Multiple myeloma   Micrograph of a plasmacytoma Multiple myeloma and other plasma cell neoplasms are dieases in which the body makes too many plasma cells. Normally, when bacteria or viruses enter the body, some of the B cells will change into plasma cells. The plasma cells make a different antibodyto fight each type of bacteria or virus that enters the body, to stop infectionand disease. Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell. Plasma cell neoplasmsare diseases in which there are too many plasma cells, or myeloma cells, that are unable to do their usual work in the bone marrow. When this happens there is less room for healthy red blood cells, white blood cells, and platelets. This condition may cause anemiaor easy bleeding, or make it easier to get an infection. The plasma cells also make an antibody protein called M protein that is not needed by the body and does not help fight infection. These antibody proteins build up in the bone marrow and can cause the blood to thicken or can damage the kidneys. As the number of myeloma cells increases, fewer red blood cells, white blood cells, and platelets are made. The myeloma cells also damage and weaken the hard parts of the bones. Sometimes multiple myeloma does not cause any symptoms. And sometimes it does. Bone pain, often in the back or ribs. Bones that break easily. Fever for no known reason or frequent infections. Easy bruising or bleeding. Trouble breathing. Weakness of the arms or legs. Feeling very tired. A tumor can damage the bone and cause hypercalcemia (too much calcium in the blood).

Lab tests are done to see if a protein called M protein or M spike is in the patient's blood and urine. The amount of M protein is one way to estimate the stage of the myeloma. Another protein called light chainscan be found in the myeloma patient's urine.  

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The whole immunoglobulin is composed of two larger pieces (heavy chains) and two smaller pieces (light chains) attached to each other. The Bence Jones protein (light chains) made by M protein are small enough to pass through the kidney and enter the urine, where they can be detected. When excreted in large amounts, Bence Jones protein can cause renal injury and kidney failure. There is a newer, special test to check for light chains. This test is

Mainstream Myeloma-specific therapies include

Drug Therapy.  Drug therapy is the main treatment for myeloma. Before drug therapy begins, patients with symptomatic myeloma are assessed to determine if they are candidates for stem cell transplant. For transplant candidates, drug treatment begins with induction agents that do not cause bone marrow damage, for example, thalidomide (Thalomid®) and dexamethasone, bortezomib (Velcade®) and dexamethasone, or Velcade, pegylated liposomal doxorubicin (Doxil®) and dexamethasone. For patients who are not candidates for transplant, treatment may begin with a combination drug therapy, such as melphalan and prednisone, with Thalomid or Velcade. As many as six drugs are combined in some intensive treatment programs.

Drug therapy has led to sustained remissions in some patients. Temporary cessation or significant slowing of the disease may occur for a time. Achieving complete remission for long periods is being seen more often as newer, more effective drugs are developed.

Some Drugs Used To Treat Myeloma

Another 2009 review stated "the role of maintenance therapy with thalidomide, lenalidomide, or bortezomib for patients with multiple myeloma is not definitively established; such therapy should be performed only in the context of a clinical trial." Cf. "Managing the side effects of lenalidomide and bortezomib". 2009. p. 58. http://www.communityoncology.net/journal/articles/0602053.pdf.

Stem Cell Transplantation. Autologous stem cell transplantation is an important therapy for many myeloma patients. This procedure uses the patient's own stem cells to restore blood cell production after intensive chemotherapy. Autologous transplant is associated with good response rates. It is relatively safe for many patients, including older patients. However, it is not appropriate for all patients and it is not a cure for myeloma. Patients should discuss the benefits and risks of transplantation with their physicians.

Allogeneic stem cell transplantation and reduced-intensity allogeneic stem cell transplantation are being studied in clinical trials for myeloma.

Radiation therapy. This treatment uses high-energy rays to kill myeloma cells. It is the main treatment for localized myeloma, such as solitary myeloma or plasmacytoma. Patients sometimes receive radiation therapy in preparation for stem cell transplantation. Carefully selected patients whose bone pain does not respond to chemotherapy may receive radiation therapy as well.  

Some side effects of myeloma treatment may include

In myeloma, staging has traditionally been based upon the following criteria: level of hemoglobin ( RBC level), degree of M protein elevation, serum calcium levels, and the presence of bone lytic lesions. Early stage disease is deemed to be stage I, while extensive disease is deemed stage III. Intermediate findings suggest stage II disease. Recently, a newer International Staging System has proposed the use of serum beta-2 microglobulin and albumin levels to determine stages I-III, suggesting that such markers may more accurately define treatment decisions and, potentially, outcome.

Relapse

The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant.

Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect. Rajkumar SV (2004). "Multiple myeloma". N. Engl. J. Med. 351 (18): 1860–73. doi:10.1056/NEJMra041875. PMID 15509819. 

Some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib(or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is usually proposed.

Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.

