Encouse B. Golden, Philip Y. Lam, Adel Kardosh, Kevin J. Gaffney, Enrique Cadenas, Stan G. Louie, Nicos A. Petasis, Thomas C. Chen, and Axel H. Schonthal*
Department of Pathology, University of Southern California (USC) Keck School of Medicine (KSOM), Los Angeles, CA, United States
Department of Molecular Pharmacology and Toxicology, USC School of Pharmacy (SoP), Los Angeles, CA, United States
Department of Molecular Microbiology and Immunology, USC KSOM, Los Angeles, CA, United States
Department of Chemistry, USC College of Letters, Arts and Sciences, Los Angeles, CA, United States
Department of Clinical Pharmacy and Pharmaceutical Economics and Policy, USC SoP, Los Angeles, CA, United States
Department of Neurosurgery, USC KSOM, Los Angeles, CA, United States
* Corresponding author; email: firstname.lastname@example.org.
The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this ‘miracle herb’ in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (Velcade®) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by bortezomib in vitro and in vivo. This pronounced antagonistic function of EGCG was only evident with boronic acid-based proteasome inhibitors (bortezomib, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with bortezomib and blocked its proteasome inhibitory function; as a consequence, bortezomib could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of bortezomib and suggest that consumption of green tea products may be contraindicated during cancer therapy with bortezomib.
Before I got cancer, I made sure I had an AFLAC cancer policy. They’ve been great, and I recommend that everyone who is planning on having cancer enrolls in one of their plans before getting it. The trouble is, you don’t know if/when you might get cancer, so you better just plan for it. Expect the worst and hope for the best, some say.
I filed my claim for 2008 a week or so ago and was really surprised when I received a check in the mail for $4600. Something wasn’t right. It should have been $900. I’ve been filing these claims for years, so I knew a mistake had been made. I picked up the phone and called AFLAC. They’re going to investigate it and will send a letter when they figure out what happened. Wouldn’t it be nice if they said it was a reward for making it 6 years with myeloma?
My doc gave me an rx for Lyrica a few weeks ago to help with the neuropathy. I posted on the mailing list to get an idea of what kinds of side effects others had experienced when they used it. Mostly, I’d say they were not very positive responses. Almost everyone quit taking Lyrica because of side effects such as edema. One patient’s experience was pretty severe. I won’t be taking it. My PN isn’t present 100% of the time (although the numbness is). I’ll just take tramadol or some other medication PRN.
The issue is that I plan on making a very long trip out of the country in the spring. The PN is worse when I can’t either be moving or have my legs up, so I was concerned about taking an extremely long flight. It might just be best for me to be prepared with some vicodin (someone recommended this). Once I’m there, I’ll just need a good night’s sleep to recover and all will be well.
If you have any experience with chemo-induced PN, let me know how you handle it.
Message: Hi Beth,
Here are some data highlights from The 50th Annual American Society
of Hematology (ASH) Meeting this week:
Updated results from the ECOG study evaluating Revlimid plus low-dose dexamethasone in newly diagnosed patients was presented by Dr. Rajkumar in a joint symposium of the American Society of Clinical Oncology and ASH. The results are the highest 3 year overall survival rates ever reported in this patient group.
Data presented by Dr. San Miguel showed that relapsed/refractory patients who received continuous treatment with Revlimid and dexamethasone after achieving their best response lived longer and had increased time to disease progression compared to those who discontinued treatment after ten months or less.
Dr. Lacy presented data which showed that pomalidomide with dexamethasone has promising activity for patients with relapsed/refractory MM. Results from this ongoing trial showed high remission rates.
Many Multiple Myeloma patients have been damaged by the high cost of drug treatment and worse some do not receive treatment at all because of cost. The following is a brief summary of how I came to intimately know the drug Thalidomide and the journey it has taken me on.
I was diagnosed early in 2001 at the age of 54 and underwent an Autologous Stem Cell Transplant that summer. The result was fantastic. Life with my family was back to normal and my recovery was so complete I could play hockey, backpack and do physical work as I did pre MM. I was the happiest guy in town.
The cancer slowly gained another foot hold and in January of 2005 I had a second SCT but that one did not work and I was in trouble! My Calgary Oncologist suggested that I try Thalidomde. (In Canada procedures like SCT’s are covered so there is no serious treatment cost to the patients but when it comes to drugs that can be a different matter.)
