands on the full study until she returns, but the abstract gives us enough information for a preliminary report: genistein down-regulates NF-kappaB and related gene products…bcl-2 and bcl-x (well, well…well!) and others. But the main point is that genistein kills human myeloma cells, thus providing the molecular basis for the treatment of myeloma patients with this pharmacologically safe agent.

 

I had paid no serious attention to genistein because of the well-known problem of genetically modified soy…oh, right, because genistein derives mainly from soybeans, though small quantities can be found in other legumes, such as chickpeas. But from now on I will be keeping closer tabs on it. And perhaps eating more chickpeas…

 

This morning I bumped into another reason to keep an eye on genistein. A 2002 abstract (see: http://tinyurl.com/86ednx) discussed lab tests showing that genistein stimulates osteoblasts and inhibits osteoclasts; that is, it stimulates bone formation and prevents bone destruction. But these results had not been verified on human subjects…until 2002, that is.

 

That is when Italian researchers performed a randomized double-blind placebo-controlled study to evaluate and compare with hormone-replacement therapy (HRT) the effect of the phytoestrogen genistein on bone metabolism and bone mineral density (BMD) in postmenopausal women.

You can read many more details in the abstract, but the point is that This study confirms the genistein-positive effects on bone loss already observed in the experimental models of osteoporosis and indicates that the phytoestrogen [genistein, that is] reduces bone resorption and increases bone formation in postmenopausal women.

Excellent news for us myeloma folks…but before getting too excited about genistein and testing it on ourselves, my advice is to do more research into any possible risks and side effects (allergic reactions to soy and so on). I am definitely not in the genistein camp yet…but I am still reading, even though my task is rendered more difficult by the obnoxious presence of blatantly biased (one way or the other) websites. We need to find objective, more reliable sources…

Vitamin K and myeloma

/ / 4 Comments

Premise: my interest in most vitamins, except for vitamin D and (occasionally) a few others, has always been marginal. I also do not take a multivitamin or any individual vitamins.

 

Recently, though, I happened upon a Japanese study on vitamin K and myeloma: http://tinyurl.com/4tg824. I had already read about vitamin K on Don’s “Myeloma Hope” blog. But what this particular study revealed was news to me. As follows:

 

Vitamin K inhibits the growth of myeloma cells.

 

Before taking a look at the study, though, what is vitamin K, and can we obtain it from our diet? It’s a fat-soluble vitamin known as the “clotting” vitamin (the “K” in fact derives from the German word Koagulation), because our blood would not clot without it. (Note: warfarin, or Coumadin, is a vitamin-K antagonist because it inhibits coagulation.)

 

There is a lot of helpful but very technical information on the Linus Pauling Institute website: http://tinyurl.com/33dlfy

 

A few observations. Vitamin K is essential for the health of our bones. One of the consequences of vitamin K deficiency is, in fact, a reduction in osteoblast, i.e. bone-building, activity (see the LP Institute’s “Disease Prevention” section). And, surprise surprise!, I read that vitamin K deficiencies frequently occur in multiple myeloma patients. Hah.

 

Our bodies are unable to store vitamin K for long periods of time or in large amounts, which is why it is crucial to eat foods that contain it (unless you are taking warfarin). Vitamin K is present in cabbage, kale, broccoli, cauliflower, spinach and leafy vegetables in general. A partial vitamin K food list can be found on the LP Institute website (scroll down to “Sources”).

 

Interesting excerpt: To consume the amount of vitamin K associated with a decreased risk of hip fracture in the Framingham Heart Study (about 250 mcg/day), an individual would need to eat a little more than 1/2 cup of chopped broccoli or a large salad of mixed greens every day. Well, that’s not too difficult!

 

An excellent source of information on vitamin K is the World’s Healthiest Foods: http://tinyurl.com/ewrbe It tells us how vitamin K works and clearly explains the difference between the three different forms of vitamin K: Vitamin K1, phylloquinone, is the plant form of this nutrient. Vitamin K2, menaquinone, is produced from K1 by the bacteria in animal and human intestines. Vitamin K3, menadione, is a synthetic version. The one that is of interest to us myeloma folks, as we will see in a second, is vitamin K2, found mainly in eggs, liver (bleah!), some cheeses and fermented foods. This page also provides a long list of foods high in vitamin K. Very, very useful!