REFERENCES

CURE WITH HOLISTIC MEDICINE

Book review: Curious ways to fight cancer
By Martin Sieff
Published 7/31/2002 1:55 PM

WASHINGTON, July 31 (UPI) -- If you are suffering from cancer, read this book, "Living Proof: A Medical Mutiny," by Michael Gearin-Tosh (Scribner, New York, $25, 331 pages).

If you have any family members or friends suffering from cancer, read this book. If you think there is any chance that you or any loved ones may ever suffer from cancer, read this book. And if none of the above applies, read it anyway.

This is a quite extraordinary story told in an exceptionally authoritative way. At the age of 54, Michael Gearin-Tosh was diagnosed in 1995 with myeloma, bone marrow cancer, one of the most lethal cancers known.

The usual survival time with treatment is two to three years; without it, one year. Seven years later, when this book was published, the cancer was still in remission and Gearin-Tosh remained active and although understandably careful about his health, remarkably robust, a fully functioning member of society.

The odds against his survival beyond three years were 99.995 percent. He calls himself "The 0.005 Percent Survivor."

Gearin-Tosh rejected chemotherapy, the universally accepted treatment for his form of cancer, just as it is used for many others. An expert in the field, Ernst Wynder, former professor at Sloan-Kettering Hospital and recipient of a medal from the American Cancer Association, advised a mutual acquaintance to warn the author, "If your friend touches chemotherapy, he's a goner." This message understandably had a sobering effect.

Gearin-Tosh fought his cancer with a truly bizarre combination of therapies physical and spiritual. He undusted an old juicer and applied himself to the Gerson Therapy, which required an astonishing daily intake of freshly squeezed vegetable juices -- and also at least three coffee anemas a day to repeatedly flux out the digestive system and purge the liver. He took regular acupuncture treatments. He consumed enormous daily doses of vitamin Cas Dr. Linus Pauling prescribed, ignoring conventional medical claims that it was only a placebo.

He did Chinese breathing exercises, thousands of years old. In these he had to visualize for at least an hour at a time breathing oxygen in through his toes. In other visualization exercises, he repeatedly imagined the heroic Imperial Russian armies that defeated Napoleon in 1812 marching through his body looking for white cancerous cells to hunt out and destroy.

Gearin-Tosh is no crackpot. He is a fellow in English literature at St. Catherine's College, Oxford, and a visiting professor at Stanford University. His friends include some of the leading conventional oncologists in the world. Two of them contributed medical assessments to this book. Other world-famous medical experts have enthusiastically praised it. Gearin-Tosh really had a cancer that is invariably fatal yet he beat it using a combination of exceptionally unconventional alternative therapies, and he remained alive and well and active to tell his story.

In large part, Gearin-Tosh owed his survival to being a scholar of English literature. His academic discipline, by training and experience, gave him an exceptional understanding of the weasel words and code language that doctors use to manipulate their patients into taking courses of treatment that will inflict horrendous suffering upon them for astonishingly little, if any, long-term benefit.

A respected cancer specialist trying to persuade the author to take chemotherapy treatment writes him a warm and friendly letter. In it, he casually remarks: "I am sorry I forgot to mention to you that the best way of administering this chemotherapy is through a Hickman line which can be placed into one of the big veins, and tunneled out under the skin of your chest wall. This then stays in place for the duration of your treatment."

Gearin-Tosh comments, "His phrase 'I forgot to mention' makes me paranoid about gradual disclosure, about bad news dripping out. Will there be more?

"And I saw a Hickman line at the Marsden (hospital): a patient's shirt was open and a rubber tube hung from his chest ... I decline the treatment."

Gearin-Tosh's description of the de-constructive interpretation he puts to the carefully calibrated soothing language aimed to coax him into a regime of chemotherapy while hiding its horrors and ultimate hopelessness is worth the price of the book itself. It is a stunning demonstration of why all values and qualities in any society, including technological progress and the struggle to maintain social justice and human liberty, ultimately depend on the honest and accurate use of language. "In the beginning was the Word." And without it there is no salvation.

And no physical cure or relief either.

Gearin-Tosh is a glorious writer, and appears to be a uniquely attractive human spirit as well. He never loses his sense of humor, his tolerance or his intellectual curiosity. He does not trivialize or lessen the terrors and horror of his cancer treatment odyssey. But from the very beginning, it appears to have been a voyage of spiritual as well as physical discovery and renewal for him as well.

Compare Your Body Is The Mirror Of Your Life by Martin Brofman, Ph.D.
who healed himself of terminal cancer through a consciousness shift.

He meets wonderful people along the way. There is Sir David Weatherall, Regius professor of medicine at Oxford University and head of the Institute of Molecular Medicine, who frankly tells him, "What you must understand, Mr. Gearin-Tosh, is that we know so little about how the body works."

A captain from the Russian army -- President Vladimir Putin's, not Marshal Kutuzov's one of 1812 -- stays with him and gives him needed encouragement.

Gearin-Tosh's book invariably invites comparison with another recent classic cancer memoir, the late John Diamond's "C: Because Cowards Get Cancer Too." The books complement each other to an astonishing degree.

