The green kind

December 12, 2008 / / 3 Comments

Yesterday I finished watching “Cranford,” the 2007 BBC series based on the homonymous novel by Elizabeth Gaskell, a 19^th century English writer whom I happen to admire.

I am mentioning this series today because of a couple of amusing (to me, at least) sentences uttered by one of the characters, elderly Miss Matty—wonderful brilliant fabulous Judi Dench.

A few explanatory words: due to difficult financial circumstances, Miss Matty is forced to begin selling tea to the inhabitants of her village. And this is what she has to say about going into trade:

I will stock any sort of tea except the green kind. It is so fearfully bad for the digestion.

I thought I was going to choke. 🙂

This morning I found the green tea episode in the novel (which I have in my library but haven’t read yet). Miss Matty considers green tea to be “slow poison, sure to destroy the nerves, and produce all manner of evil.” Hehe. Note: in the end, though, due to customer demand, she resigns herself to selling it.

There were many “Cranford” sentences that tickled my funny bone. Here are a few of my favourites:

1. The village rector, whose daughter has been taken ill, is told by the elderly doctor: Lavish your daughter with eggs and affection.

2. Miss Deborah (Miss Matty’s sister): I would prefer it if I did not enjoy oranges. Consuming them is a most incommodious business. (Mental note: must use “most incommodious” in my writing.)

3. Miss Matty: I have never liked the notion that the world is round. It makes me feel so giddy.

4. Miss Matty: I shall arrange myself by the window.

Brilliant. Charming. Terrific acting all around. Perfect for those of us who enjoy BBC period dramas (ahhh, Mr. Darcy/Colin Firth…).

This afternoon I am starting on the BBC 2005 adaptation of Dickens’ “Bleak House.” There is definitely something to be said for having a cough and being “forced” to rest for part of the day…(though I am much much better now! Another two days, and I will be as fit as a fiddle…drat, no more excuses for lying in bed with the kitties and watching period dramas…). 😉

Zalypsis

December 11, 2008 / / 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.

DMAPT: targeting leukemic stem cells

December 8, 2008 / / 7 Comments

Thanks to a Google Alert, yesterday I learned about a new article written by Craig T. Jordan, Ph.D., an Associate Professor at the James P. Wilmot Cancer Center, U of Rochester School of Medicine. Here is the link to the abstract: http://tinyurl.com/695g3g. As usual, I asked Sherlock (gracias!) to get the full study for me. Well, this was quite an interesting (and easy) read, which also gave me a few possible clues as to why the DMAPT clinical trial hasn’t yet begun in the UK. But let’s proceed by degrees, as usual.

Dr. Jordan brings up an issue that is no news to us: can the same results obtained in laboratory tests be obtained in patients as well? Eh.

He then mentions a series of small molecules, such as a proteasome inhibitor named MG-132, which target leukemic stem cells. But I would like to focus on what he writes about the substance that interests me perhaps above all others right now: parthenolide (PTL). As you may recall, I am currently testing a feverfew supplement that contains 3% PTL (the highest % I could find). I am taking the dosage recommended on the bottle, which is minimal, I know, especially since PTL is poorly bioavailable. I read that a group of cancer patients took as many as 4 grams of PTL/day in a 2004 Phase I dose escalation trial. I am presently taking less than one-fourth of that. But my motto is primum non nocere, and I am going to stick to it. I can always increase the dose, right?

So let’s see what Dr. Jordan has to say about PTL: Parthenolide, a naturally occurring molecule found in the medicinal plant feverfew, induces apoptosis in acute myeloid leukemia (AML) stem cells. Interestingly, he then mentions celastrol (see my Page on celastrol or “thunder of god”), which targets both “bulk” and stem AML cells. But his focus is on PTL.

And here we get to one of the most promising substances I have come across in my research, one that I dearly hope will quickly turn out to be effective and non toxic in Phase I trials: DMAPT, the PTL analogue. The acronym stands for dimethylamino-parthenolide. (I have a Page on PTL and DMAPT, by the way.)

Dr. Jordan tells us that, unlike PTL, DMAPT is readily water soluble and is 70% orally bioavailable. Pharmacologic studies in rodents and dogs have shown the drug to be tolerable well beyond the level at which in vitro activity is observed, without any known associated acute toxicity.

As we know from previous studies, in addition to inhibiting NF-kappa B, DMAPT targets ONLY cancerous stem cells, leaving healthy cells alone. And, When canines with severe acute leukemia were treated with 50 mg/kg daily DMAPT, the levels of CD34-positive cells were largely reduced.

A detailed description of an experiment conducted on animals (mice, mainly) follows. I won’t go into details, but the results were that leukemic stem cells were impaired, at least in the context of a large animal with a spontaneous leukemia.

This paragraph ends with words that sound like a Mozart symphony to my ears: Based on the preclinical findings, the drug is proceeding towards clinical trials. As my darling niece would comment, “Sweet!”

Dr. Jordan then provides a possible explanation for why it is taking so long to start the DMAPT clinical trials (this is my own interpretation, mind you, since the reason could merely be endless heaps of red tape): It is still unclear how to effectively assess whether leukemic stem cells are actually being targeted. Ah. Big problem, here.

He adds that A targeted agent could be used as part of a maintenance regimen to destroy the residual leukemic stem cells in patients in remission. However, he soon adds, there is no evidence that any of the agents currently available can target leukemia stem cells in a remission patient. Oh.