 

Okay, let’s go back now to the Japanese study that I mentioned at the beginning of the post. It examines the effect of vitamin K2 (aha!) specifically on myeloma cells. Previous studies showed that vitamin K2 can kill cell lines derived from patients with myelodysplastic syndrome (MDS) and acute leukemia, as well as freshly isolated leukemic cells.

 

An excerpt from the study’s Discussion: VK2 may be a good candidate therapeutic agent for myeloma patients since it caused growth inhibition, induced apoptosis via the mitochondrial pathway, activated apoptosis-inducing p38 MAPK,37-39 and generated reactive oxygen species.

 

Another important result was that vitamin K2 and dexamethasone were found to work synergistically against myeloma cells. And, by the way, the study mentions our old enemy, Bcl-x. When exposed to vitamin K2, Bcl-x was reduced. Hah!

 

Before filling up on vitamin K2, though, we should know that high doses could cause adverse effects such as thromboembolic events. This is of particular clinical relevance, because it is now recognized that thalidomide leads to increased rates of thromboembolic events in MM patients, especially when used in combination with other anti-myeloma agents (e.g., dexamethasone or alkylators). Therefore, if VK2 were to be used clinically as one of the therapeutic agents, it would have to be started at a low dose and with meticulous care to avoid thrombotic events.

 

Final considerations. The researchers point out that these were in vitro experiments done at high-dose concentrations for short periods. The long-term effects of vitamin K2 are not known. However, they add, supplementation with vitamin K2 might be useful in the treatment of elderly patients or patients who are unable to undergo harsh conventional treatments.

 

I will not take a vitamin K supplement, but I will print the WHF chart of vitamin K food sources and hang it up in my kitchen…just to make sure now and again that my vitamin K intake is adequate. I am so glad I did this bit of research today!

Zalypsis

/ / 4 Comments

It sounds like the name of a new videogame or a deadly disease, but Zalypsis is actually a newly-discovered (by a University of Salamanca research team) potent anti-myeloma substance, a new synthetic alkaloid related to various compounds isolated mainly from marine sponges. You can almost envision the excitement of these Spanish researchers when they declare that Zalypsis is the most active antimyeloma agent tested in our laboratory (see study abstract: http://tinyurl.com/59faqe). Further on, in the full study, they write that Zalypsis is at least 10 times more potent than any of the antimyeloma agents we have tested so far. 10 times…wow.

 

Okay, I will now launch into the full study, provided by Sherlock (grazie!) and pointed out to me by a blog reader (another grazie!).

 

Zalypsis was tested on nine different myeloma cell lines and bone marrow samples from myeloma patients. In every single case, including two cases of plasma cell leukaemia, it killed the cancerous cells. Apoptosis…

 

As for Zalypsis and healthy cells, I thought it would be good to copy the relevant paragraph: Upon analyzing the efficacy of a new agent a mandatory experiment is to investigate its toxicity in normal cells. These experiments are usually conducted on normal peripheral blood samples. We have developed an ex vivo technique that allows to simultaneously analyze the cell death induced by a particular agent both on the malignant cells and the residual BM cells. Now, for the first time using multiparametric flow cytometry, we have analyzed the action of Zalypsis on the cell subset that mainly corresponds to the normal stem cells (CD34+, CD38-, CD33-) and have seen that Zalypsis does not affect this cell population although is toxic for the more mature myeloid population. So, good news. Too bad that Zalypsis, from what I gather, is not effective against the myeloma stem cell population…

 

Another important discovery: Zalypsis inhibited IL-6 and eliminated the protection offered to myeloma cells in the bone marrow microenvironment, which confers protection to myeloma cells through their adhesion or through the production of several cytokines such as IL-6 […]. Precisely. Excellent.

 

Zalypsis was also found to work in synergy with and increase the efficacy of Dexamethasone, Melphalan, Doxorubicin, Bortezomib and Lenalidomide, which are all conventional drugs used to treat myeloma. In particular, it was effective when combined with Dex and Lenalidomide. It also increased tumour-killing p53 levels in most cell lines, more effectively and strongly than doxorubicin.

 

And remember our “friend,” Bcl-x? Well, Zalypsis also inhibited Bcl-x (but not Bcl-2; well, we can’t have everything…).