Gearin-Tosh's memoir, for all its unrelenting honesty and accuracy, is a warm and welcoming read.

The author comes across as an exceptionally nice man, a literary voice who immediately becomes a lifelong companion and cherished friend. He is open-minded and intellectually curious about alternative therapies. He claims to be repeatedly terrified and afraid and that is probably true, but the heady, intoxicatingly joyous contagion one picks from him instead is his gloriously resilient courage.

Poor Diamond, a star columnist for the London Times, went through the torments of the damned with conventional chemotherapy and died terribly, anyway. His account is as terrifying as the memories of an inmate at Dachau.

It revives Alexander Solzhenitsyn's haunting metaphor of the cancer ward as a medical gulag.

Yet, Gearin-Tosh notes that Diamond's Times obituary records, "He hated complementary (or alternative) medicine." This provokes Gearin-Tosh to ask, "What is it to be a rationalist cancer patient? What is meant by a rationalist's hate of complementary medicine? Do not cancer patients have choices? Is there, from the start, a note of fatalism in this so-called rationalist position?" In other words, to accept Diamond's position, you have to accept and obey what conventional medicine tells you to do, even though you know it will torture you and soon you will die anyway.

Gearin-Tosh does not have to spell out the ultimate contrast between him and Diamond. He survived to continue living a happy and fulfilling life. Diamond, who repeatedly sneered at alternative therapies and put his fate in the conventional wisdom of contemporary medicine, did not.

The list of testimonials to this book is almost as astonishing as its contents. "Except for two forms of cancer, chemotherapy does not cure. It tortures and may shorten life -- no one can tell from the available data." These are not the words of a crank. They were written by Dr. Candace Pert of the Georgetown University School of Medicine. She goes on to ask "whether that very intimidating emperor (the modern cancer industry) is quite naked after all."

Dr. Robert Kyle of the Mayo Clinic advises, "All physicians should read this book. He concludes that "the role of the 'unorthodox' treatments in (Gearin-Tosh's) own experience deserve scientific study and scrutiny."

Indeed.

Other glowing testimonials come from John Bayley, husband of the late great novelist Iris Murdoch and a prominent literary critic himself and from the beloved actress Dame Diana Rigg.

Cancer memoirs from Solzhenitsyn to Diamond share one characteristic. They are invariably terrifying. This one is not. It is one of the most inspiring works you will ever read. It cries out to be made into an HBO or Showtime movie. Perhaps even TNT could get Disney or Hallmark to sponsor it. It cannot be recommended highly enough.
Copyright © 2001-2003 United Press International

Epidemiology

Multiple myeloma is the second most prevalent blood cancer (10%) after non Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death.

Source: Collins CD (2005). "Problems monitoring response in multiple myeloma". Cancer Imaging 5 Spec No A: S119–26. doi:10.1102/1470-7330.2005.0033. PMID 16361127.

Does hair dye cause cancer?

Int J Epidemiol. 2009 Dec;38(6):1512-31. Epub 2009 Sep 14.

Risk of cancer among hairdressers and related workers: a meta-analysis.

Takkouche B, Regueira-Méndez C, Montes-Martínez A.

Department of Preventive Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. bahi.takkouche@usc.es

PMID: 19755396 [PubMed - indexed for MEDLINE]

...women who used permanent hair dyes at least once a month experienced a 2.1-fold risk of bladder cancer relative to non-users... We estimate that 19% of bladder cancers in women in Los Angeles County, California, may be attributed to permanent hair-dye use. (Gago-Dominguez et al. 2001)

The use of hair color products appears to increase the risk of non-Hodgkin's lymphona... If these results represent a causal association, use of hair coloring products would account for 35% of non-Hodgkin’s lymphoma cases in exposed women and 20% in all women. (Zahm et al. 1992)

Many dye products contain ingredients called "coal tar dyes" that are specifically exempt from federal authority over adulterated products that can harm health. These include dyes made by Clairol, Revlon, L'Oreal, and others. Coal tar hair dyes are one of the few products for which FDA has issued consumer advice on the benefits of reducing use, in this case as a way to potentially "reduce the risk of cancer" (FDA 1993).

Coal tars and coal tar pitches are known human carcinogens (IARC 1987). The specific components of coal tar used in hair dyes — aromatic amines — have been shown to mutate DNA (IARC 1993), and to cause cancer in animals (Sontag 1981). An increasing number of studies of humans link long-time hair dye use with cancer, including bladder cancer, non-Hodgkin's lymphoma, and multiple myeloma. Ingredients that fall under FDA's definition of "coal tar dyes" can now be derived from either petroleum or coal tar, but studies have not been done to determine if these differences in manufacturing influence the dyes' potency with respect to cancer.

Much of the evidence linking hair dyes with bladder cancer comes from studies of hairdressers. In seven of 10 populations studied (from the US, Norway, Sweden, Finland, Denmark, Japan), scientists found elevated incidence of bladder cancer among hairdressers, barbers, beauticians and cosmetologists exposed to hair dyes — 40 percent higher, on average, than population-wide risks. Hair dye exposure was also linked to bladder cancer in seven of 12 case-control studies focused specifically on occupational history among bladder cancer victims (Gago-Dominguez et al. 2001).