And then we get to a fascinating, thought-provoking excerpt: The biology of cells in minimal residual disease conditions appears to be very different from that of cells found in a de novo and heavy tumor-burden context. This difference can impact whether the drugs work or not. As clinical trials progress, the targeted agents may fail because of the physiology of the tumor cells, not because the drug is ineffective with all leukemic stem cells. Well then, I say, why not test DMAPT also on leukemic/myeloma patients who have never had any conventional treatments? (Not that I have anyone specific in mind… 😉 )

Reading on, we stumble upon what might be another reason for the DMAPT clinical trial delay: Cancers are heterogeneous, and this is exceptionally true of leukemic stem cells. From patient to patient, molecular markers for stem cells differ greatly. […] This heterogeneity makes determining the frequency of the leukemic stem cell in an individual patient extremely difficult.

Dr. Jordan defines leukemic stem cells as highly dynamic and highly unstable. So the question arises: how can they possibly be monitored? In comparison, it would seem that keeping individual tabs on millions of agitated grasshoppers in a field would be a much easier task…

As I see it, these seem to be the main problems facing clinical trial investigators: 1. how to identify the stem cells in each individual patient in the first place; 2. how to determine if these cells are being targeted by the specific treatment (DMAPT, e.g.).

And here follows something that perhaps for the first time I have seen spelled out in a study: During chemotherapeutic challenge, patients can experience a dramatic change in the phenotype of their leukemic stem cell. From my layperson’s point of view, it would appear that this “dramatic change” would also be a problem.

Furthermore, just because your total tumour burden decreases doesn’t necessarily mean that your stem cells have been affected. Another problem.

But there seems to be a way of getting around all of this. Dr. Jordan writes that Clinical trials must be temporal and patient-specific. Specimens must be gathered before, during, and after treatment. The phenotype of each patient’s leukemic stem cell population must be defined up front and verified by a functional assay to help quantitate it. In the course of treatment, the population must be continuously monitored […]. It sounds extremely painstaking and time-consuming, doesn’t it?

Dr. Jordan’s final considerations: Just as cancers are heterogeneous, so too are leukemic stem cells, and the ability to target and quantitate leukemic stem cells is complicated by this heterogeneity. As research expands our understanding of leukemic stem cell biology and physiology, investigators must incorporate that knowledge into their strategies for targeting and analyses for quantifying leukemic stem cells. They must also determine where agents that target leukemic stem cells will be of most use: as maintenance therapy that targets minimal residual disease in remission patients, or as treatment for relapsed or refractory patients.

To this, I would add: “…or as treatment for patients who have not yet had any chemotherapy.”

Tall women/heavy men at risk for myeloma

December 7, 2008 / / 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 factorfor 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).

Eat your apigenin…

December 6, 2008 / / 1 Comment

In my November 30^th post I had a look at chemoresistance. Well, it just so happens that a few days ago, in a rather vain attempt to catch up on my Science Daily readings, I came across a bit of info (see http://tinyurl.com/56qhxh) that might be particularly useful to those doing chemo right now.

A recent study shows that apigenin, a naturally occurring dietary agent found in vegetables and fruit, can make cancer cells more susceptible to chemotherapy.

Here’s what happens: apigenin apparently localizes tumor suppressor p53, a protein, in the cell nucleus – a necessary step for killing the cell that results in some tumor cells responding to chemotherapy. […] In many cancers, p53 is rendered inactive by a process called cytoplasmic sequestration. Apigenin is able to activate p53 and transport it into the nucleus, resulting in a stop to cell growth and cell death. Now wait a sec. Why wouldn’t this phenomenon also help those of us who are not doing chemotherapy? Well, actually, I guess that would be implied in the researchers’ recommendation that fruit and veggies be included in everyone’s diet to prevent the development of cancer.

So where do we find apigenin? For the most part, in fruit (including apples, cherries, grapes), vegetables (including parsley, artichoke, basil, celery), nuts and plant-derived beverages (including tea and wine). It has been shown by researchers to have growth inhibitory properties in several cancer lines, including breast, colon, skin, thyroid and leukemia cells. It has also been shown to inhibit pancreatic cancer cell proliferation. Thumbs up!

If you do a search for apigenin on my blog, you will find my August 8 2008 post, reporting that this flavonoid doesn’t inhibit Bortezomib, which of course is a good thing for those who are on Velcade.

I did a quick online search on apigenin. Lots of interesting stuff came up, including a 2004 study (http://tinyurl.com/5o4lhw) on rats, which concludes that our body may be able to accumulate apigenin because it is metabolized, absorbed and eliminated slowly. So slowly, in fact, that apigenin was found in the rats’ blood nine days after administration. Incredible, huh? By the way, according to this study, apigenin can also be found in rosemary and camomile, and in honey, fennel and wheat germ.

In this November 2008 study (http://tinyurl.com/5sq5qt), we can read that apigenin inhibits NF-kappaB and also the molecules regulated by this transcription factor, such as Bcl-x (aha!) but not Bcl-2. It also inhibits COX-2. This is very good news for celery fans.

I haven’t been that interested in apigenin because, to my knowledge, there are no specific studies on apigenin and myeloma. But from now on I will try to keep half an eye on it.

Apigenin and leukemia: http://tinyurl.com/6hfgdk

Apigenin and ALL: http://tinyurl.com/5be38e

Apigenin and ovarian cancer: http://tinyurl.com/6qfooo

Apigenin and pancreatic cancer: http://tinyurl.com/6p3k9o

Apigenin and breast cancer: http://tinyurl.com/5qtva2

Apigenin and neuroblastoma: http://tinyurl.com/5ldg8o

The list goes on…

Margaret's Corner

Month: December 2008