Posted by Brad Weeks, MD on October 16, 2009
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Posted by Brad Weeks, MD on March 8, 2010
Dr. Weeks’ Comment: A great start!
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Proposed 28th Amendment to the United States Constitution
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Congress shall make no law that applies to the
citizens of the United States that does not apply equally to
the Senators and/or Representatives; and, Congress shall
make no law that applies to the Senators and/or
Representatives that does not apply equally to the citizens
of the United States.
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Argument
For too long we have been too complacent about the
workings of Congress. Many citizens had no idea that
members of Congress could retire with the same pay after
only one term, that they didn’t pay into Social
Security, that they specifically exempted themselves from
many of the laws they have passed (such as being exempt from
any fear of prosecution for sexual harassment) while
ordinary citizens must live under those laws. The
latest is to exempt themselves from the Healthcare Reform
that is being considered … in all of its forms.
Somehow, that doesn’t seem logical. We do not have
an elite that is above the law. I truly don’t
care if they are Democrat, Republican, Independent or
whatever. The self-serving must stop. This is a
good way to do that. It is an idea whose time has come.
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Action
Each person contacts a minimum of 20 people on
their address list, in turn asking each recipient to do likewise.
In three days, most people in the United States of America
will have the message.
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Posted by Brad Weeks, MD on March 8, 2010
Dr. Weeks’ Comment: This is a well established problematic relationship: gluten from wheat and neurological gut and brain dysfunction. Worth ruling out !
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Gluten sensitivity and brain disease: neuronal transglutaminase
March 8th, 2010
The authors of this paper published in Annals of Neurology make an important statement:
“Gluten sensitivity typically presents as celiac disease, a chronic, autoimmune-mediated, small-intestinal disorder. Neurological disorders occur with a frequency of up to 10% in these patients. However, neurological dysfunction can also be the sole presenting feature of gluten sensitivity.”
Antibodies directed toward transglutaminase in the gut are a well-known diagnostic feature of celiac disease. These investigators have identified another member of the transglutaminase family:
“…a novel neuronal transglutaminase isozyme and investigated whether this enzyme is the target of the immune response in patients with neurological dysfunction.” They found that “Whereas the development of anti-transglutaminase 2 IgA is linked with gastrointestinal disease, an anti-transglutaminase 6 IgG and IgA response is prevalent in gluten ataxia, independent of intestinal involvement.”
(Ataxia is loss of the ability to coordinate muscle movement, especially as it appears with difficulty walking.) Their conclusion:
“Antibodies against transglutaminase 6 can serve as a marker…to identify a subgroup of patients with gluten sensitivity who may be at risk for development of neurological disease.“
If you are gluten sensitive, you can have neurological disease without celiac involvement.
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Categories: Wheat | Tags: | No Comments »
Posted by Brad Weeks, MD on March 7, 2010
Dr. Weeks’ Comment: This quotation was made in the year 1790 by Dr. Alexander Tytler, Professor of General History, University of Edinburgh.
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“A Democracy cannot exist as a permanent form of government.
It can only exist until the voters discover that they can vote themselves largess out of the public treasury.
From that moment on, the majority always votes for the candidate promising the most benefits from the public treasury, with the result that a democracy will always collapse from a loose fiscal policy (burden of large public debt),
always to be followed by a dictatorship.”
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Categories: Big Insurance | Tags: | No Comments »
Posted by Brad Weeks, MD on March 7, 2010
SOURCE http://www.sourcewatch.org/index.php?title=Talk:Government-industry_revolving_door
Ann Mulkern, “When advocates become regulators,“ Denver Post, May 23, 2004: “President Bush has installed more than 100 top officials who were once lobbyists, attorneys or spokespeople for the industries they oversee.”
Daniel E. Troy, lead counsel for the U.S. Food and Drug Administration, extended the government’s help in torpedoing certain lawsuits. Among Troy’s targets: claims that medications caused devastating and unexpected side effects.
Pitch us lawsuits that we might get involved in, Troy told several hundred pharmaceutical attorneys, some of them old friends and acquaintances from his previous role representing major U.S. pharmaceutical firms.
The offer by the FDA’s top attorney, made Dec. 15 at the Plaza Hotel, took the agency responsible for food and drug safety into new territory.
“The FDA is now in the business of helping lawsuit defendants, specifically the pharmaceutical companies,” said James O’Reilly, University of Cincinnati law professor and author of a book on the history of the FDA. “It’s a dramatic change in what the FDA has done in the past.”
Troy’s switch from industry advocate to industry regulator overseeing his former clients is a hallmark of President Bush’s administration.
Troy is one of more than 100 high-level officials under Bush who helped govern industries they once represented as lobbyists, lawyers or company advocates, a Denver Post analysis shows.
In at least 20 cases, those former industry advocates have helped their agencies write, shape or push for policy shifts that benefit their former industries. They knew which changes to make because they had pushed for them as industry advocates.
The president’s political appointees are making or overseeing profound changes affecting drug laws, food policies, land use, clean-air regulations and other key issues.
Government watchdogs call it a disturbing trend, not adequately restrained by existing ethics laws.
Among the advocates-turned-regulators are a former meat-industry lobbyist who helps decide how meat is labeled; a former drug-company lobbyist who influences prescription-drug policies; a former energy lobbyist who, while still accepting payments for bringing clients into his old lobbying firm, helps determine how much of the West those former clients can use for oil and gas drilling.
“When you go to work in lobbying, it is clearly understood and accepted that your job is to advocate for the interests of those who hired you,” said Terry L. Cooper, a University of Southern California ethics and government professor. “When you go to work in government, you are supposed to be responsible for upholding and maintaining whatever you can identify as the public interest.”
The Bush administration says the regulators were chosen for their abilities.
“The president appoints highly qualified individuals who make their decisions based on the best interests of the American people,” said White House spokesman Jim Morrell. “Any individual serving in the administration must abide by strict legal and ethical guidelines, including full disclosure of past lobbying activities.”
Six of the former industry advocates have faced ethics investigations or resigned amid conflict-of-interest charges. Those and at least 14 others have been lambasted by public-interest groups.
Government ethics standards are part of the problem because they don’t fully address the kind of issues that now permeate Washington, Cooper and some inside government say. The rules focus mainly on direct financial conflicts. Other, more nuanced conflicts aren’t addressed
“There are so many ways around, over and under these (ethics) bans … they almost never work,” said Paul Light, who for decades has studied the appointment process for the Brookings Institution, a think tank in Washington. “There’re more screen doors than steel doors.”
Categories: FDA, quis custodiet ipsos custodes? | Tags: | No Comments »
Posted by Brad Weeks, MD on March 7, 2010
Dr. Weeks’ Comment: “Iatrogenesis”, a word they teach all 3rd medical students as we swarm out of the classrooms and into the real world of the hospitals, is rarely mentioned, except behind the closed doors of a Grand Rounds or at “M&M” meetings. (M&Ms are the weekly events where doctors get together and scratch their heads about troubling cases while meeting to discuss reasons for morbidity and mortality (M&M). Here doctors review details to try and learn 1)where things went wrong, 2) why things went wrong and 3) what we can do to prevent future tragedies. At every step of the way, nobody mentions the word “iatrogenesis” but we are all thinking it.
The first death I ever experienced while in medical school occurred in a hospital setting and was clearly caused by the attending doctor ordering the wrong medicine followed by an fatal allergic response in an already dying elderly man. When the error was reported to the Attending the next morning, he responded to his medical team of residents and medical students all gathered to receive his wisdom (and I will remember his response to my own dying day) with the following casual assessment: “Well, live and learn.” - I thought to myself: “That is easy for you to say since you are the one who gets to live AND learn but what about the patient who was killed by your error!” It was my first direct experience with iatrogenesis. Death caused by a well-intended but erring or careless doctor. In civil courts, you might know this act by another term: second -degree murder.
A new form of iatrogenesis is spreading across the land. Today, as Nicholas Kristoff of the NYTimes points out, something approaching murder, agricultural iatrogenesis for profit, is seeping out and into all our commercially prepared food. The FDA, bought and sold to Industry (actually staffed by industry according to most current analysis http://weeksmd.com/?p=3387 and http://www.psrast.org/ecologmons.htm ) is not protecting us and so, as Kristoff concludes, the witches cauldrons of agribusiness where our food is produced today on Pharms and no longer on family farms has resulted in our “brewing some perfect storms”.
“Trust me, I’m your farmer.” or “Trust me, I’m your grocer.” rings as hollow today as “Trust me, I’m your doctor” rang in the ears of a young medical student who was being trained to “live and learn” many years ago.
“Iatrogenesis.” Look it up. Learn its definition. Teach it to your friends. Ask your doctor about it! Live it up a bit and learn, while you have your health (assuming, of course, that you are already eating organic…)
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March 7, 2010
Op-Ed Columnist
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The Spread of Superbugs
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By NICHOLAS D. KRISTOF
Until three months ago, Thomas M. Dukes was a vigorous, healthy executive at a California plastics company. Then, over the course of a few days in December as he was planning his Christmas shopping, E. coli bacteria ravaged his body and tore his life apart.