In 1993 the International Agency for Research on Cancer found that "occupation as a hairdresser or barber entails exposures that are probably carcinogenic" (IARC 1993), and a recent study by scientists from the University of Southern California's School of Medicine shows that hairdressers and barbers with more than 10 years on the job face a five-fold increase in bladder cancer risk compared to people not exposed to hair dye (Gago-Dominguez et al. 2001).

Is cancer a risk outside the beauty industry, for consumers who dye their hair? In 1982 the National Bladder Cancer Study failed to find a relationship between hair dye use and bladder cancer risk among 3,000 bladder cancer victims. While this study has provided some assurance of low risks from hair dye exposure among people outside the beauty industry, a growing number of more sensitive, focused studies are heightening concerns that long-time or frequent hair dye use does, in fact, substantially increase cancer risks. These findings have been catalyzed by more sophisticated research techniques that include the collection of detailed information on the type of hair dye used, and the inclusion of factors that account for an individual's genetic susceptibility to cancer.

In 2001 researchers from the University of Southern California's (USC) School of Medicine found that women using permanent hair dye at least once a month more than double their risk of bladder cancer (Gago-Dominguez et al. 2001). Earlier studies had failed to segregate the use of permanent dye from semi-permanent and temporary dyes; the USC study showed this may be a critical distinction. The authors estimate that “19% of bladder cancers in women in Los Angeles County, California, may be attributed to permanent hair-dye use” (Gago-Dominguez et al. 2001). This study is to date the largest and most scientifically rigorous on permanent hair dye and bladder cancer incidence.

USC researchers also found that women who are genetically vulerable to bladder cancer (so-called “slow acetylators” who are exposed to some carcinogens for longer periods of time) more than quadruple their risk of bladder cancer with long-time or frequent use of permanent hair dye (Gago-Dominguez et al. 2001). These associations see further confirmation in a study performed by researchers at Dartmouth Medical School that also found links between permanent hair dye use and bladder cancer (Andrew et al. 2004).

New studies have identified the particular chemicals in hair dye thought to be linked to bladder cancer as aromatic amines, chemicals derived from coal tar but best known as potent bladder carcinogens in cigarette smoke (Yu et al. 2002). Association of permanent hair dyes with non-Hodgkin’s lymphoma, mutiple myeloma, colorectal adenocarcinoma, lung and upper aerodigestive tract cancers has been studied but associations have been both positive and negative, or only preliminarily studied (Czene et al. 2003; Skov and Lynge 1994; Zahm et al. 1992; Brown et al. 1992; Grodstein et al. 1994; Herrinton et al. 1994; Holly et al. 1998; Robinson and Walker 1999). Among the stronger findings from these studies are those from the National Cancer Institute, where researchers found that 20 percent of all cases of non-Hodgkin’s lymphoma may be linked to hair dye use (Zahm et al. 1992).

References

Andrew, A.S., Schned, A.R., Heaney, J.A., Karagas, M.R. (2004). Bladder cancer risk and personal hair dye use. Int. J. Cancer 109, 581-586.

Brown, L.M., Everett, G.D., Burmeister, L.F., Blair, A. (1992). Hair dye use and multiple myeloma in white men. Am. J. Public Health 82, 1673-1674.

Czene, K., Tiikkaja, S., Hemminki, K (2003). Cancer risks in hairdressers: Assessment of carcinogenicity of hair dyes and gels. Int. J. Cancer 105, 108-112.

Food and Drug Administration (FDA) (1993). Hair Dye Dilemmas. FDA Consumer. April 1993. Accessed online May 6 2004 at http://vm.cfsan.fda.gov/~dms/cos-818.html.

Gago-Dominguez, M., Catelao, J.E., Yuan, J., Yu, M.C., Ross, R.K. (2001). Use of permanent hair dyes and bladder-cancer risk. Int. J. Cancer 91, 575-579.

Grodstein, F., Hennekens, C.H., Colditz, G.A., Hunter, D.J., Stampfer, M.J. (1994). A prospective study of permanent hairdye use and hematopoietic cancer. J. Natl. Cancer Inst. 86, 1466-1470.

Herrinton, L.J., Weiss, N.S., Koepsell, T.D., Daling, J.R., Taylor, J.W., Lyon, J.L., Swanson, G.M., Greenberg, R.S. (1994). Exposure to hair-coloring products and the risk of multiple myeloma. Am. J. Public Health 84, 1142-1144.

Holly, E.A., Lele, C., Bracci, P.M. (1998). Hair-color products and risk for non-hodgkin's Lymphoma: A population-based study in the San Francisco bay area. Am. J. Public Health 88, 1767-1773.