 

According to the researchers, Zalypsis has been found to have an acceptable toxicity profile. In this particular “Blood” study, they tested Zalypsis on three groups of mice (one control group and two groups receiving different Zalypsis doses) and found that no significant systemic toxicity was associated with Zalypsis treatment, and only a slight weight loss (around 10% of body weight as compared to the controls) was observed with the highest of the doses. Nevertheless, an important local toxicity was caused at the site of injection of Zalypsis with ulcerations and necrosis of the tail in some of the mice. Ok, we aren’t mice and don’t have tails, but should we be concerned?

 

The Phase I clinical trial (http://tinyurl.com/6yud2r) has ended. According to an October 2008 PharmaMar (the company marketing Zalypsis) press release (http://tinyurl.com/5tr5fu), […] the safety of Zalypsis in 37 patients with solid tumors or lymphoma was evaluated. The trial shows a good safety profile of the drug, which enables the continuation of its clinical development.

 

The press release informs us that Zalypsis was also tested in some childhood malignancies: The most significant results in in vitro tests were obtained in neuroblastoma and rhabdomyosarcoma cell lines. The evaluation of the compound in animal models also showed significant results, especially in the activity in rhabdomyosarcoma.

 

So, to sum up, Zalypsis was effective on myeloma cell lines that had become resistant to conventional chemo drugs. It worked synergistically with several anti-myeloma drugs, especially Lenalidomide and Dexamethasone. It also profoundly affected the growth of plasmacytomas in mice. The list goes on. Yes, it sounds like a very promising substance to me.

 

Study’s conclusion. The action of Zalypsis in MM therefore involves several interlaced pathways that move into an apoptotic response, likely initiated by direct DNA damage. These pathways may include p53-dependent and p53–independent routes that by acting on caspases and other apoptotic signalling pathways hamper MM cell proliferation and trigger apoptosis. The potent antimyeloma action of Zalypsis, together with the particular mechanism of action of this compound strongly supports the initiation of clinical studies in MM patients.

Tall women/heavy men at risk for myeloma

/ / 6 Comments

A blog reader (thanks!) sent me the link (http://tinyurl.com/6cvgnv) to an interesting bit of statistical news. In an attempt to test the hypothesis that increasing obesity (=impaired immunity) might be a reason for the growing number of cases of multiple myeloma and non-Hodgkin’s lymphoma or NHL, the “European Prospective Investigation into Cancer and Nutrition” (EPIC) examined hundreds of cases all over Europe.* The results were published in “Haematologica” in October 2008.

 

The study concluded that height is a multiple myeloma (and NHL) risk factor for women just as weight is for men. Doesn’t that sound peculiar?

 

The full study is available at the above link, so I will quote only some of the relevant bits, as follows: Height was associated with overall non-Hodgkin’s lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14–1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin’s lymphoma and multiple myeloma. This part then examines the risk associated with large B-cell lymphoma (heavier women are at risk) and follicular lymphoma (ditto for taller women).

 

MM has also been examined in a number of studies. In contrast to our finding of an elevated risk of MM among taller women, the Iowa women’s cohort study observed no association. Among men, the most prominent MM risk factors were weight, BMI and WC as categorized according to well-established definitions. (BMI=body mass index; WC=waist circumference.)

 

Factors that have been associated with multiple myeloma (MM) include high doses of ionizing radiation, and occupational exposure to products used in farming and petrochemical industries. Not my case, as far as I know.

 

In conclusion, the study found that height was a strong risk factor for NHL and MM risk in women.

 

A strong risk factor, eh? That’s quite a statement. My height would not get me into the book of Guinness World Records, but, growing up, I was always the tallest girl in my class. Always. This did not make me happy, mind you. In all of my (Italian) school photos, I am always stuck in the back with the tallest boys. All of the other girls were much shorter than I. And, come to think of it, so were most of the boys. A nightmare, back then. I am now 1.73 meters tall, which I think is about 5 foot 7 inches. Do I qualify as tall? Not sure. And why is tallness a risk factor for myeloma, anyway? The study doesn’t go into that, unless I missed a crucial part.