Mr. Dukes is a reminder that as long as we’re examining our health care system, we need to scrutinize more than insurance companies. We also need to curb the way modern agribusiness madly overuses antibiotics, leaving them ineffective for sick humans.
Antibacterial drugs were revolutionary when they were introduced in the United States in 1936, virtually eliminating diseases like tuberculosis here and making surgery and childbirth far safer. But now we’re seeing increasing numbers of superbugs that survive antibiotics. One of the best-known — MRSA, a kind of staph infection — kills about 18,000 Americans annually. That’s more than die of AIDS.
Mr. Dukes, 52, picked up a kind of bacteria called ESBL-producing E. coli. While it’s conceivable that he touched a contaminated surface, a likely scenario is that he ate tainted meat, said Dr. Brad Spellberg, an infectious-diseases specialist and the author of “Rising Plague,” a book about antibiotic resistance.
Vegetarians are also vulnerable to antibiotic resistance nurtured in hog barns. Microbes swap genes, so antibiotic resistance developed in pigs can jump to microbes that infect humans in hospitals, locker rooms, schools or homes.
Routine use of antibiotics to raise livestock is widely seen as a major reason for the rise of superbugs. But Congress and the Obama administration have refused to curb agriculture’s addiction to antibiotics, apparently because of the power of the agribusiness lobby.
The ESBL E. coli initially remained in Mr. Dukes’s colon, causing no particular damage. But then he suffered an inflammation that perforated his colon — and the bacteria escaped.
Mr. Dukes began suffering stomach pains and saw his doctor, who gave him Cipro, a strong antibiotic that had previously worked against the infection. This time, the pain grew worse. The next evening, he was in surgery to remove eight inches of his colon.
A culture attributed the infection partly to ESBL E. coli. Doctors inserted a tube to administer an intravenous antibiotic in an effort to save his life.
If ESBL E. coli is frightening, there are even more potent superbugs emerging, like Acinetobacter.
“We are seeing infections caused by Acinetobacter and special bacteria called KPC Klebsiella that are literally resistant to every antibiotic that is F.D.A. approved,” Dr. Spellberg said. “These are untreatable infections. This is the first time since 1936, the year that sulfa hit the market in the U.S., that we have had this problem.”
The Infectious Diseases Society of America, an organization of doctors and scientists, has been bellowing alarms. It fears that we could slip back to a world in which we’re defenseless against bacterial diseases.
There’s broad agreement that doctors themselves overprescribe antibiotics — but also that a big part of the problem is factory farms. They feed low doses of antibiotics to hogs, cattle and poultry to make them grow faster.
A study by the Union of Concerned Scientists found that in the United States, 70 percent of antibiotics are used to feed healthy livestock, with 14 percent more used to treat sick livestock. Only about 16 percent are used to treat humans and their pets, the study found.
More antibiotics are fed to livestock in North Carolina alone than are given to humans in the entire United States, according to the peer-reviewed Medical Clinics of North America. It concluded that antibiotics in livestock feed were “a major component” in the rise of antibiotic resistance.
Legislation introduced by Louise Slaughter, a New Yorker who is the only microbiologist in the House of Representatives, would curb the routine use of antibiotics in farming. The bill has 104 co-sponsors, but agribusiness interests have blocked it in committee — and the Obama administration and the Senate have dodged the issue.
After weeks of receiving intravenous antibiotics, Mr. Dukes is now recovering at home in Lomita, Calif. He must use a colostomy bag, but he hopes to be patched up and ready to return to work next month. Still, he knows that the ESBL E. coli remains in his gut.
“As long as it’s contained in my colon, I’m a happy camper,” he said. “But if it gets out again, I’m in trouble.”
Dr. Martin J. Blaser, chairman of the department of medicine at New York University Langone Medical Center, and a former president of the Infectious Diseases Society of America, agrees that agricultural use of antibiotics produces cheaper meat. But he says the price may be an enormous toll in human health.
“You could have very lethal pandemics,” he said. “We’re brewing some perfect storms.”
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Categories: Corrective foods, Infectious Disease, Organic, Power to People | Tags: | No Comments »
Posted by Brad Weeks, MD on March 6, 2010
Dr. Weeks’ Comment: Here (finally!) is some research accomplished in 2009 which supports the clinical practice of IPT which was called quackery in 1940. It demonstrates that the IGF-1 receptor is the back door, unguarded, which we can use to bring chemo drugs preferentially into the cancer cell. Elegant research in 2009; stupendous clinical work in 1940.
Lucky they who listened to Dr. Perez Garcia and didn’t wait around for the experts to endorse the work.
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Transl Res. 2009 Jun;153(6):275-82. Epub 2009 Mar 14.
Novel insulin-like growth factor-
methotrexate covalent conjugate
inhibits tumor growth in vivo at lower
dosage than methotrexate alone.
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McTavish H, Griffin RJ, Terai K, Dudek AZ.
IGF Oncology, LLC, Saint Paul, MN 55110, USA.
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The insulin-like growth factor receptor is overexpressed on many types of cancer cells and has been implicated in metastasis and resistance to apoptosis. We report here the development of a novel covalent conjugate that contains the antifolate drug methotrexate coupled to an engineered variant of insulin-like growth factor-1 (IGF-1), long-R3-IGF-1, which was designed to target methotrexate to tumor cells that overexpress the membrane IGF-1 receptor. The IGF-methotrexate conjugate was found to contain at least 4 methotrexate molecules per IGF-1 protein. The IGF-methotrexate conjugate bound to MCF7 breast cancer cells with greater than 3.3-fold higher affinity than unconjugated long-R3-IGF-1 in a competition binding assay against radiolabeled wild-type IGF-1. Compared with free methotrexate, the IGF-methotrexate conjugate required slightly higher concentrations to inhibit the in vitro growth of the human prostate cancer cell line LNCaP. In vivo, however, in a mouse xenograft model using LNCaP cells, the IGF-methotrexate conjugate was more effective than free methotrexate even at a 6.25-fold lower molar dosage. Similarly, MCF7 xenografts were inhibited more effectively by the IGF-methotrexate conjugate than free methotrexate, even at a 4-fold lower molar dosage. Our results suggest that the targeting of the IGF receptor on tumor cells and tumor-related tissues with IGF-chemotherapy conjugates may substantially increase the specific drug localization and therapeutic effect in the tumor.
Categories: Ask Your Doctor About, Chemotherapy, IPT | Tags: | No Comments »
Posted by Brad Weeks, MD on March 6, 2010
Dr. Weeks’ Comment: Back in the summer of 2002, a very skeptical Dr. Brad Weeks traveled to Chicago to the office of Dr. Steven Ayre and had his world rocked! Dr. Ayre taught him the procedure of IPT -insulin potentiated therapy which seemed too good (too simple, really!) to be true.
I want to share this information with you now and I encourage you to think it through and then to ask your oncologist why he or she doesn’t look into this safe and potent treatment protocol.
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Typically used for delivering chemotherapy drugs at 10% dosage to people with cancer, IPT started out in the early 1940’s as “Cellular Therapy” whereby penicillin was administered to patients paralyzed by polio once their low blood sugar or “therapeutic moment” was attained. The old scratchy home movies demonstrate young patients who had paralytic polio receiving IPT and subsequently walking, skipping and dancing after treatment. Other uses for this innovative and effective treatment modality were administering low dose drugs for the treatment of malaria and more recently for the treatment of Lyme’s Disease -again, treatment being delivered when the pathological cells are most vulnerable: at a hypoglycemic moment. In another post, http://weeksmd.com/?p=3364 we cite research demonstrating that insulin makes cancer cells 10,000 times more vulnerable to chemo drugs (No, that was not a typo: I did mean to type “10,000″ – yes “ten thousand” !)
So read a bit about this innovation, consider the pros and cons of taking a treatment which is comprised of chemo drugs delivered at 10% the normal dosage and know that IPT patients call it “side-effect free chemotherapy”.
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The Physiology and Clinical Pharmacology of Insulin in Relation to its Application in Insulin Potentiation Therapy (IPT)
By Steven Ayre, M.D.