International Agency for Research on Cancer (IARC) (1987). Overall evaluations of carcinogenicity. IARC Monographs on the evaluation of carcinogenic risks to humans. Suppl 7

International Agency for Research on Cancer (IARC) (1993). Occupational exposures of hair dressers and barbers and personal use of hair colourants: some hair dyes, cosmetic colourants, industrial dyestuffs and aromatic amines. IARC Monographs on the evaluation of carcinogenic risks to humans. 57

Robinson, C.F. and Walker, J.T. (1999). Cancer mortality among women employed in fast-growing U.S. occupations. Am. J. Ind. Med. 36, 186-192.

Skov, T. and Lynge, E. (1994). Cancer risk and exposures to carcinogens in hairdressers. Skin Pharmacol. 7, 94-100.

Sontag, J.M. (1981). Carcinogenicity of substituted-benzenediamines (phenylenediamines) in rats and mice. J. Natl. Cancer Inst. 66, 591-602.

Yu MC, Skipper PL, Tannenbaum SR, Chan KK, Ross RK. (2002). Arylamine exposures and bladder cancer risk. Mutat Res. 2002 Sep 30;506-507:21-8.

Zahm, S.H., Weisenburger, D.D., Babbitt, P.A., Sall, R.C., Vaught, J.B., Blair, A. (1992). Use of hair coloring products and the risk of lymphoma, multiple myeloma, and chronic lymphocytic leukemia. Am. J. Public Health 82, 990-998.

Updates Results From
Multiple Myeloma Stem Cell Transplant Trials
Click here for the story.

Thalidomide Continues to Show Benefits Against Myeloma
Click here for the story.

UAMS Performs Record 7,000th Myeloma Stem-Cell Transplant Click here for the story.

Part two: Living with Multiple Myeloma
Click here for the story

Myeloma: Quest for CR May Be Misplaced
Click here for the story

For 10 years, artist Cathy Joyce has been cancer-free. But she still takes life one day a time
Click here for the story

Myeloma Patients Flock to Little Rock
Click here for the story

Does a 10-year 10% Continuous Complete Remission Rate for Myeloma Patients Suggest Cure?
Click here for the story

Click here to see Modeling for the Cure: Total Therapy Trials for Newly Diagnosed Multiple Myeloma: Let theMath Speak!. Presented at annual meeting of ASH (American Society of Hematology), held in New Orleans December 5-8, 2009.

TEA AND M.M.

Abstract

 

Results

 

EGCG induces inhibition of myeloma cell growth

INA6, ARP, and OPM1 MM cells were cultured in the presence or absence of EGCG at various concentrations and for variable lengths of time and viable cell number was determined as described. EGCG induced both time- and dose-dependent decline in survival of myeloma cells; at 10 μM concentration it induced 85% and over 55% cell death in INA6 and ARP myeloma cells, respectively, at day 3 and more than 99% cell death in INA6 and ARP cell lines at day 5 and OPM1 cells at day 7 (Figure 1A-C). In all myeloma cell lines tested and primary myeloma cells derived from 3 different patients, exposure to 10 or 20 μM EGCG led to a significant inhibition of cell proliferation as assessed by 3H-thymidine incorporation, within 72 hours treatment (Figure 1D-E). Importantly, the same concentrations of EGCG (10 or 20 μM) had no effect on survival of normal diploid fibroblasts and normal PBMCs from 4 healthy donors (Figure 1F-G). Normal PBMCs were treated with EGCG and cell proliferation was assessed by trypan blue exclusion or 3H-thymidine incorporation or both. As seen in Figure 1G, EGCG at 10 or 20 μM had no effect on cell proliferation following 72 hours of treatment. To further confirm the lack of effect on normal cells, normal PBMCs were activated with anti-CD3 antibody and treated with EGCG. As indicated by 3H-thymidine incorporation, exposure to 10 μM EGCG did not have inhibitory effect on proliferation of PBMCs. These data confirm that EGCG, at concentrations used, specifically inhibits the proliferation of myeloma cells while having no significant effect on normal cells.

Figure 1. Effect of EGCG on cell survival. MM cells were cultured in the medium containing no EGCG or various concentrations of EGCG ranging from 0.1 to 10 μM. Cells were harvested at different time points as indicated and proliferative potential was assessed (more ...)

Figure 1.

Effect of EGCG on cell survival. MM cells were cultured in the medium containing no EGCG or various concentrations of EGCG ranging from 0.1 to 10 μM. Cells were harvested at different time points as indicated and proliferative potential was assessed by trypan blue exclusion or 3H-thymidine labeling. The growth curves show the mean of 3 independent experiments, with SEM. (A) IL-6-dependent INA6 myeloma cells. (B) ARP myeloma cells. (C) OPM1 myeloma cells. (D) Myeloma cell lines MM1S, INA6, OPM1, 8226, and Waldenstrom cells (BCWM) were treated with 10 and 20 μM EGCG for 72 hours and proliferative potential was assessed by 3H-thymidine incorporation. (E) Three samples of CD138+ purified myeloma cells derived from patient bone marrow were treated with 10 and 20 μM EGCG for 72 hours and cell proliferation was evaluated by 3H-thymidine incorporation. (F) Effect of EGCG treatment in normal diploid fibroblasts and PBMCs from a healthy donor at days 1, 3, and 5. (G) Effect of EGCG on proliferation of PBMC from healthy donors is shown by trypan blue exclusion and 3H-thymidine incorporation, following 72 h treatment with 10 and 20 μM drug. (H) PBMCs from healthy donors (donors 4 and 5) were activated with anti-CD3 antibody, treated with 10 μM EGCG for 72 hours, and cell proliferation was evaluated by 3H-thymidine incorporation.