I clearly remember asking my Oncologist, Dr. Stewart, “What does this drug cost” and he sort of grimaced and said, “it is kind of expensive……… it will cost you around $3000 a month”. I just about fell off my chair and asked him to confirm that this was the same basic thalidomide that caused horrific birth defects back in the 60’s. How in the world could an old drug like that cost thousands of dollars? As it turned out, my Doctor was wrong as the drug cost more that $4,000 per month. Fortunately for me, while I was being treated in the Province of Alberta I am a resident of British Columbia and The British Columbia Cancer Agency was the last Provincial body in Canada to cover the cost of the drug, so my Thalomid was funded. (Due to the escalating cost of the drug the Agency no longer covers Thalomid for new MM patients but does pay for those on the shrinking list that have been grandfathered in)
The price of this drug simply did not make sense to me. I could clearly remember that the gas I pumped in high school, back in 1966, cost 40 cents per gallon and I wondered what did Thalidomide cost then……maybe at most just a few dollars for a prescription. I contacted the Pharmacy of the B.C. Cancer Agency looking for historical pricing which they could not provide past June of 2000 but what I learned was absolutely stunning and left me with the instant opinion that something was very wrong with this picture. Hence, I committed to do what I could to expose and help correct the situation. I will leave you to form your own conclusions but these are the historical facts.
Note: All prices are in USD and a bottle contains thirty 50 mg. capsules. June 2000: $98.40. January 2002: $210:00. May 2003: $363.00. November 2003: $592.50. April 2005: $898.50. Note: The Cancer Agency does not add a dispensing fee or up charges so the prices quoted above is what the Agency or patients of the Agency paid Celgene for the Drug. Prices increased over 800% in less than five years.
I quickly learned that thalidomide was available in other countries at fractional prices. For example, the drug is currently (January, 2008) available at Serral Laboratories in Mexico for a cost of $90 for 50, 100 mg capsules so a typical 200 mg. dose would costs $3.60 / day and just last week an acquaintance (not an MM sufferer) had a prescription for Thalidomide filled in India and that drug cost her $5.60 for a 200 mg. dose. (Courier and Bank charges included) Compare the 2005 Celgene price for that same dose and you will see it cost $119.30 / day. I wondered if Canadians alone were being charged excessively high prices but learned that people in the United States were also facing the same outlandish costs.
It struck me that the best way to expose the matter was to contact the media. I assumed when the public and elected representatives found out what was going on the proverbial poop would hit the fan. Early in 2005 The Vancouver Sun, The Globe and Mail and my town’s local paper all did excellent articles focusing on the extreme cost of this long Orphaned drug. Global Television sent a crew to my home in Windermere, B.C. and a story aired on Global National evening news. Later CBC regional radio interviewed Health Canada looking for answers. I’m sure the facts presented by the media caused people to shake their heads but nothing changed.
My letters and extensive support materials sent to the former and current Minister of Health expressing concerns about the outrageous pricing received little consideration. Direct questions were not answered and crafted “say nothing” replies were all I got back from Ottawa. The whole effort left me frustrated and a bit cynical but recent events suggest there may be hope for a little justice. This is what we know.
Celgene has been bringing Thalidomide (Thalomid) into Canada under the Special Access Program since 1995. Currently, Health Canada does not have the authority to require the company to make a new drug submission and file a Notice of Compliance. HC has repeatedly encouraged Celgene to do so they have not co-operated. Why not? The answer is clear. If the drug followed the usual channels a new drug submission and NOC would have been filed and without patent protection, a generic form of the drug could be made and competition would bring the price down.
If a drug is patented it comes under the jurisdiction of the Patented Medicine Prices Review Board whether it comes into Canada under SAP or if the Company files a Notice of Compliance, the PMPRB has jurisdiction. Celgene maintained that the PMPRB did not have jurisdiction over SAP drugs but the board ruled on January 21, 2008 that it does have jurisdiction and that has important implications.
Celgene received a patent for the drug on April 4th, 2006.