The hormone insulin is recognized as having actions that affect the transmembrane transport of different substances, particularly glucose, into numerous different kinds of cells. Insulin is a large polypeptide molecule with a molecular weight of 5808. It consists of an A chain and a B chain, connected together by two disulfide bridges. The hormone is made in the beta cells of the pancreas, and the stimulus for its secretion into the blood stream is a rise in the blood glucose concentration. Its actions on liver, adipose tissue, and skeletal muscle have all been studied in great detail, and it is now recognized that insulin also affects a wide variety of tissues in addition to just these three.(1)
Apart from the membrane transport of glucose, insulin also regulates the transport of some amino acids, some fatty acids, potassium, magnesium, and certain other monosaccharides. Furthermore, it mediates the formation of macromolecules in cells which are used in cell structure, energy stores, and in the regulation of many cell functions. It stimulates glycogenolysis, lipogenesis, proteogenesis, and nucleic acid synthesis. It also increases glucose oxidation and magnesium-activated sodium-potassium ATPase activity.(1)
There is a single mechanism involved in the initiation of all these biological effects, and this is the interaction of the hormone with its specific receptor. The insulin receptor consists of two alpha subunits (Mr 135,000) and two beta subunits (Mr 95,000) which are linked together by disulfide bonds. The alpha unit is predominantly located on the outer surface of the cell membrane, and the insulin binding domain is located here. The transmembrane beta subunit contains tyrosine kinase activity on its cytoplasmic domain that results in rapid receptor autophosphorylation. Activation of the kinase towards exogenous substrates is apparently preceded by this insulin-dependent autophosphorylation reaction of the beta subunit. Action on other cellular substrates ultimately leads to the expression of the full range of insulin actions at the cellular level.(2)
After insulin binds to the receptor with activation of the kinase, followed by receptor autophosphorylation, the insulin-receptor complex is endocytosed into the cell cytoplasm. This phenomenon accounts for the down-regulation of insulin receptor activity that ensues following insulin stimulation. With this endocytosis, a variety of events may then take place. Insulin dissociates from the receptor and, following fusion of the endocytotic vesicle with cellular lysosomes, it is degraded by lysosomal enzymes. The free receptor may itself be degraded by the lysosomal enzymes, or it may recycle back to the surface of the cell membrane. Finally, the free phosphorylated receptor may proceed to activate other substrates in the cytoplasm or within cellular organelles (Golgi apparatus, nucleus, etc) to produce the plethora of changes described above.(3)
The most commonly recognized action of insulin is that of lowering blood glucose. This is accomplished via a process of facilitated diffusion across cell membranes. It is hypothesized that the mechanism of this facilitated diffusion involves the translocation of a glucose transport protein from the cytoplasm out to the cell membrane. This translocation process involves the fusion of intracytoplasmic vesicles with the membrane of the cell. These vesicles contain the glucose transport protein in their enclosing membranes. Once exteriorized on the cell surface, the transport proteins serve as channels for glucose to enter the cell. This particular protein has been identified as a 40,000 molecular weight moiety found by centrifugation to be associated with the Golgi rich fraction.(4) The process of translocation is reversible via endocytosis of the membrane fragment containing the transport proteins, reconstituting the intracytoplasmic vesicles. The whole activity of the glucose transport protein is dependent on metabolic energy, and independent of protein synthesis.(5) The precise nature of the signal through which insulin turns this process on and off remains to be elucidated.
Insulin receptors are widely distributed in mammalian organisms with there being from 100 to 100,000 receptors per cell in different tissues. Rarely are there any cells having no receptors at all.(6) A number of malignant neoplastic tissues have also been found to have a plentiful supply of insulin receptors,(7-9) reflecting established cancer cell metabolism and the need that malignant cells have for glucose. Insulin may also play a role here in the stimulation of cancer cell growth,(10,11) and many different cancers have been found to actually produce and secrete their own insulin.(12-19) The conclusion to be made here is that insulin receptors on cancer cell membranes, plus autocrine secretion of insulin by cancer cells, function as an endogenous mechanism evolved in these cells allowing them to parasitize host energy substrate (glucose), and to stimulate their rapid and autonomous growth.
Investigation of many of the actions of insulin on insulin receptors in numerous species have demonstrated that the properties of insulin receptors in mammalian tissues are remarkably similar, irrespective of cell type.(1,6,20) This being so, it may be anticipated that what the activated insulin/insulin-receptor complex does in one tissue, it will do in all. This would of course be dependent on there being the necessary metabolic machinery within a particular tissue to react to insulin activation. Not all tissues are similarly endowed in this regard.
Brain is a tissue which does have insulin receptors, but which does not have the same insulin-dependent glucose transport mechanism common to many other of the body’s tissues. Insulin receptors are found both on the capillary endothelium of the BBB, as well as on the glial elements within the substance of the brain. These receptors do not seem to play any role, in conjunction with insulin, in the transmembrane transport of the glucose which is so essential for proper brain metabolism. The capillary endothelium of the blood-brain barrier (BBB) has its own unique transport system for glucose, as well as a number of other nutrient transport systems for substances such as choline, adenine, adenosine, lactate, glutamate, phenylalanine, and arginine.(21) The composition of the scant interstitial fluid of the brain is carefully controlled by the very selective functioning of the BBB. Having access to this space, across the BBB, substances then have free access to the brain cells.
The glucose transport system in brain responds to chronic changes in blood glucose levels, and there is some interesting clinical correlation for this. The system is up-regulated during prolonged periods of hypoglycemia(22) which can explain why some patients with chronic hypoglycemia or insulinomas may not have symptoms of brain glucopenia at blood glucose concentrations of less than 50 mg%. In a similar fashion, the brain glucose transport system is down-regulated during prolonged periods of hyperglycemia, such as can occur with poorly controlled diabetes.(23) When such patients are brought under rapid control with insulin therapy, because of this down-regulation of the BBB glucose transporter, they may develop symptoms of hypoglycemia due to CNS glucopenia even though the blood glucose level may be in the normal range.(24)
Glucose transport across the BBB is insulin-independent, and yet insulin receptors are found on the same BBB capillary endothelium which carries the glucose transport system. This insulin transport system is just one of a number of peptide transport systems found on the BBB. Others carry the insulin-like growth factors I and II, and transferrin.(21) The blood-brain barrier insulin receptor is a glycoprotein having structural characteristics typical of the insulin receptor in peripheral tissues. It may be part of a combined endocytosis-exocytosis (transcytosis) system for the transport of the peptide through the BBB in man. A transcytosis of insulin through the human BBB would allow for distribution of circulating insulin into brain interstitial space and insulin action on brain cells.(25)
The role of insulin in the regulation of brain function continues to be a major unsolved problem in insulin physiology. Evidence to date shows that it seems to be primarily involved with brain growth and development, and this seems to be more important in the newborn mammalian brain.(26) Research continues in efforts to elucidate this question in its entirety. It has been through such research, looking to find the extent of insulin’s role in brain physiology, that some interesting possibilities have come to light concerning the applications as a pharmacologic adjunct which this hormone may have in clinical situations other than in the management of diabetes mellitus.
In tissues possessing insulin receptors, including the membranes of the capillary endothelial cells comprising the BBB, it seems that insulin can potentiate the pharmacologic actions of drugs that may be administered in conjunction with it. In an experiment measuring the brain-uptake index in rats there was seen to be a 33 percent increase in the intra-CNS accumulation of radiolabeled AZT in the insulin pretreated animals as compared to non-insulin treated controls.(27) Drug potentiation appears to be a function of increased intracellular concentration of drug obtained due to some action of insulin on the target cell membranes. The question as to the exact mechanism of insulin’s pharmacologic action in this non-diabetic context remains an open one. Research in the field points to several different possibilities.
In skeletal muscle, insulin has been shown to deliver enzyme-insulin-albumin conjugates into the intracellular compartment of the cells. The whole complex was transported into the cells by a process resembling receptor-mediated endocytosis, and the enzyme-albumin-insulin complex retained its enzymatic activity and its ability to bind antibodies to insulin.(28) In experiments with rat fibroblasts, the fragment A of diphtheria toxin conjugated to insulin gained access to the intracellular milieu via a process of endocytosis through insulin receptors,(29) and in human lymphocytes, insulin has been shown to carry a photoactivatable psoralen derivative into these cells, again by a process of insulin receptor-mediated endocytosis.(30)
In brain, it has been pointed out that specific peptide receptor transport systems in the blood-brain barrier may be available for peptide delivery into the brain, and it has been suggested that coupling peptides or even enzymes to insulin could result in the uptake of the chimeric peptide by cells via the insulin receptor-mediated uptake system.(31) This concept has been investigated in an animal experiment with rats, wherein it was shown there is a statistically significant increase in the brain-uptake index of 3H-zydovudine under the influence of insulin.(32) In this case, it was free drug that was co-administered along with insulin, and not a chimeric drug-or-enzyme/ insulin complex. No determination has been made as to whether or not this observed effect was due to an insulin receptor-mediated phenomenon as in the cases cited above. Other research indicates that there may be alternative possibilities here.