EGCG induces apoptotic cell death

Myeloma cells (INA6 and ARP) were treated with EGCG (10 μM) and analyzed for apoptotic cell death. Both untreated or EGCG-treated myeloma cells were sequentially treated with annexin V-biotin and FITC-streptavidin and apoptotic cells were evaluated by a fluorescence microscope. Approximately 200, representing at least 5 distinct microscopic fields, were analyzed to assess the fraction of annexin V+ cells for each sample. Following a 3-day exposure to EGCG, 92% ± 8% INA6 cells and 73% ± 6% of ARP cells were annexin V+, whereas only 8% ± 2% and less than 2% of untreated INA6 and ARP cells, respectively, were annexin V+ (Figure 2), indicating that EGCG induces apoptosis in myeloma cells.

Figure 2. Apoptosis following EGCG treatment of myeloma cells. Myeloma cells were treated with 10 μM EGCG for 72 hours and analyzed for apoptosis using annexin V-biotin apoptosis detection kit. Cells were sequentially treated with annexin V-biotin and FITC-streptavidin. (more ...)

Figure 2.

Apoptosis following EGCG treatment of myeloma cells. Myeloma cells were treated with 10 μM EGCG for 72 hours and analyzed for apoptosis using annexin V-biotin apoptosis detection kit. Cells were sequentially treated with annexin V-biotin and FITC-streptavidin. FITC-streptavidin-labeled apoptotic cells within the same microscopic field were viewed and photographed by phase contrast (PC) or by fluorescence emitted at 518 nm (FITC filter). Using the FITC filter, apoptotic cells appear bright green. (A) INA6 myeloma cells, untreated (i-ii) or treated with EGCG (iii-iv). (B) Bar graph shows percent apoptotic cells in control or EGCG-treated INA6 cells. (C) ARP myeloma cells, untreated (i-ii) or treated with EGCG (iii-iv). (D) Bar graph shows percent apoptotic cells in control or EGCG-treated ARP cells. (B, D) Error bars indicate SEM of percentage of apoptotic cells in 5 distinct microscopic fields.

EGCG mediates its activity via LR1

EGCG has been reported to confer its effects through its interaction with LR1 (67 kDa).28 We therefore evaluated the protein levels of LR1 in myeloma cell lines and patient samples using Western blot analysis. As seen in Figure 3Ai and quantitation following normalization with α-tubulin levels (Figure 3Aii), a 10-fold or greater increase in the protein levels of LR1 in all myeloma cell lines and patient samples is observed.

Figure 3. Role of LR1 in EGCG-induced myeloma cell death. (A) Elevated levels of LR1 (67 kDa) protein in myeloma cells. (Ai) Protein levels of LR1 were evaluated in 2 samples of normal PBMCs, 9 myeloma cell lines, and 5 myeloma patient samples, using a monoclonal (more ...)

Figure 3.

Role of LR1 in EGCG-induced myeloma cell death. (A) Elevated levels of LR1 (67 kDa) protein in myeloma cells. (Ai) Protein levels of LR1 were evaluated in 2 samples of normal PBMCs, 9 myeloma cell lines, and 5 myeloma patient samples, using a monoclonal antibody specific for LR; (ii) bar graph shows expression of LR1 protein, normalized to GAPDH levels, in normal and myeloma cells. (B-C) INA6 myeloma cells were cotransfected with Cy3-labeled nontargeting control (cont) and laminin receptor 1 (LR1) siRNAs. (B) Transfected cells were incubated for 72 hours and uptake of siRNA was monitored by a fluorescence microscope equipped with a Cy3 filter. (C) INA6 cells were transfected as described for panel B and LR1 protein level was determined by Western blot analysis. (D) EGCG induced myeloma cell death. INA6 myeloma cells were transfected with control siRNAs or siRNAs directed against LR1, and 24 hours later treated with 10 μM EGCG. Cell viability was determined on alternate days. Error bars indicate SEM of 3 independent experiments.

Next, to confirm the role of LR1 in EGCG-mediated growth inhibition of MM cells, we transfected INA6 myeloma cells with Cy3-labeled nontargeting control siRNA or siRNA directed against LR1. Uptake of siRNA was confirmed by fluorescence microscopy (Figure 3B), and reduction of LR1 protein level was confirmed by Western blot analysis (Figure 3C). Transfected cells were treated on the next day with EGCG (10 μM) and cell viability was measured on alternate days for 7 days. As seen in Figure 3D, EGCG had no significant effect on the growth of INA6 cells transfected with LR1-specific siRNA, whereas more than 98% of cells transfected with control siRNAs died within 3 days following exposure to EGCG.