It seems clear to me that Celgene believes it can charge what ever it wants for the drug and did not want the price reviewed by the Patented Medicine Prices Review Board because that board may determine that the price is too high, according to the board’s Excessive Price Guidelines, and require the company to bring the price down. Also, that board can require a company that has over charged for a drug to refund money to the Crown (government) and that money may in turn, be returned to the Provinces, medical plans and maybe even to individuals. It is curious that the price had been hiked to the current peak level in 2005. Celgene would know of the PMPRB and maybe they thought the board would only look at the drug price post patent date. (April 4, 2006)
In my opinion Celgene has clearly over charged and they deserve to have their finger slapped in a big way. (If readers wish to read the current judgement and related laws I will be pleased to offer directions to online sources.
Companies like Celgene often try to justify profits by claiming that they plow most of their gains back into Research and Development but you know that does not wash. The former CEO Mr. Jackson rode off into the sunset with tens of millions of dollars gained from Celgene stock options.
Celgene discriminates against Cancer patents. They have charged one price for thalidomide when it was used for AIDS but a much higher price when the drug is used for Cancer. The company has been blatant about its discriminatory practices as the follow quotations demonstrate. “When we launched it, it was going to be an AIDS-wasting drug,” says Celgene’s chief executive, John Jackson. “We couldn’t charge more or there would have been demonstrations outside the company.” (When Celgene Corp. got its first drug approved, it priced a 50-milligram capsule at $6) “After new information suggested the drug helped treat MM, Mr. Jackson said he felt justified in increasing the price because the drug had gained value-it appears to help cancer patients in addition to those with AIDS”. In Canada, and in most places around the world, discrimination is not condoned or accepted.
Please understand, I am very thankful for the drug and one of the many that are living proof that thalidomide is an effective short term treatment for Myeloma but that does not change the facts of the matter and that is: Celgene has been taking advantage of us by over charging.
Revlimid, the analog drug of thalidomide, is priced much higher compared to Thalomid and again the company charges excessive prices because they can. They seem to see MM patients as a captive market and act without conscience. The truth is MM patients are a captive market and we essentially just have the big bomb drugs, Velcade and Thalidomide/Revlimid for treatment of our disease. Each drug company wants to stay price competitive with the other but usually we associate competition with bargains or at least fair pricing. In this case we have the companies competing to see if they are pricing their drug as high as the other and they talk of market share in their investment literature as if they were selling buttons instead of life extending drugs. What happened to making something that helps people and making a reasonable profit? Keep in mind Celgene simply found a new application for the old drug Thalidomide and while they did have huge expenses to test and gain approvals for the drug this does not justify charging what they do.
People in the United States are being exploited too. I do not exactly understand what gives Celgene the market protection that they enjoy but it seems to boil down to the STEPS program. It took me almost three years to fully understand the whys and the wherefores of the situation in Canada and I expect that the same careful positioning for profit also exists South of the Canadian border. Celgene seems to enjoy unique market protection in New Zealand, Australia and other countries and I do not know exactly why.
So what to do? In Canada it seems clear that we should pressure our elected representative to influence the Supreme Court of Canada to hear the appeal case between the Patented Medicine Pricing Review Board and Celgene. Nine months have passed since it was ruled that the PMPRB had jurisdiction. Celgene appealed that decision and that court case has not even been scheduled. In the mean time Celgene continues to rack up huge profits. I truly hope that President Obama will keep his word and investigate big drug companies. It seems clear to me that Celgene and the case of Thalidomide is a very clear example of how big drug companies take advantage of captive, dependent people. This is the worst form of gouging. To date the Canadian Government has done next to nothing concerning this issue. It is my hope that the new Minister of Health will do something.
? ConsumerInformant has written more from personal experience on this blog. His mother has taken thalidomide.
Genetic variants in the DNA of patients with multiple myeloma appear to strongly influence survival, a groundbreaking new genomic study has concluded.
In this first pass at identifying genetic markers for survival, treatment response, and complications in the disease, a group of 3,400 variants predicted early or late mortality 76% of the time, Dr. Brian Van Ness said in an interview about the initial report (BMC Medicine 2008 Sept. 8 [doi: 10.1186/1741-7015-6-26]).