Breast and colon cancer cell membranes have been characterized as having plentiful insulin receptors.(7-9) Autoradiographic studies have shown that radiolabeled insulin binds predominantly to breast cancer cell membranes rather than to stromal elements (fat cells, firbrolasts) within tumors.(7) Other studies have demonstrated that, quantitatively, there are six times more insulin receptors on breast cancer cell membranes than on membranes of stromal cells within tumors.(33, 34) And most significantly for the purposes of this discussion, yet another study demonstrated that, in vitro, insulin increased the cytotoxic effect of methotrexate in MCF-7 human breast cancer cells by a factor of up to ten thousand.(35) The authors of this study attributed this effect to metabolic modification within the cancer cells, rendering them more sensitive to the effects of the methotrexate. However, in a related study it was shown that “insulin has significant effects on the intramembrane methotrexate transport system of MCF-7 (human breast cancer) cells. Enhanced cytotoxicity may be related to an increased capacity of the cells to accumulate free intracellular methotrexate. Insulin-induced changes in cellular lipid synthesis and perhaps in membrane lipid profile could result in changes in membrane fluidity and enhanced methotrexate transport.”(36)
In another research context unrelated to the actions of insulin, experiments manipulating the chemical structure and physical properties of membrane phospholipids has made it possible to alter phase transitions of fluidity in the membranes that come to incorporate these compounds, and to thereby influence and control biological membrane processes. Alkyl glycerides have been shown to modify the properties of biological membranes quickly and reversibly to increase the permeation of active compounds. An important example of this is the improved transport of cytostatic drugs across the blood-brain barrier in the presence of l-pentylglycerol.(37)
Insulin is recognized as having a widespread effect on lipid metabolism, and the following may explain its putative drug-potentiating effect. It is recognized that cell membrane permeability varies directly with cell membrane fluidity, and the fluidity of cell membranes is a function of the degree of unsaturation of its component fatty acids on account of the lower melting point of unsaturated versus saturated fatty acids. Insulin has a particularly significant effect on the activity of the enzyme delta-9 desaturase, which catalyses the transformation of the saturated fatty acid stearic acid into the mono-unsaturated oleic acid.(38) The melting point of the triacylglycerol, tristearin, (with three stearic acid residues attached to a glycerol backbone) is 73 0 C, while that of the corresponding trioleic congener is only 5.5 0 C. At physiologic temperatures, a widespread transformation of this sort would account for considerable changes in the physical properties of biomembranes, and would significantly affect cell membrane permeability.(39)
In summary, though not yet definitively characterized as to its specific mechanisms, there is compelling evidence upon which to propose the following. Through its interaction with specific insulin receptors widely distributed in human malignant tissues, insulin facilitates the passage of drug molecules from the extracellular compartment into the intracellular compartment of these cells. Rather than relying just on the law of mass action in concert with relatively high doses of parenteral anticancer drugs, insulin used as a pharmacologic adjunct to lowered dose therapy accords a potentially safer as well as more effective methodology.
Insulin and a related compound – IGF-I – are integral parts the mechanisms of malignancy in cancer cells. The combination of insulin and IGF-I operates autonomously at the cellular level within the tumor, and this operation is free from any higher level of integrated control. The two work together in an autocrine and/or paracrine manner and in a complementary fashion, with IGF-I being the major anabolic hormone responsible for mediating messages about growth in the tumor, while insulin regulates and provides the fuel for these processes.(40)
An added dimension to insulin’s drug potentiation in malignant neoplastic tissues is its effect on cancer cell growth via cross-reaction with the IGF-I receptor. It is well recognized that the cell-cycle phase-specific anticancer drugs work best on cells in S-phase of the growth cycle. Growth in cancer cells is mediated by a number of different mitogens, one of the most potent of which in breast cancer cells is insulin-like growth-factor I(IGF-I).(33,41,42) IGF-I – like insulin – is manufactured and secreted by many cancer cell lines, and cancer cell membranes are – again, as for insulin – liberally endowed with the specific receptors for this mitogen.(41,42) Furthermore, there is 45 percent homology between the amino acid sequence of the insulin receptor (IR) and the insulin-like growth-factor I receptor (IGF-IR), and both insulin and IGF-I can effectively cross-react with both of these receptors.(43) As stated above, human cancer cell membranes, particularly breast, have been characterized as possessing far more IR and IGF-IR than the cell membranes of normal tissues within the host and, finally, it is a well recognized fact of mammalian physiology that the intensity of a ligand’s effect on a tissue is a function of the specific receptor concentration on that target tissue.
Thus, overall, the role of insulin in Insulin Potentiation Therapy is to stimulate cancer cell membrane insulin receptors to facilitate drug entry into cells, and to cross-react with cancer cell membrane IGF-I receptors causing a recruitment of the cancer cells into S-phase, making them more susceptible to the pharmacologic action of anticancer medication. The synergy between these actions of insulin potentiates drug effects within the cancer cells, resulting in a more effective cell kill. Furthermore, because of the much richer distribution of insulin and IGF-I receptors on cancer cell membranes versus normal somatic cells, these drug potentiating effects will predominate in the cancer cells with a relative sparing of normal tissues.
INSULIN-INDUCED HYPOGLYCEMIA IN INSULIN POTENTIATION THERAPY The dosage of insulin used in applications of insulin potentiation therapy (IPT) is 0.1 to 0.4 U/kg body weight, given as a single bolus injection intravenously. The 0.4U/kg dose is the most widely used because it provides optimal hypoglycemic responses, is well tolerated clinically, and is easily controlled medically. The lower doses are used for individuals exhibiting increased sensitivity to insulin as evidenced by greater than the desired levels of hypoglycemia. The type of insulin used is Humalog, insulin lispro injection, recombinant DNA origin (Lilly). This is the preferred preparation because it is reported to have a faster onset of action, as well as a shorter overall duration of action of only two hours. The clinical experience with Humalog bears out the fact of its shorter duration of action, however the onset of the desired level of hypoglycemia which it produces has been observed to be no faster than that observed with Humulin or other regular insulin preparations of animal origin.
Regular insulin may be administered in other non-diabetic circumstances in clinical medicine. Growth hormone secretion in humans is evaluated by means of the insulin tolerance test, wherein subjects receive 0.05 to 0.1 U/kg body weight.(44) Also, the evaluation of insulin resistance in subjects with Syndrome-X employs a continuous infusion of low-dose insulin over a number of hours. It is not possible to compare doses administered to these Syndrome-X subjects with the dose given in IPT because of the differences in the pharmacodynamics and physiologic response seen with a bolus dose versus the continuous, long term infusion.
On the other hand, it is quite evident that the dose of insulin used in IPT is significantly higher than that given in the insulin tolerance test. While the degree of hypoglycemia produced in IPT is therefore more pronounced, this may be satisfactorily managed through close clinical observation of the subject over time followed, when appropriate, by the administration of hypertonic glucose solution. Competent and experienced management of insulin-induced hypoglycemia during treatment is central to the safe performance of the IPT protocol.
A number of studies have been done in human subjects to determine the factors important in glucose counterregulation following insulin-induced hypoglycemia.(45-48) In these studies, it has been shown that insulin-induced hypoglycemia stimulates the release of glucagon, epinephrine, growth hormone, cortisol, and norepinephrine (from sympathetic nerves). Glucagon plays the primary role in restoration of normoglycemia, while neither growth hormone, cortisol nor norepinephrine contribute to immediate glucose homeostasis in these test situations. Epinephrine plays a secondary role in the process, and this is only important when glucagon secretion is deficient.
Patients with longstanding type I diabetes mellitus have a deficient glucagon response to insulin-induced hypoglycemia, and hypoglycemic responses to insulin would be particularly profound in those patients who may also be also taking beta blocker medication (diminished epinephrine response). While growth hormone and cortisol secretion do not play a role in the immediate recovery from insulin-induced hypoglycemia, patients with hypofunction in their secretion of cortisol (Addison’s Disease, Sheehan’s Syndrome) must be handled with greater care. These patients, as well as those with type I diabetes mellitus, and those receiving beta blocker therapy should be started with the 0.1U/kg dose, and observed carefully. As IPT therapy is usually done in a series of twice-weekly or weekly treatments, these subjects may have their insulin dose gradually increased in increments of 0.05U/kg at successive treatments, as tolerated.
The clinical experience with the IPT protocol has demonstrated that hypoglycemic symptoms have their onset approximately 25 to 30 minutes after the insulin administration. This timing corresponds to the nadir glucose concentration measured in the aforementioned studies. The actual timing by the clock of the onset of hypoglycemia is not as reliable as is clinical observation of hypoglycemic symptoms. Subjects characteristically experience adrenergic symptomatology at this time (sweating, tachycardia) and this is when a 25 cc quantity of 50 percent hypertonic glucose solution is administered – directly after administration of whatever drug therapy as indicated by the diagnosed condition being treated.
The administration of 50 percent hypertonic glucose has consistently proven effective in supporting the body’s physiological responses geared to reestablish normoglycemia (glucagon immediately, growth hormone and cortisol in the longer term). It has been consistently observed to be adequate to serve to avoid any of the more profound (neuroglycopenic) symptoms of hypoglycemia. The physician is in attendance at all times during an application of IPT. Patients are always prepared with ready access to a vein in order to receive supplementary intravenous glucose if necessary on account of any idiosyncratic reactions to insulin.
Blood glucose determinations by Accucheck are done three times during IPT treatments: in the fasting state before administration of the insulin; at the glucose nadir at 25 minutes; and after the recovery phase. Typical values here are 80 to 110 mg % for the initial and final readings, and 35 to 40 mg% at the nadir reading.