EGCG induces apoptosis in myeloma cells in vivo

To evaluate in vivo activity of EGCG on MM cells, OPM1 MM cells were injected subcutaneously in CB17/ICr-SCID mice, and following appearance of palpable tumors, mice were given intraperitoneal injections of PBS alone or EGCG dissolved in PBS. As the tumors reached more than 2 cm in size, the mice were humanely killed, the tumors were excised, and the cell-cycle profile of MM cells was analyzed using PI staining and flow cytometry. Percentage of apoptotic cells in tumors derived from 3 control mice remained less than 1%, whereas the fraction of apoptotic cells in EGCG-treated mice ranged from 32% to 39%, indicating significant (P < .004) in vivo antimyeloma activity.

Consistent with these data, the survival of EGCG-treated mice was also prolonged relative to control mice (Figure 4B).

Figure 4. Effect of EGCG on proliferation of myeloma cells in vivo. CB-17 SCID mice were inoculated subcutaneously in the interscapular area with 5 × 106 OPM1 myeloma cells. Following appearance of tumors, the mice were treated intraperitoneally with PBS (more ...)

Figure 4.

Effect of EGCG on proliferation of myeloma cells in vivo. CB-17 SCID mice were inoculated subcutaneously in the interscapular area with 5 × 106 OPM1 myeloma cells. Following appearance of tumors, the mice were treated intraperitoneally with PBS alone or EGCG 33 mg/kg/d. When mice were humanely killed, tumors were excised and analyzed for apoptosis by flow cytometry. (A) Cell-cycle profiles of tumor cells derived from control and EGCG-treated mice. (B) Survival curve of control and EGCG-treated mice.

EGCG activates multiple proapoptotic pathways

To identify the molecular mechanisms of EGCG-induced apoptosis, we analyzed change in gene expression profile of INA6 cells following exposure to 10 μM EGCG for 24 hours, using HG-U133A GeneChip array (Affymetrix), as reported previously.20,21,29,30 Reproducibility of expression change was confirmed by correlation coefficients (0.96-0.99) of independently conducted experiments.

Exposure of myeloma cells to EGCG led to up-regulation of major regulatory genes involved in apoptosis and cell cycle arrest as well as down-regulation of genes implicated in oncogenic transformation (Figure 5).

Figure 5. Effect of EGCG on gene expression in myeloma cells. Gene expression profile was analyzed in untreated or EGCG-treated (10 μM for 24 hours) MM cells using HG-U133A gene arrays (Affymetrix). Fold change in the expression in EGCG-treated cells relative (more ...)

Figure 5.

Effect of EGCG on gene expression in myeloma cells. Gene expression profile was analyzed in untreated or EGCG-treated (10 μM for 24 hours) MM cells using HG-U133A gene arrays (Affymetrix). Fold change in the expression in EGCG-treated cells relative to expression in untreated INA6 cells is shown by the intensity of red (induction) or blue (suppression) colors.

EGCG activated multiple pathways associated with growth arrest by inducing the expression of: (1) death-associated protein kinase 2 (DAPK2), a multifunctional protein kinase implicated in apoptotic pathways mediated by death receptors, p19/p53, and modulation of cytoskeleton; (2) initiators and mediators of death receptor-mediated apoptosis including Fas, Fas ligand, and caspase 4; (3) p63, a p53-like protein involved in induction of apoptosis; (4) caspase recruitment domain proteins (CARD10 and CARD14) associated with induction of apoptosis via activation of BCL10 and NF-κB; and (5) cyclin-dependent kinase inhibitors, p16 and p18 (Figure 5), which induce cell-cycle arrest by inhibiting phosphorylation of retinoblastoma (RB).

For selected genes, we have further confirmed the observed changes in gene expression profile at protein levels. Myeloma cells were treated with EGCG at 10 μM for 24 hours and the cell lysates were resolved on a gradient SDS-polyacrylamide gel, electroblotted, and probed with specific antibodies. Consistent with gene expression data, the exposure of MM cells to EGCG was associated with elevated protein levels of DAPK2, p18, and p63 (Figure 6A-D). Both the gene expression (not shown) and Western blot (Figure 6C-D) analyses indicated no change in level of p53 following exposure to EGCG. However, the Western blot analysis indicated a 6-fold increase in p73 protein (Figure 6C-D). Overall these data confirm the gene expression and protein changes and provide the molecular basis for observed growth arrest and apoptosis following exposure of myeloma cells to EGCG.

Figure 6. The effect of EGCG on protein expression in INA6 myeloma cells. Equal amounts of protein were fractionated on SDS-polyacrylamide gels and electroblotted onto nitrocellulose membranes. The membranes were sequentially treated with primary antibodies and (more ...)

Figure 6.

