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Alert Number 94

Buddy Can You Spare a Little Blood to Get this Research Going?

Date: May 16, 2005

A little blood from you can get an important research project on its way.

In a recent article on our website we discussed the role of omega-3 PUFA (poly unsaturated fatty acids) in maintaining good health. I am quite impressed by the quality of recent research on the subject as well as the implications it has for us as cancer patients. The American Heart Association is already on record, recommending that you eat more cold water "oily" fish (or take fish oil capsules), in order to balance the completely out-of-whack ratio of Omega 3: Omega 6 oils in our modern diet. You can read the details by clicking here Omega 3 PUFAs

One of the best review articles I found on the subject of fish oils (active ingredients are thought to be EPA and DHA) comes from scientists at Indiana University School of Medicine. Their abstract is given below, and if you want the full text PDF of this important review for your files, write to us and we will help you locate it. Mind you, this is a scholarly review meant for researchers, but I have no doubt you will be impressed by the depth of the information presented in it. One of the snippets of information that caught my eye is that fish oil in the diet is able to modify the lipid (fat) composition of cell membranes. Fish oil is able to corral important cell signaling markers into lipid islands floating on the cell membrane surface, and these lipid rafts make it easier to get signals though to the inside of the cell. CLL cells are hard to kill because they are able to block and turn a deaf ear to suicide commands coming in. Even our favorite drug Rituxan works better when the CD20 markers it targets are all nicely corralled into a tight little group in lipid rafts, making for more effective bonding with Rituxan (see the second abstract below).

That raises the million dollar question: can we improve the responses that CLL patients get to Rituxan by the addition of fish oil? Wow, that would be cool. I wrote up this concept, along with a boat load of abstracts to support it, as an area of interest to patients, and sent it to the CLL Global Research Foundation - click here to read our letter.

On a more optimistic note, I have been fortunate to establish contact with Dr. Rafat Siddiqui and Dr. Gary Zaloga, the two lead authors of the outstanding Omega-3 review article I mentioned above. At my request, Dr. Siddiqui kindly agreed to look at the possible synergy between fish oil and Rituxan, in CLL cell lines. In addition, he and Dr. Zaloga want to test actual CLL cells gathered from patients, to see if some patients are more sensitive to the effects of fish oil modulation than other patients. This is the usual preclinical work that has to be done before formal clinical trials can be started with live human patients. Dr. Zaloga is willing to consider initiating Rituxan + fish oil as a clinical trial for CLL patients, after completing the cell line study and after looking at CLL patient blood samples.

It is my honest opinion this is important research, likely to yield improved therapy options for CLL patients, and at no additional toxicity. No one has ownership rights to (or expectation of drug-like profits from) fish oil. This research will not get done, but for the patient community pushing for it, and because we are able to reach dedicated researchers such as these folks at Indiana University School of Medicine. Here is the game plan:

The patient blood from which the CLL cells must be collected has to be absolutely fresh. In other words, it is not possible to have the blood drawn and sent by FedEx.

We need your help. Any of you living within driving distance of Indianapolis, and willing to go in to donate one or two tubes of your blood, please arrange to do so.

In return, you will get a very nice thank you from Dr. Zaloga and me, and once the testing is done he will share with you the results as they pertain to you. It might be good for you to know if you fall into the category of patients who responds like gangbusters to something as non-toxic as fish oil, and if this little adjuvant will make your Rituxan therapy down the road work much better.

Dr. Zaloga's contact information is given below. Please call or send him an email first, to set up a date and time for you to come in to donate your blood. Tell him you are a member of CLL Topics, and you want to help with the CLL study. Send us an email too, and keep us in the loop.

My guess is that Dr. Zaloga will be looking for patients with a hefty WBC count, lots of little CLL cells swimming around. But you can verify that when you contact him.

Dr. Gary P. Zaloga, MD
Medical Director, Methodist Research Institute Clinical Professor of Medicine
Indiana University School of Medicine
1812 N. Capitol Ave
Wile Hall, Room 120
Indianapolis, IN 46202
Phone: 317-962-6478
e-mail: mail

Here are a couple of links that give you more information about these two doctors. The first is a CV for Dr. Zaloga that I found on the web, but I have no idea if it is up to date. The second is an impressive list of Dr. Siddiqui's publications.

Zaloga CV.
Siddiqui publications.

We talk about the slow pace of clinical research, how frustrating it is for us to wait for some of these important studies to get done. Here is your chance to do something about it, it won't cost you much more than a little driving time and gasoline for the car. Drs. Zaloga and Siddiqui are doing this work pro-bono, so to speak, out of their existing research grants and at our request. Our contribution to this effort as members of the patient community is to provide them with some authentic blood samples. Down the road, if the results continue to look as good as the preliminary results Dr. Siddiqui has obtained already with the cell line studies, formal clinical trials are the next step. Make us proud, you guys!