There are certain conditions that can alter individual reactivity to low blood glucose levels. The entry of glucose across the blood brain-barrier (BBB) and into the brain is mediated by an insulin-independent glucose transport protein (GTP).(49) The rate at which this BBB-GTP operates to transport glucose varies, as it is up-regulated or down-regulated according to blood glucose levels. The system gets up regulated during prolonged and repeated episodes of hypoglycemia,(50) which explains why certain individuals with insulinomas or chronic reactive hypoglycemia may not have symptoms of brain glucopenia at blood glucose concentrations well below 50 mg %. In a like fashion, the BBB-GTP is down-regulated during prolonged periods of hyperglycemia such as can occur with undiagnosed or poorly controlled type II diabetes.(51) When such patients are brought under rapid control with appropriate therapy, because of this down-regulation of the BBB-GTP, they may develop symptoms of brain glycopenia even though the blood glucose level is in the normal range.(52) These factors have to be kept in mind when interpreting the reactions certain individuals may have during their treatments with Insulin Potentiation Therapy
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12. Spring-Mills E, Stearns SB, Smith TH, et al. Immunoreactive hormones in human breast tissues. Surgery 94(6):946-950, 1983
13. Pavelik L, Pavelik K, Vuk-Pavlovic S. Human mammary and bronchial carcinomas: in vivo and in vitro secretion of substances immunologically cross-reactive with insulin. Cancer 53(11):2467-2471, 1984
14. Shames JM, Dhurandhar NR, Blackard WG. Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med 44:632-637, 1968
15. Kiang DT, Bauer GE, Kennedy BJ. Immunoassayable insulin in carcinoma of the cervix associated with hypoglycemia. Cancer 31:801-804, 1973
16. Pavelik K, Bolanca M, Vecek N, et al. Carcinomas of the cervix and corpus uteri in humans: stage-dependent blood levels of substance(s) immunologically cross-reactive with insulin. J Natl Cancer Inst 68:891-894, 1982
17. Pavelic K, Popovic M. Insulin and glucagon secretion by renal adenocarcinoma. Cancer 48:98-100, 1981
18. Oleesky S, Bailey I, Samos S, Bilkus D. A fibrosarcoma with hypoglycemia and a high serum insulin level. Lancet 2:378-380, 1962
19. Pavelic K, Odavic M, Pekic B, et al. Correlation of substance(s) immunologically cross-reactive with insulin, glucose and growth hormone in Hodgkin’s lymphoma patients. Cancer Lett 17:81-86, 1982
20. Bar RS, Roth J. Insulin receptor status in disease states of man. Arch Int Med 137:474-481, 1977
21. Pardridge WM. Receptor-mediated peptide transport through the blood brain barrier. Endocrine Reviews 7:314-330, 1986
22. McCall A, Chick W, Ruderman N. Chronic hypoglycemia increases brain glucose transport and glucose metabolism by brain microvessels. Abstract] Diabetes 32:25A, 1983
23. McCall AL, Millington WR, Wurtman RJ. Metabolic fuel and amino acid transport into the brain in experimental diabetes mellitus. Proc Natl Acad Sci USA 79:5406-5410, 1982
24. DeFronzo RA, Hendler R, Christensen N. Stimulation of counterregulatory hormonal responses in diabetic man by a fall ~n glucose concentration. Diabetes 29:125-131, 1980
25. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier insulin receptor. J Neurochem 44:1771-1778, 1985
26. Frank HJL, Jankovic-Vokes T, Pardridge WM, Morris WL. Enhanced insulin binding to blood-brain barrier in vivo and to brain microvessels in vitro in newborn rabbits. Diabetes 34:728-733, 1985
27. Ayre SG. New approaches to the delivery of drugs to the brain. Med Hypoth 29:283-291, 1989
28. Poznansky MJ, Singh R, Singh B, Fantus G. Insulin: Carrier potential for enzyme and drug therapy. Science 223:1304-1306, 1984
29. Yoshimasa S, et al. A New approach to the detection of autoantibodies against insulin receptors that inhibit the internalization of insulin into human cells.Diabetes 33:1051-1054, 1984
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32. Ayre SG, Skaletski B, and Mosnaim AD. The blood-brain barrier passage of azidothymidine: effect of insulin. Res Commun Chem Pathol Pharmacol 63(1):45-52, 1989
33. Cullen JK, Yee D, Sly WS, et al. Insulin-like growth factor receptor expression and function in human breast cancer. Cancer Res 50:48-53, 1990
34. Papa V, Pezzino V, Constantino A, et al. Elevated insulin receptor content in human breast cancer. J Clin Invest 86:1503-1510, 1990
35. Alabaster O, Vonderhaar BK, Shafie SM. Metabolic modification by insulin enhances methotrexate cytotoxicity in MCF-7 human breast cancer cells. Eur J Cancer Clin Oncol 17:1223-1228, 1981
36. Schilsky RL, Bailey BD, Chabner BA. Characteristics of membrane transport of methotrexate by cultured human breast cancer cells. Biochem Pharmacol 30:1537-1542, 1981
37. Eibl H. Phospholipids as functional constituents of biomembranes. Angew Chem Int Ed Engl 23:257-271, 1984
38. Jeffcoat R and Jame AT. The regulation of desaturation and elongation of fatty acids in mammals. Numa S. (Ed), Fatty Acid Metabolism and its Regulation. Elsevier Science Publishers BN. p.85-112, 1984.
39. Jeffcoat R. The biosynthesis of unsaturated fatty acids and its control in mammalian liver. Essays Biochem 15:1-36, 1979.
40. Zapf J, Froesch ER. Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role. Hormone Res 24:121-130, 1986
41. Lippman ME, Dickson RB, Kasid A, et al. Autocrine and paracrine growth regulation of human breast cancer. J Steroid Biochem 24:147-154, 1986
42. Hilf R. The actions of insulin as a hormonal factor in breast cancer. In: Pike MC, Siiteri PK, Welsch CW, eds. Hormones and Breast Cancer, Cold Spring Harbor Laboratory, 1981, 317-337.
43. King GL, Kahn CR, Rechler MM, Nissley SP. Direct demonstration for separate receptors for growth and metabolic activities of insulin and multiplication-stimulating activity (an insulin-like growth factor) using antibodies to the insulin receptor. J Clin Invest 66:130-140, 1980
44. Cryer PE. Glucose homeostasis and hypoglycemia. Williams RH (Ed), Textbook of Endocrinology. W.B. Saunders Company, Philadelphia, p. 989-1017, 1985.
45. Gerich J, Davis J, Lorenzi M, et al. Hormonal mechanisms of recovery from insulin-induced hypoglycemia in man. Am J Physio1236:E380-E385, 1979.
46. Cryer PE, Tse TF, Clutter WE, and Shah SD. Roles of glucagon and epinephrine in hypoglycemic and nonhypoglycemic glucose counterregulation in humans. Am J Physiol 247:E198-E205, 1984.
47. Rizza RA, Cryer PE, Gerich JE. Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. J Clin Invest 64:62-71, 1979
48. Clarke WL, Santiago JV, Thomas L, et al. Adrenergic mechanisms in recovery from hypoglycemia in man: adrenergic blockade. Am J Physiol 236:E147-E152, 1979.
49. Pardridge WM. Receptor-mediated peptide transport through the blood-brain. Endocrine Reviews 7:314-330, 1986
50. McCall A, Chick W, Ruderman N. Chronic hypoglycemia increases brain glucose transport and glucose metabolism by brain microvessels. (Abstract) Diabetes 32:25A, 1983
51. McCall A, Millington WR, Wurtman RJ. Metabolic fuel and amino acid transport into the brain in experimental diabetes mellitus. Proc Natl Acad Sci USA 79:5406-5410, 1982
52. DeFronzo RA, Hendler R, Christensen N. Stimulation of counterregulatory hormonal responses in diabetic man by a fall in glucose concentration. Diabetes 29:125-131, 1980
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Categories: Ask Your Doctor About, Chemotherapy, IPT | Tags: | No Comments »
Posted by Brad Weeks, MD on March 6, 2010
Dr. Weeks’ Comment: why not use a simple process which primes the cancer cells to be 10,000 times more vulnerable to chemo?
Seriously!
This protocol is 50+ years old and still being ignored.
Read carefully.
Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients.
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Cancer Chemother Pharmacol. 2004 Mar;53(3):220-4. Epub 2003 Dec 4
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Lasalvia-Prisco E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Gordon W.
Department of Medicine, School of Medicine, University of Uruguay, Montevideo, Uruguay. research@pharmablood.com
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PURPOSE:
It has been reported that insulin increases the cytotoxic effect in vitro of methotrexate by as much as 10,000-fold.