The effect of EGCG on protein expression in INA6 myeloma cells. Equal amounts of protein were fractionated on SDS-polyacrylamide gels and electroblotted onto nitrocellulose membranes. The membranes were sequentially treated with primary antibodies and HRP-conjugated secondary antibodies, and the proteins were detected using an enhanced chemiluminescence. The same blots were then stripped and incubated with a monoclonal antibody for α-tubulin. Signal intensity of each band was quantitated and the amount of each protein was normalized to that of α-tubulin. (A) Expression of DAPK2 and p18 proteins in INA6 cells, untreated or treated with 1 μM and 10 μM EGCG for 24 hours. (B) Bar graph shows relative expression of DAPK2 and p18 proteins, following normalization with corresponding α-tubulin levels. (C) Expression of p53 family of proteins (p53, p63, p73) in INA6 cells, untreated or treated with 10 μM EGCG for 24 hours. (D) Bar graph shows fold induction of p53 family members, following normalization with corresponding α-tubulin levels.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895573/

 

 

INNOVATIVE THERAPIES FARE BETTER THAN MAINSTREAM ONCOLOGY FOR M.M.

 


In 2007, data was compiled from 100 multiple myeloma patients treated with various combinations of innovative therapeutic agents (3). These patients were treated by oncologist, James R. Berenson, MD the Medical and Scientific Director of IMBCR.

The median overall survival of these patients was 117 months, or 9.75 years from diagnosis. The 5-year survival was approximately 80%. These numbers far surpass those predicted by the ACS and ISS demonstrating the effectiveness of the newer combination therapy used in Dr. Berenson's clinic.

Breakthrough Research, IMBCR tests drug compounds both in vivo and in vitro

Because of our unique position as the only independent cancer research institute dedicated to myeloma, we have accomplished several breakthroughs over the last year:

1. Identified a new target that when blocked will treat myeloma directly and stop early blood vessels that feed myeloma.

2. Developed a peptide that blocks myeloma growth directly as well as stops bone loss in myeloma patients.

3. By using the IMBCR proprietary animal models, optimized many different combinations of chemotherapy with new anti-myeloma drugs that will be tested in clinical trials.

4. Tested genetic constructs that will ONLY target myeloma cells and leave the rest of the body unaffected, this ongoing initiative is called, "The Cure Myeloma Project" under the guidance of lead scientist, Zhi-Wei Li, Ph.D. who joined our staff in January 2008 from the Lee Moffitt Cancer Center affiliated with the university of South Florida.

Presentations and Publications

Our research findings have been presented at annual meetings of the American Society of Clinical Oncologists (ASCO), the American Association for Cancer Research, American Society of Hematology and the bi-annual International Myeloma Workshop in Greece. Our research has been published in publications including, Blood, Journal of Clinical Oncology, Proceedings of the National Academy of Sciences, Cancer, Clinical Cancer Research, Clinical Lymphoma and Myeloma, Oncogene, and the British Journal of Haematology.

References

1. American Cancer Society: Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society, 2007. Also available online. Last accessed September 7, 2007.

2. Greipp PR, San Miguel J, Durie BG et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23:3412-20.

3. Berenson JR, Yellin O, Crowley J et al. Factors That Determine Overall Survival among Patients (Pts) with Multiple Myeloma (MM) Treated with Zoledronic Acid (ZOL): Lack of Skeletal-Related Events (SREs) and Occurrence of Osteonecrosis of the Jaw (ONJ) Predict Improved Survival. Blood 2007; 110:4842.



IS A VEGAN DIET RECOMMENDABLE ?

Paraproteins can also cause a
hyperviscosity syndrome, which makes
it difficult for blood to pass through
capillaries, and so causes wider organ
dysfunction.

By naturally thinning the blood via a vegan diet, we may favor a better control of hyperviscosity. Including, but not limited to a living vegan foods diet. See the Jus Cogens daily program.

 

 

Nouvelles études sur le ph du sang et comment le modifier via la bio-chimie alimentaire



Dans les vallées du Tibet et Mongolie, le goji est honoré pendant deux semaines chaque année. Des études montrent qu'un bon nombre de ces habitants vivent plus de cent ans sans maladies chroniques. Toutes les variétés du goji contiennent les acides aminées essentielles et un combinatoire puissant de minéraux, de polysaccharides, carotenoides, anthocyanines et autres phyto-nutrients utiles en revitalisation cellulaire. Nous en avons plantés le potager.

 

En matière de immuno-stimulation et de cancérologie holistique, voir l'echinacée ,la sanguinaire, l'ortie, la renouéedes oiseaux, la plante pau d'arco (lapacho), l'artemisia, les racines de "burdock, ginseng, ginger ou curcuma, le cat's claw et beaucoup d'autres plantes que nous passerons en revue lors de ce stage.

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WEB-PAGE INACHEVÉE, EN CONSTRUCTION, SOUS RÉSERVE.

 

A bientôt !

"L'art de la médecine consiste à amuser le patient en attendant que la nature guérisse la maladie"   Voltaire

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