 

At any rate, according to this study, you are safe from developing multiple myeloma if you are a short, fat or thin woman, OR a thin, tall or short man…

*The EPIC is a multicenter prospective cohort study designed to examine the association between nutrition and cancer. […] participants were enrolled from the general population between 1993–1998 at 23 centers in ten European countries: Denmark (Åarhus, Copenhagen), France, Germany (Heidelberg, Potsdam), Greece, Italy (Florence, Varese, Ragusa, Turin, Naples), the Netherlands (Bilthoven, Utrecht), Norway (Lund), Spain (Asturias, Granada, Murcia, Navarra, San Sebastian), Sweden (Malmö, Umea) and the United Kingdom (Cambridge, Oxford).

More on healthful purring

/ / 3 Comments

A blog reader (thank you soooo soooo much!) translated the cat-relevant part of the 2003 Swedish study, Purr as a cat–and avoid osteoporosis, which I mentioned in my recent cat purring/bone healing post. Fabulous! So today I am going to post a quick update containing most of his translation. I have highlighted (in bold) a few of the more important, in my opinion, passages:

 

WHY do cats have such strong bones and so rarely bone defects and fractures compared with dogs? According to new evidence and theories, it is their purring which seems to be healing and strengthening for bone tissue. Purring provides vibrations which stimulate bone cells.

 

The cat achieves its purring via nerve pulses to the musculature of the throat and abdomen, according to A. L. Lyons, veterinarian at the University of California, Davis. In doing so, it sets an elastic sinew, between the clavicle and the windpipe, in vibration. The sinew vibrates at both inhalation and exhalation of the domestic cats according to a fixed pattern and frequency. Variations in frequency range between 25-150 hertz, and cats can vary the strength of their purr. Among big cats, however, the vibrations are limited to exhalation. The frequency range is especially interesting because it corresponds well with the frequencies that researchers in animal experiments have found can stimulate bone density and the healing of fractures.

 

Cats are hunters and strongly dependent on speed and strength of muscles and skeleton.  The cheetah, the fastest land animal on Earth, creeps up slowly on its prey and then accelerates lightning-fast to speeds that can approach 100 km per hour, then it strikes down its quarry within about 20 seconds. The final hunting phase rarely lasts more than a minute.

 

An animal weighing between 40 and 65 kg can make bring down a catch of up to 40 kg. But it eats an average of under 3 kg of meat a day. Therefore, its life on the savannah consists largely of lying still – the greatest risk factor for osteoporosis and muscle atrophy! The small amount of physical activity these quadrupeds normally expose their bones and muscles to in their survival on the savannah is hardly sufficient for them to be in the highest trim.

 

But purring is a mechanism that requires small amounts of energy and yet can still stimulate muscles and bone to strength and explains the cat’s performance ability despite the low level of exercise [=my Puzzola in this recent photo]. Perhaps it can also provide the background to the proverb that the cat has nine lives, as the purr vibrations should facilitate the healing of fractures and other tissue damage in reference to what has been shown in animal experiments in the laboratory environment.

 

Obviously, it is tempting to argue that cats purr for them to feel satisfied, but it’s more likely that their purring is partly a way for them to communicate and that it is also a potential source of self-healing and strengthening of the muscles and skeleton.

 

[…] Maria Sääf at the Karolinska Hospital in Stockholm, who has long studied the issues surrounding osteoporosis, […] was very enthusiastic about the possibility that vibration could also be beneficial for people with osteoporosis. A couple of pieces fell into place when she told me how vibrations are already being used in sports medicine to stimulate healing processes for injured elite athletes and that there is a new prototype machine at a school for children with limited movement which actually works with vibration technology. Her database search gave many hits of studies of the effects of vibrations on bone strength in animal experiments. But unfortunately there was a lack of work with results from human trials.

 

My reader/Swedish translator told me about a purring 2003 “Scientific American” article. I looked it up: http://www.sciam.com/article.cfm?id=why-do-cats-purr And, while reading it, I remembered that all of my cats purred like mad after they had been “fixed.” At the time, I thought that they were simply happy to be home. How silly of me! Now their purring makes more sense: they were healing themselves, and, in fact, I bet that their purring helped alleviate the pain that they must have been feeling, poor dears.

 

The SciAm article confirms that purring corresponds to sound frequencies that have been shown to improve bone density and promote healing. And, interestingly, both the Swedish study and the SciAm article discuss the fact that cats do not display as many muscle and bone abnormalities as their more strongly selected carnivore relative, the domestic dog. Perhaps cats’ purring helps alleviate the dysplasia or osteoporotic conditions that are more common in their canid cousins.