The purpose of this study was to explore the clinical value of insulin as a potentiator of methotrexate. PATIENTS AND METHODS: Included in this prospective, randomized clinical trial were 30 women with metastatic breast cancer resistant to fluorouracil + Adriamycin + cyclophosphamide and also resistant to hormone therapy with measurable lesions. Three groups each of ten patients received two 21-day courses of the following treatments: insulin + methotrexate, methotrexate, and insulin, respectively. In each patient, the size of the target tumor was measured before and after treatment according to the Response Evaluation Criteria In Solid Tumors. The changes in the size of the target tumor in the three groups were compared statistically. RESULTS: Under the trial conditions, the methotrexate-treated group and the insulin-treated group responded most frequently with progressive disease. The group treated with insulin + methotrexate responded most frequently with stable disease. The median increase in tumor size was significantly lower with insulin + methotrexate than with each drug used separately. DISCUSSION: Our results confirmed in vivo the results of previous in vitro studies showing clinical evidence that insulin potentiates methotrexate under conditions where insulin alone does not promote an increase in tumor growth. Therefore, the chemotherapy antitumoral activity must have been enhanced by the biochemical events elicited in tumor cells by insulin. CONCLUSIONS: In multidrug-resistant metastatic breast cancer, methotrexate + insulin produced a significant anti-tumoral response that was not seen with either methotrexate or insulin used separately.
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Study protocol: Insulin and its role in cancer.
Harish K, Dharmalingam M, Himanshu M.
ABSTRACT: BACKGROUND: Studies have shown that metabolic syndrome and its consequent biochemical derangements in the various phases of diabetes may contribute to carcinogenesis. A part of this carcinogenic effect could be attributed to hyperinsulinism. High levels of insulin decrease the production of IGF-1 binding proteins and hence increase levels of free IGF-1. It is well established that bioactivity of free insulin growth factor 1 (IGF-1) increases tumor turnover rate. The objective is to investigate the role of insulin resistance/sensitivity in carcinogenesis by studying the relation between insulin resistance/sensitivity and IGF-1 levels in cancer patients. We postulate that hyperinsulinaemia which prevails during initial phases of insulin resistance (condition prior to overt diabetes) increases bioactivity of free IGF-1, which may contribute to process of carcinogenesis. Methods / Design: Based on our pilot study results and power analysis of the same, we have designed a two group case-control study. 800 proven untreated cancer patients (solid epithelial cell tumors) under age of 50 shall be recruited with 200 healthy subjects serving as controls. Insulin resistance/sensitivity and free IGF-1 levels shall be determined in all subjects. Association between the two parameters shall be tested using suitable statistical methods.
DISCUSSION: Well controlled studies in humans are essential to study the link between insulin resistance, hyperinsulinaemia, IGF-1 and carcinogenesis. This study could provide insights to the role of insulin, insulin resistance, IGF-1 in carcinogenesis although a precise role and the extent of influence cannot be determined. In future, cancer prevention and treatment strategies could revolve around insulin and insulin resistance.
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Ann Surg Oncol. 1998 Mar;5(2):194-201.Links
Altered serum levels of insulin-like growth-factor binding proteins in breast cancer patients.
Ng EH, Ji CY, Tan PH, Lin V, Soo KC, Lee KO.
Department of Surgery, Singapore General Hospital, Republic of Singapore.
BACKGROUND: Insulin-like growth factor 1 (IGF-1) has mitogenic properties for breast cancer cell lines and has been proposed to be an important factor in breast carcinogenesis. We hypothesized that differences in IGF-1 or its binding proteins might increase susceptibility to breast cancer. This case-control study was designed to investigate whether patients with breast cancer have altered levels of either IGF-1 or its intermediary modulatory proteins, the IGF binding proteins (BP). METHODS: Serum was collected from 90 patients (63 with breast cancer and 27 with benign breast disease) after an overnight fast and before surgery. IGF-1, BP1, and BP3 levels were determined by immunoradiometric assays. In a subset of 66 patients, Western ligand blots were also performed for a semiquantitative measurement of functioning BP levels. A forward stepwise logistic regression model to adjust for other confounding variables (age, menopausal status, parity, age at menarche, use of oral contraceptives, history of breast biopsy, family history of breast cancer, hormone replacement therapy, and body-mass index) was used in the multivariate analysis.
RESULTS: Serum IGF-1 levels were similar in cases and controls. However, levels of BP3 (p < 0.001), BP4 (p < 0.01), and BP1 (p < 0.05) were significantly associated with risk of breast cancer. The level of BP3 was the most significant factor predictive of breast cancer. The odds ratio for breast cancer in women with BP3 levels >2066 ng/ml was 0.18 (95% CI, 0.05-0.55). Correspondingly, women with BP1 levels higher than 39 ng/ml had an odds ratio of 0.21 (95% CI, 0.07-0.68) for breast cancer. When considering only cancer patients (n = 63), decreasing levels of BP4 (p < 0.01) and increasing levels of BP1 (p < 0.02) were significantly associated with progesterone receptor positivity (PR+) in the tumor. The odds ratio of PR+ in patients with BP1 levels higher than 34 ng/ml was 7.49 (95% CI, 1.5-37.4). Better grade of tumor (well and moderately differentiated) was observed in patients with higher levels of BP3 (p < 0.03).
CONCLUSIONS: Distinct differences in BP profiles exist among patients with breast cancer and also among those with high-grade, hormonal receptor-negative tumors. These findings suggest that the bioavailability of IGF-1 as mediated by its binding proteins may participate in both breast carcinogenesis and selection of more aggressive breast carcinomas.
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Advanced breast cancer: anti-progressive immunotherapy using a thermostable autologous hemoderivative.
Breast Cancer Res Treat. 2006 Nov;100(2):149-60. Epub 2006 Jul 4.
Lasalvia-Prisco E, Garcia-Giralt E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Larrañaga J.
PharmaBlood Inc, Research & Development Department, 2050 NE 163rd Street, # 202, North Miami Beach, Florida 33162, USA. research@pharmablood.com
INTRODUCTION: Advanced breast cancer patients, acquired-chemotherapy resistant and in progression, are therapeutically terminal. We tested a recently described medical procedure using a thermostable autohemoderivative purported to inhibit tumor growth possibly through an immunological mechanism of action. PATIENTS AND METHODS: Metastatic breast cancer patients, chemotherapy-resistant, high CEA and CA 15-3 plasma levels of tumor markers, in progression, were 2-group randomized. Group 1 received the test procedure and Group 2 adequate measures to be comparable control. From 121 included patients, 108 could be evaluated. During 8-month follow-up period, tumor growth, number of cases attaining clinical non-progressive status and mortality were monthly assessed. Immunologic effect was assessed by delayed type hypersensitivity test and lymphocyte proliferation assay. Responding-tumors histopathologies were studied. The proteome of the autologous immunogen was characterized by 2-D electrophoresis. RESULTS AND DISCUSSION: In a significant number of cases, the test procedure promoted inhibition of tumor growth, non-progressive disease status, and lower cumulative mortality. These clinical results were associated with polyvalent immunization against several tested antigens: the hemoderivative used for treatment, the blood tumor markers and the derivative obtained from a regulatory lymphocyte population (CD4+CD25+). Interference with this regulatory activity could explain the selective autoimmunity suggested by the histopathology findings in responding tumors. The thermostability could be an essential property of the immunogen hemoderivative. CONCLUSION: The thermostable autohemoderivative tested is antigenically polyvalent and promoted a polytargeted immune response associated to a tumor anti-progressive effect, consequently, acting as an autohemoderivative cancer vaccine.
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Advanced colon cancer: antiprogressive immunotherapy using an autologous hemoderivative.
Med Oncol. 2006;23(1):91-104.
Lasalvia-Prisco E, Garcia-Giralt E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Larrañga J.
Department of Research & Development, PharmaBlood Inc, 2050 NE 163rd Street, # 202, North Miami Beach, Florida 33162, USA. research@pharmablood.com
INTRODUCTION: Advanced colon cancer patients, acquired-chemotherapy resistant and in progression, are therapeutically terminal. We tested a recently described medical procedure using a thermostable autologous hemoderivative purported to inhibit tumor growth possibly through an immunological mechanism of action. PATIENTS AND METHODS: Metastatic colon cancer patients chemotherapy-resistant, high CEA plasma levels, in progression, were 2-group randomized. Group 1 received the test procedure and Group 2 adequate control measures. During an 8-mo follow-up period (n = 101), tumor growth, number of cases attaining clinical nonprogressive status, and mortality were assessed monthly. Immunological effect was assessed by delayed-type hypersensitivity test and lymphocyte proliferation assay. Responding-tumors histopathologies were studied. RESULTS AND DISCUSSION: In a significant number of cases, the test procedure promoted inhibition of tumor growth, nonprogressive disease status, and lower cumulative mortality. These clinical results were associated with polyvalent immunization against several tested antigens: the hemoderivative used for treatment, the blood tumor markers, and the regulatory lymphocyte population (CD4+CD25+). Interference with this regulatory activity could explain the selective autoimmunity suggested by the histopathology findings in responding tumors. CONCLUSION: The autologous hemoderivative tested is antigenically polyvalent and promotes a polytargeted immune response associated with a tumor antiprogressive effect, consequently, acting as an autologous hemoderivative cancer vaccine.
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Antitumoral effect of a vaccination procedure with an autologous hemoderivative.
Cancer Biol Ther. 2003 Mar-Apr;2(2):155-60.
Lasalvia-Prisco E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Gordon W.