“Clearly, inherited genetics influenced survival,” said Dr. Van Ness
of the University of Minnesota, Minneapolis. “What we have not yet done is identify which specific variants are responsible for these differences. Our hypothesis is that it won’t be a single variant driving response or survival, but a complex interaction of many.”
After narrowing down the initial 3,404 candidate single nucleotide polymorphisms (SNPs), Dr. Van Ness and his colleagues are now focusing on 1,000 SNPs found to be most strongly associated with the outcome
measures. More studies are on the way using this genetic panel, he said.
Indeed, just 2 weeks after the first study appeared, a coinvestigator, Dr. Gareth Morgan of London’s Royal Marsden Hospital, published findings on the association between certain SNPs and the incidence of
treatment-associated venous thromboembolism (VTE). The analysis showed that some of the variants associated with thalidomide-related VTE occurred in pathways important in drug transport and metabolism.
“The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium,” Dr. Morgan and his colleagues wrote (Blood 2008 Sept. 19 [Epub ahead of print]).
“Another study, currently submitted, has identified an association between some of the variants and the development of severe myeloma bone disease,” Dr. Van Ness said.
The initial investigation used a genetic screen developed from two DNA data sets: cells from the Coriell Institute for Medical Research, and samples obtained from multiple myeloma patients enrolled in two
randomized drug trials, as well as some unaffected spouses. The samples came from white, black, Hispanic, and Asian patients from North America and Europe. The candidate SNPs, occurring on 983 genes, were chosen based on the most recent genetic research and included on a myeloma-specific gene-testing chip.
The investigators chose extremes of survival as the first test of the panel, because this comparison was most likely to show the effects of any genetic variant. “We took the worst outcomes – people who died in
the first year of their disease – and the best outcomes – those who survived at least 3 years without progression,” Dr. Van Ness said. After repeatedly running the screen on both data sets, the team concluded that, as a whole, it discriminated the survival groups correctly 76% of the time.
Further drilling down identified several SNPs of particular interest, including some associated with drug metabolism, transport, and export; a variant that induces myeloma apoptosis; one associated with cellular
migration and angiogenesis; and several linked to proliferative responses.
Although not designed to detect racial differences, the initial screen did identify some interesting variations: 401 of the SNP variants occurred only in black patients. In whites, there was no difference in these SNPs between cases and controls.
“We know that African Americans have a two- to threefold increase in the incidence of myeloma, but we don’t yet know why,” Dr. Van Ness said. “We’ll be trying to identify those genetic variants that might uniquely increase the risk for one race to develop myeloma over another.”
Neither this initial analysis nor subsequent ones will examine the possible interplay of environment with genetics. But, Dr. Van Ness said, such studies may be forthcoming. The International Myeloma Foundation of North Hollywood, Calif., is conducting a patient survey to begin assessing what role – if any – environmental exposure plays in disease development. The 36-page survey asks patients to detail their environmental, dietary, and geographical exposures. The National Cancer Institute will collaborate with the group in evaluating the data.
The International Myeloma Foundation is also the curator of the DNA samples used in the analysis through its Bank on a Cure program. “Bank on a Cure was developed by an international group of physicians and scientists to deal with a disease that’s difficult to deal with,” Dr. Van Ness said. “It’s not a high-incidence cancer, so it’s not easy to research.”
The Bank on a Cure group developed cooperative agreements with national and international clinical trial groups, and the studies were funded by the International Myeloma Foundation. While exploration of genetic variants relevant to multiple myeloma is in its infancy, Dr. Van Ness predicted the effect could be profound.
On the mailing list we had a discussion about bone disease in MM. Here’s what Nancy said about it. I hadn’t realized before that IgA patients are less prone to bone disease. One of my doctors did tell me we’re more likely to have kidney involvement though.
Some people never have bone disease…that’s just the way their myeloma is; just as some people never have kidney problems. The names given to the variations of myeloma are not different. Patients with IgA myeloma are less likely to have bone disease than those with IgG myeloma…and those with IgG myeloma are less like than those with IgA myeloma (or Bence Jones myeloma) to have kidney problems.
Perhaps by “classic myeloma” they are referring to myeloma that is in the bone marrow…as opposed to extramedullary myeloma which is outside the bone marrow….rather than affecting the bones. However, about 80% of patients do have bone involvement, so it is the most common symptom of myeloma.