 

So snuggle up to your cat or cats, as I have been doing more and more lately. Let me warn you that snuggling could have unfortunate consequences. You see, now, every time I sit or lie down during the day, Priscilla demands in no uncertain terms to get under my sweater (see photo: so far, this is the best shot I have been able to get of her under my sweatshirt). Ignoring her is not an option. And her insistence can get to be a real drag when I am busily typing or reading. But then I think about my bones and how her purring may prevent future problems for me…

IgE and survival

/ / 13 Comments

A blog reader, thank you!, sent me a 2007 study on IgE written by an Italian research team. The full study is available here: http://tinyurl.com/4do9nx.

 

Intriguing, I must say. As a myeloma patient, you tend to read mostly about IgG (my type of myeloma), IgA and IgM…but not much about the other immunoglobulins. I looked up IgE and found that it triggers our body’s response to allergens such as cat dander, dust mites and pollen, and it also protects us from parasitic worms.

 

Well, I’d never even thought of having my IgE levels tested, so I was particularly interested in this study. The “Discussion” part tells us that This is the first study reporting polyclonal IgE levels in a large series of MGUS subjects and MM patients. To the best of our knowledge, it is also the first study reporting an association between IgE levels and Hb, and, even more interestingly, between IgE levels and survival in patients with hematologic malignancies. (“Hb” stands for haemoglobin, by the way.)

 

IgE levels are connected to survival? Well, well. Let’s keep reading.

 

The Italian researchers checked IgE levels in a large number of myeloma patients and MGUS folks and compared the results to a control group in order to determine survival and prognostic factors. They found that IgE levels progressively decreased from controls to MGUS and from MGUS to MM. And patients with high IgE levels lived 2 to 3 years longer than those with low or intermediate levels.

 

They concluded that high IgE levels are positive predictors of overall survival (P = 0.03 and 0.08,respectively) and strongly correlated with hemoglobin values.

 

Problem is, though, that total IgE levels are highly variable in general population, depending on many factors, such as age, gender, race, atopy, genetics, immune status, season of the year, tobacco smoke, and concomitant diseases. Further on we read that the Ranges of normal IgE levels are very variable, and no consensus among laboratories has been reached to define normal and pathologic values. Okay, so that could be a reason why IgE has not been taken into consideration in myeloma patients…until now, at any rate.

 

Another interesting finding: IgE is connected to haemoglobin (Hb) and Beta-2 microglobulin (B2M) levels. The researchers found that a high IgE meant a higher Hb and a lower B2M, and this in turn meant a better prognosisl. 

 

In the Discussion part we find the following titbit: The positive association between IgE levels and survival can be interpreted as an indication that (a) the immune system of MM patients with higher IgE levels is less deteriorated […]. Ah.

 

At any rate, because IgE is an antibody connected to allergy response, the possibility that myeloma patients with allergies such as asthma would be more protected than others in terms of disease progression really (!) got my attention since I suffer periodically from bad attacks of asthma (these attacks have returned, by the way, but I think it’s just because of the change in season from hot to chilly) and other allergic reactions. Hmmm, I thought for a second, have I finally discovered something positive about having asthma and rosacea??? Unfortunately, my hopes were dashed when I read that it is unlikely that allergies play a protective role in myeloma. Bummer!

 

This study is particularly interesting because for the first time ever a group of researchers has found a connection between IgE levels and survival prognosis. The higher those levels, the better off you are. I wonder if I could have my IgE levels tested…just out of curiosity. Or…on second thought…do I really want to know…???

Sea squirts blast myeloma cells

/ / 3 Comments

A blog reader (thank you!!!) sent me a bunch of interesting links, among which was one (see: http://tinyurl.com/5dc2us) about a marine-derived anti-tumour compound that annihilates myeloma cells in vitro and is extracted from a tunicate called Aplidium albicans.

According to Wikipedia, tunicates are underwater saclike filter feeders…weird-looking creatures that eat by filtering sea water through two openings in their bodies (“in” and “out” openings, sort of). They feed mainly on plankton. Not the prettiest creatures I have ever set my eyes on, that is for sure…ah, by the way, they are more familiarly known as sea squirts.