School of Medicine, University of Uruguay, Uruguay. telemedical@pharmablood.com
Lately, the promising results obtained with autologous cancer vaccines are stimulating new research in the old field of cancer immunotherapy. This paper describes the development of a procedure previously reported by us that is used to obtain an autologous hemoderivative with antitumoral properties. The procedure has been tested in a phase I-II, randomized, controlled clinical trial of 28 cancer patients with different primary malignancies in metastatic and chemotherapy-resistant stages. The histology of the lesions that responded to this treatment was consistent with the characteristic histology observed in malignant lesions treated with a similar antitumoral hemoderivative: proliferation of stromal connective tissue, T-lymphocyte infiltration, and a reduction in the amount of tumor cells and blood vessels. We concluded that vaccination had elicited an immune response because a delayed-type hypersensitivity test made with the autologous hemoderivative produced a significantly more intense response in the responding treated patients. We propose that an immune mechanism acting on tumor cells and/or the regulatory system for stromal growth explains the histological results observed. The use of blood to obtain the immunogen allows vaccination to be repeated, so this method could avoid tumor escape responses due to mutations in the antigen library of the tumor. The results of our study justify further research to optimize the antitumoral effect of vaccination.
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Serum markers variation consistent with autoschizis induced by ascorbic acid-menadione in patients with prostate cancer.
Med Oncol. 2003;20(1):45-52.
Lasalvia-Prisco E, Cucchi S, Vázquez J, Lasalvia-Galante E, Golomar W, Gordon W.
School of Medicine, University of Uraguay, Montevideo, Uriguay. telemedical@pharmablood.com
In vitro exposure of malignant prostate cell lines to ascorbic acid-menadione showed that tumor cells were killed through a mechanism named autoschizis. Experimental animal studies showed that autoschizis is also evident when ascorbic acid-menadione is administered to nude mice with implanted human prostate tumors. Prostate-specific antigen (PSA) is a known serum marker of prostate tumor cells specific activity. Recently, total serum homocysteine has been identified as a marker of tumor cell numbers with sensitivity for early detection of tumor cell death induced by treatments. A clinical trial with prostate cancer patients submitted to the association of ascorbic acid-menadione was performed and PSA/homocysteine was assessed in the follow- up. The early response in serum PSA and homocysteine levels was reported. The results showed that ascorbic acid-menadione produced an immediate drop in tumor cell numbers as assessed by homocysteine levels. Serum PSA levels showed an early rise and later dropped. These results suggest that autoschizis can also be induced by this pharmacological association at the clinical level in prostate cancer patients. Further studies are being performed in order to research if these results can be found with other primary tumors as it was shown in in vitro and experimental models. Ascorbic acid-menadione could be emerging as a new antitumoral chemotherapy.
Categories: Cancer, IPT | Tags: | No Comments »
Posted by Brad Weeks, MD on March 6, 2010
Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis.
Bjelakovic G, Nikolova D, Simonetti RG & Gluud C
The Lancet 364;1219-1227,2004
Problems:
1) underdosing
2) already had cancer
These authors reviewed all the randomized trials comparing anti oxidant supplements with placebo for prevention of gastrointestinal cancers. They found little evidence that the anti oxidants they studied prevent these cancers. But they carefully hedged their conclusions with the statement that these anti oxidants alone or in combination “do not seem to have much effect”. They are correct to have been so careful since the claims made that these anti oxidants did have some preventive effect were based upon doses of some of these anti oxidants that were substantially larger than those used in these studies .
The studies used beta carotene 15 to 50 mg daily, vitamin A 1.5 to 15 mg. According to these authors only beta carotene increased morbidity. But this was based on only two large studies involving men who were heavy smokers and some had been exposed to asbestos whereas a third study on physicians who were non smokers did not shows any toxic effect from the beta carotene. Most of the studies with beta carotene found a relationship. The Finnish Antioxidant and Lung Cancer study appeared to show an increase in the incidence of lung cancer. But this is not what the dozens of authors of this study concluded. They found that beta carotene did not decrease the incidence of lung cancer. On the contrary there was a statistically insignificant increase in the beta carotene group. It is therefore very important to know exactly the method used in this study.
They used a large population of male smokers ages 50 to 69. One group was given the synthetic dl-alpha tocopherol. Another group was given 20 mg of beta carotene, a third group was on placebo, and the fourth group received both antioxidants. All the subjects smoked 5 or more cigarettes daily for over 35 years. They were followed for 5 to 8 years. But the beta carotene group smoked one year more than the control group. How significant is one year more of heavy smoking in increasing the number of advanced lung cancers. The authors do not discuss this.
At the end of the study men in the placebo group with the highest blood levels of these two antioxidants had the lowest incidence of lung cancer. In the dl-alpha tocopherol group there was a insignificant 2% reduction in incidence of lung cancer (P = 0.8). In the beta carotene group there was an 18% increase in incidence. Out of 14,560 men on beta carotene, 474 developed cancer, while out of 14,573 men not on beta carotene 402 did. The incidence increased from 2.76% for the control group to 3.26% for the treated group. I suggest that this minor difference is surely not of clinical significance, even though it is statistically significant. In this statistically sophisticated study dividing 3.26 by 2.76, yields the much larger number of 18 percent which appears enormous and will be the only figure the unwary reader will remember and probably the only figure which will be used by the popular press. With large sample sizes such as these, a minor variation becomes fully blown up to a major finding.
There must have been something very odd about that Finnish group of men. For one thing, the authors reported that 34% of the men on beta carotene developed yellow skin. This is totally foreign to my experience. I have started at least 500 subjects on this amount of beta carotene and more, and have never seen any yellowing of the skin with this dose but have seen some with higher doses. Does this mean that these heavy smokers had so compromised their livers that they could not deal even with normal doses of beta carotene? The authors do point out the many possible factors which might have given them these results, and in an editorial in the same issue the commentators also refer to them. These authors write ” Finally, study findings regarded as showing supplementation to be beneficial or harmful may occur by chance”.
I consider that this study simply proved nothing, except that if you give tiny doses of Vitamin E nothing will happen, and if you give heavy chronic smokers 20 mg of beta carotene their incidence of lung cancer will not change. Challem re-analyzed the Finnish study and concluded that alcohol, synthetic beta carotene and hasty conclusions may have created the study fiasco.
Cancer is probably present and undetectable in patients for a long time, perhaps many years, before it is finally discovered. The truly preventive study should therefore start long before any tumors have started, which could mean many years. With this group of heavy smokers it is certain that a large fraction already had the cancer. This was therefore a mixed study consisting of (1) treatment for those already with cancer, (2) prevention for those who did not have any. Unfortunately, it will never be possible to say how much each group contributed. I would suggest that future studies start with a much younger population in whom there is much less chance of already having cancer.
The protective effect of dietary vitamin A against cancer was reported in 1975. Since then a large number of studies have consistently shown that higher levels of vitamin A in food are associated with decreased incidence of cancer. In vitro and animal studies have also found that vitamin is protective against cancer. Vitamin A supplements have been used to potentiate the action of chemotherapy. There has been no outcry against using this antioxidant in combination with chemotherapy. In Japan investigators used vitamin A, 5FU and cobalt-60 radiation to hundreds of patients with head and neck tumors. The combination was very effective. Head and neck tumors are particularly difficult to treat. In a study in Vancouver, Canada 60 mg/week (nearly 200,000 IU) for 6 months led to complete remission in oral precancerous lesions in 57% of the cases.
From a survey of the literature Goodman concluded, “that vitamin A and carotenoids are of considerable importance to the prevention and treatment of many diverse cancers. In addition they are potentially valuable in potentiating and mitigating against many of the toxic effects of radiotherapy and chemotherapy”.
Furthermore the Lancet review found that beta carotene in combination with other nutrient did not increase over all mortality. The title of their paper should have been “The antioxidant supplement beta carotene may increase morbidity but the other nutrient anti oxidants do not”.
Ascorbic acid 120 to 2000 milligrams was the dose range used. For ascorbic acid the usual dose range for treating cancer is 10 grams and more orally daily and up to 125 grams intravenously over a five to six hour period two or three times each week. They reported that vitamin C did not increase overall mortality. I will now add this Lancet report to my list of references which show that vitamin C is not harmful to cancer patients.
Vitamin E 30 to 600 milligrams. The more common doses of the water soluble form of vitamin E succinate 800 IU daily and with selenium from 400 mcg to 600 mcg and in a few studies even more. The Lancet report does not tell us which vitamin E was used. It has been known for some time that the fat soluble form does not have any anti cancer properties. These studies are typical of the many older studies where investigators wedded to the old paradigm used very small doses of these anti oxidants. They did find a little evidence that selenium, also an anti oxidant, might have had some protective effect. So how could the authors conclude that “they found little evidence that the anti oxidants prevented cancer. They should have written that they found little evidence that the anti oxidants they tested and listing each one by name has little effect and that the anti oxidant selenium did shows some effect. Thus in one trial selenium decreased the incidence of hepatocellular cancer in high risk subjects as in at risk families or in patients with hepatitis B surface antigen.