Be well,



Mini Rev Med Chem. 2004 Oct;4(8):859-71.

Omega 3-fatty acids: health benefits and cellular mechanisms of action.

Siddiqui RA, Shaikh SR, Sech LA, Yount HR, Stillwell W, Zaloga GP.

Methodist Research Institute, Indianapolis, Indiana 46202

Epidemiological evidence has established that ingestion of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs), abundant in fish oils, have profound effects on many human disorders and diseases, including cardiovascular disease and cancer. Here we briefly review the dietary recommendations and the food sources that are naturally enriched by these fatty acids. There are also a number of products including eggs, bread, and cereals available to supplement omega-3 fatty acid dietary intake. Some of these supplements are proposed to aid different pathological conditions. While the beneficial effects of omega-3 fatty acids can no longer be doubted, their molecular mechanism of action remains elusive. Without question, the action of omega-3 fatty acids is complex and involves a number of integrated signaling pathways. This review focuses on one of the possible cellular mechanisms by which the omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may function. Studies with cancer cells suggest that DHA induces cell cycle arrest and apoptosis by activating protein phosphatases, leading to dephosphorylation of retinoblastoma protein (pRB). Protein phosphatases are also involved with the protein Bcl2, which regulates the release of cytochrome c from mitochondria, and eventually, activation of the apoptotic enzyme caspase 3.

PMID: 15544547

Cancer Res. 2003 Jan 15;63(2):534-40.

Anti-CD20 therapeutic antibody rituximab modifies the functional organization of rafts/microdomains of B lymphoma cells.

Semac I, Palomba C, Kulangara K, Klages N, van Echten-Deckert G, Borisch B, Hoessli DC.

Department of Pathology, Faculty of Medicine, Centre medical universitaire, 1211 Geneva 4, Switzerland.

Incubation of Burkitt lymphoma-derived Raji cells at physiological temperature with submicromolar concentrations of humanized anti-CD20 antibody rituximab (RTX) redistributes CD20 to liquid-ordered, plasma membrane rafts. This accumulation of the CD20 tetraspan protein in rafts does not change the existing lipid and phosphoprotein composition but makes sphingolipids and the Src regulator Cbp/PAG (Csk-binding protein/phosphoprotein associated with glycosphingolipid-enriched microdomain) transmembrane phosphoprotein more resistant to n-octyl-beta-pyranoside, a detergent that dissociates sphingolipid clusters. On the contrary, sphingolipids and Cbp/PAG are not protected by the presence of CD20 against the disruptive effects of methyl-beta-cyclodextrin, a cyclic carbohydrate that removes membrane cholesterol. After accumulation of CD20, the activity of the raft-associated Lyn kinase is down-regulated without apparent alteration of its relationship to substrates. Moreover, in rafts of lymphoblastoid cells that express lower amounts of Cbp/PAG, RTX redistributes CD20 to rafts but does not modulate the raft-associated protein tyrosine kinase activity, suggesting that the presence of Cbp/PAG protein in rafts is necessary for RTX to exert its transmembrane "signaling effects." Lastly, redistribution of CD20 in rafts renders the glycosylphosphatidyl inositol (GPI)-linked CD55 C'-defense protein hypersensitive to glycosylphosphatidyl inositol-specific phospholipases. By redistributing CD20 to rafts, RTX modifies their stability and organization and modulates the associated signaling pathways and C' defense capacity.

PMID: 12543813

J Immunol. 2002 Sep 15;169(6):2886-91.

Colocalization of the B cell receptor and CD20 followed by activation-dependent dissociation in distinct lipid rafts.

Petrie RJ, Deans JP.

Department of Biochemistry and Molecular Biology, Immunology Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

The B cell Ag receptor (BCR) and CD20, a putative calcium channel, inducibly associate with cholesterol-dependent membrane microdomains known as lipid rafts. A functional association between the BCR and CD20 is suggested by the effects of CD20-specific mAbs, which can modulate cell cycle transitions elicited by BCR signaling. Using immunofluorescence microscopy we show here that the BCR and CD20 colocalize after receptor ligation and then rapidly dissociate at the cell surface before endocytosis of the BCR. After separation, surface BCR and CD20 were detected in distinct lipid rafts isolated as low density, detergent-resistant membrane fragments. Pretreatment with methyl-beta-cyclodextrin, which we have previously shown to enhance receptor-mediated calcium mobilization, did not prevent colocalization of the BCR and CD20, but slowed their dissociation. The data demonstrate rapid dynamics of the BCR in relation to CD20 at the cell surface. Activation-dependent dissociation of the BCR from CD20 occurs before receptor endocytosis and appears to require in part the integrity of lipid rafts.

PMID: 12218101

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