 

At any rate, this particular tunicate has squirt…I mean, yielded a substance called aplidin (drug name: plitidepsin) that is now being tested in Phase II clinical trials on relapsed or refractory myeloma patients, see: http://tinyurl.com/6rzumj.

 

An interesting thing about this compound is that it has a powerful in vitro activity against myeloma cells that have become resistant to conventional anti-myeloma drugs such as dexamethasone, thalidomide and bortezomib, according to the above-mentioned July 2008 study.

 

A June 2008 study (see: http://tinyurl.com/6k8l3w) tells us that treatment with aplidin was well tolerated by myelomic mice (sigh) whose serum paraprotein concentration was reduced by 42% and BM invasion with myeloma cells was decreased by 35%. Angiogenesis was also reduced to basal values. Not bad, eh!

 

Well, these two studies have been published only recently, and the clinical trial is ongoing, so we will have to be patient and wait to see what happens. Unfortunately, Sherlock wasn’t able to access the two corresponding journals, so I cannot even take a peek at the full studies. Oh well. However, according to the first abstract I cited (the July 2008 one co-authored by Dr. Ken Anderson), the preliminary trial results appear to be favourable.

 

I don’t have time to do much research today, but I did locate a 2007 study (full study: http://tinyurl.com/69mmhe) that informs us that aplidin has been given the “orphan drug” status for the treatment of acute lymphoblastic leukemia and multiple myeloma. This may speed things up…

 

Just as I was about to publish this post, I came across another interesting titbit, a review of aplidin on the IMF website (http://tinyurl.com/5dfplb), where you can watch a video presentation on aplidin by Dr. Enrique Ocio, University of Salamanca, Spain. Here we can also read that 31 relapsed/refractory patients were enrolled in the trial, median age 65: Out of the 26 evaluable patients, 2 (8%) achieved PR and 3 (12%) MR. Eight patients (31%) remained in stable disease (SD).

 

The conclusion was: Aplidin is effective both as a single agent and in combination with dexamethasone in the in vitro and in vivo settings. Its activity in relapsed/refractory MM patients is promising with an acceptable toxicity profile. There is quite a bit of interesting information on this page, so please have a look. I have to prepare my classes for tomorrow, so I must stop here. Have a great evening, everyone!

Myeloma’s Achilles’ heel?

/ / 4 Comments

The multiple myeloma patient support list (MMSupport) has been buzzing with a bit of news that you can read about on the National Cancer Institute website: http://tinyurl.com/6rwjx8

 

In a nutshell, our myeloma cells rely on the activity of a single protein, IRF4, for the activation of a wide range of genes responsible for cell survival and spread. Blocking the production of this protein can be strikingly effective in eliminating cancer cells in laboratory models of multiple myeloma. “These findings reveal a hitherto unknown and, for myeloma cells, critical network of gene activity centered on this one protein,” said Louis M. Staudt, M.D., Ph.D., deputy chief of the Metabolism Branch at NCI’s Center for Cancer Research. “What we have now is a new window of opportunity for therapeutic development in multiple myeloma.”  The abstract of the June 22nd “Nature” study can be read here: http://tinyurl.com/47ay24

 

IRF4 is not a mutant form, by the way, but its ability to activate normally inactive genetic programs inappropriately is crucial for the survival of myeloma cells. So, by blocking IRF4, we should be able to kill our myeloma cells. Would this include our myeloma stem cells? Well, that is not clear in the news release. Perhaps there is a mention of this in the full study.

 

Speaking of which, my dear Sherlock sent me the full study, but I haven’t had time to read it yet. I will print it out and read it at some point tomorrow and then post about anything of interest, ah, but not until Sunday at least, since tomorrow my brilliant husband is going to check my computer and almost certainly take it apart in order to change or fix a few components that have been misbehaving recently. This means, by the way, that I will be offline (e-mail included) for most if not the entire weekend.

 

Anyway, I also wanted to mention that the IRF4-myeloma connection does not really appear to be a “new” discovery. There may, of course, be some new findings (I won’t know until I read the full 2008 study), but if you search PubMed you will find an IRF4-myeloma study (see: http://tinyurl.com/5cwqzv) published in “Nature Genetics”…in 1997. More than ten years ago, that is…no comment…

 

Now I just have to do some research to find a natural inhibitor of IRF4. By the way, if anyone finds out something in this sense, please let me know. Thanks! Oh, have a great weekend, everyone! Smiley face