Selenium dose range 50 to 228 mcg. In this report selenium comes off nearly as OK and perhaps having some preventive properties. Of course they do not review the large number of selenium studies which do show it has major anti cancer effects.
There is also a problem in downgrade smaller studies as compared to the large ones. They assume that the larger the study the more accurate are the observations. With this I totally disagree. The smaller studies that they downgraded and paid less attention to were probably done by researchers who did not have the clout of money to conduct large scale studies and they were probably more motivated to really examine these substance seriously. They would certainly have used quantities that were within the higher dose range. But the authors do not supply this data.
And there is another problem with their data. Were they really testing the protective properties of these substances. Even if none of the subjects had diagnosed cancers, how many were in the nascent phase of cancer. Cancer does not suddenly spring forward from nothing. It take many years to become obvious and it is certain that many of their subjects were already suffering from undiagnosed cancers. To really test prevention they should start with completely healthy people. Or they might define prevention more carefully by calling it inhibition or a slowing down not prevention. And with the design they used there can be no answer. It still remains open. The doses they used were not within the recognized therapeutic dose range as reported by studies that claimed some effectiveness. This is best known for vitamin C were 2000 milligram daily is totally inadequate.
I find even more troublesome the fact that the authors do not understand vitamins. They lump them all as anti oxidants which they are but that does not make them identical in every way. Elephants and mice are mammals but they do have certain clear cut differences. If the term anti oxidant had not been invented this report could not have appeared. It became a substitute for vitamins. For many years vitamins were so stigmatized that physicians were fearful of using them, as many still are. But they were less fearful of using the same vitamins if they were called anti oxidants. Too many are not aware that even though they have anti oxidant properties they also have many other properties which make them unique. Thus vitamin C and Vitamin E are anti oxidants. But only vitamin C will prevent and cure scurvy. Each one has its own unique properties. Biochemical specificity is very precise This must not be ignored. Vitamin B-3 is used to maintain the pyridine nucleotide cycle and is the pellagra preventive and treatment substance. It has remarkable oxidant and anti oxidant properties. It will not cure scurvy nor will ascorbic acid cure pellagra. To lump all these vitamins together Becuae they are anti oxidants makes as much sense as lumping all mammals together with resect with their ability to play basketball, or chase deer or eat rabbits. It is like expecting a small overgrown country trail being as easy to drive on at high speed as a super highway. The are both roads and one drives on them. One has to be vry careful of these ways of classifying things or events. One characteristic does not make them all alike. The term anti oxidant should never have been used and each nutrient should have been examine in its own right.
The authors review found that the three anti oxidants beta carotene, vitamin E, vitamin C did not protect against cancer. But 95% of the studies used single substances. Only 5% used any combination and there is no evidence how many used all three. In cell studies any one of the tree used alone might inhibit cell growth, have no effect of increase it but when all three were used in combination there was always a decrease in cell growth of cancer cells. In my series of over 1300 cases I never used any of the oxidants alone. I used vitamin C, vitamin E and selenium. But even these authors conclusions are correct their descript is incorrect because they lump them all together and excluded selenium which is also an anti oxidant. They reported that only patients given vitamin A and its recourse beta carotene .They reported that vitamin C separately or in combination even with Beta carotene showed no significant effect on overall mortality , nor did /Vitamin E.
And finally having concluded that beta carotene is the only one which may be toxic, having found that vitamin C, vitamin E and selenium are not toxic, they concluded that all anti oxidants are toxic and using some very elaborate fancy mathematical foot work they show that out of every million people on anti oxidants 9000 premature deaths will occur. They claim that if every United States citizen (300 million) were taking these supplements there would be nearly 3 million premature deaths???? They imply that anti oxidants are more dangerous than Viox. And they imply vitamin E, and Vitamin C are toxic factors even though they state in the report with no reservation that they are safe.
Article
Antioxidant supplements for preventing gastrointestinal cancers.
Bjelakovic G, Nikolova D, Simonetti R, Gluud C.
The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research,, Dept. 7102, H:S Rigshospitalet, Copenhagen University Hospital,, Blegdamsvej 9,, DK 2100 Copenhagen, DENMARK.
BACKGROUND: Oxidative stress may cause gastrointestinal cancers. The evidence on whether antioxidant supplements are effective in preventing gastrointestinal cancers is contradictory.
OBJECTIVES: To assess the beneficial and harmful effects of antioxidant supplements in preventing gastrointestinal cancers.
SEARCH STRATEGY: We identified trials through the trials registers of the four Cochrane Review Groups on gastrointestinal diseases, The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE, EMBASE, LILACS, and SCI-EXPANDED from inception to February 2003, and The Chinese Biomedical Database (March 2003). We scanned reference lists and contacted pharmaceutical companies. SELECTION CRITERIA: Randomised trials comparing antioxidant supplements to placebo/no intervention examining the incidence of gastrointestinal cancers.
DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. The outcome measures were incidence of gastrointestinal cancers, overall mortality, and adverse events. Outcomes were reported as relative risks (RR) with 95% confidence interval (CI) based on fixed and random effects meta-analyses.
MAIN RESULTS: We identified 14 randomized trials (170,525 participants), assessing beta-carotene (9 trials), vitamin A (4 trials), vitamin C (4 trials), vitamin E (5 trials), and selenium (6 trials). Trial quality was generally high. Heterogeneity was low to moderate. Neither the fixed effect (RR 0.96, 95% CI 0.88 to 1.04) nor random effects meta-analyses (RR 0.90, 95% CI 0.77 to 1.05) showed significant effects of supplementation with antioxidants on the incidences of gastrointestinal cancers. Among the seven high-quality trials reporting on mortality (131,727 participants), the fixed effect (RR 1.06, 95% CI 1.02 to 1.10) unlike the random effects meta-analysis (RR 1.06, 95% CI 0.98 to 1.15) showed that antioxidant supplements significantly increased mortality. Two low-quality trials (32,302 participants) found no significant effect of antioxidant supplementation on mortality. The difference between the mortality estimates in high- and low-quality trials was significant by test of interaction (z = 2.10, P = 0.04). Beta-carotene and vitamin A (RR 1.29, 95% CI 1.14 to 1.45) and beta-carotene and vitamin E (RR 1.10, 95% CI 1.01 to 1.20) significantly increased mortality, while beta-carotene alone only tended to do so (RR 1.05, 95% CI 0.99 to 1.11). Increased yellowing of the skin and belching were non-serious adverse effects of beta-carotene. In four trials (three with unclear/inadequate methodology), selenium showed significant beneficial effect on gastrointestinal cancer incidences. REVIEWERS’ CONCLUSIONS: We could not find evidence that antioxidant supplements prevent gastrointestinal cancers. On the contrary, they seem to increase overall mortality. The potential cancer preventive effect of selenium should be studied in adequately conducted randomised trials.
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Posted by Brad Weeks, MD on March 6, 2010
Insulin Potentation Therapy – Treatment at a Glance
By Dr. Steven Ayre
Insulin Potentiation Therapy (IPT) manipulates the mechanisms of malignancy to therapeutic advantage by employing insulin as a biologic response modifier of cancer cells’ endogenous molecular biology. The autonomous proliferation of malignancy is supported by autocrine secretion of insulin for glucose/energy uptake by cancer cells, and a similar autocrine and/or paracrine elaboration of cellular factors to stimulate cancer growth. Amongst these, the insulin-like growth factors have been identified as the most potent mitogens for cancer cells. Of primary importance for IPT, cancer cell membranes also have six times more insulin receptors and ten times more IGF receptors, per cell, than the membranes of host normal tissues. Further, insulin can cross-react with and activate cancer cell IGF receptors. Thus, per cell, cancer has sixteen times more insulin-sensitive receptors than normal tissues. As ligand effect is a function of receptor concentration, these facts serve to differentiate cancer from normal cells – a vital consideration for the safety of cancer chemotherapy.
In light of these revelations, exogenous insulin acts to enhance anticancer drug cytotoxicity, and safety, via 1) a membrane permeability effect to increase the intracellular dose intensity of the drugs, 2) an effect of metabolic modification to increase the S-phase fraction in cancer cells, enhancing their susceptibility to cell-cycle phase-specific agents, and 3) an effect of biochemical differentiation based on insulin receptor concentration that focuses the first two insulin effects predominantly on cancer cells, sparing host normal tissues. Significantly less drug can thus be targeted more specifically and more effectively to cancer cell populations that are more susceptible to the chemotherapy drug effects, all this occurring with a virtual elimination of the dose-related side effects of these powerful drugs.
Because of this favorable side effect profile, cycles of low-dose chemotherapy with IPT may be done more frequently. There is good patient acceptance of the hypoglycemic side effect of insulin in this protocol, and the “rescue phenomenon” occasioned by the timely administration of hypertonic glucose actually serves to provide patients with an experiential metaphor for the rapid recovery of their well being. It is acknowledged that cancer treatment can often be debilitating for patients. In those undergoing treatment with IPT, an overall gentler experience promotes their concurrent use of other important elements in a program of Comprehensive Cancer Care, which includes nutrition for immune system support, and mind-body medicine to support a healing consciousness.
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