Recently, the Journal of Clinical Oncology reported that an increasing number of cancer patients are using complementary therapies, such as Controlled Amino Acid Therapy (CAAT), as part of their treatment regimen.1 The effectiveness of biological targeted therapies such as CAAT that interfere with specific cancer cell functions, causing them to die, has also been reported:
- Albert B. Lorincz, M.D., formerly of the University of Chicago, conducted several trials with mice, reducing tumor size in most of them who took dietary preparations reduced in the amino acids phenylalanine (Lofenalac) and in this amino acid as well as in tyrosine (Product 3200AB, both by Mead Johns Laboratories, Evansville, IN). His use of a phenylalanine-restricted diet in an ovarian cancer patient in particular showed a remarkable reduction in tumor size even though the tumor was not amenable to control by hormonal substances. This dietary approach to the treatment of cancer is similar to that employed by CAAT.2
- Chi Van Dang, M.D., Ph.D., of the Johns Hopkins School of Medicine, and Douglas Spitz, Ph.D., of the University of Iowa, report how carbohydrate deprivation, a part of the CAAT protocol, kills cancer cells while having no effect on normal cells.3
- Marco Rabinovitz, Ph.D., formerly of the National Cancer Institute, reports that amino acid deprivation, such as CAAT, inhibits the working of phosphofructokinase, thereby shutting down energy supply to cancer cells and enhancing the benefits of chemotherapy.4
It is now evident that not only drugs, but specific biological compounds, such as those employed by CAAT, can attack cancer cell functions.
CAAT is an amino acid– and carbohydrate-deprivation therapy, using scientifically formulated amino acids, that arrests the growth of tumors and causes them to regress by altering or impairing the development of cancer cells. It is a six- to-nine month course of therapy (on average) that enhances chemotherapy and/or radiation, as well as lessening their toxic effects. CAAT, which is designed to be taken in the comfort of one's home, has also been proven to be effective alone.
The latest integrative medicine research findings showing how effective CAAT can be in fighting cancer were presented in April 2002 at a conference sponsored by the Harvard School of Medicine and in July 2002 at the American Institute for Cancer Research in Washington, DC.
Other pages on this Web site present a more detailed explanation of CAAT. Please feel free to call us with any questions. We look forward to the opportunity to work with you and your patients.
Sincerely,
The Team here at APJCP
Promising Weapons for Biological Warfare against Cancer
Abstract
To attack cancer, scientists now combine old and new modalities. The latest research relates the biochemistry of both normal and malignant cells to diet, nutrients, phytochemicals, and herbs. This promising biological approach, which involves the use of phytochemicals and herbs and the deprivation of carbohydrates and certain amino acids, resembles chemotherapy because it inhibits DNA and protein synthesis and angiogenesis, the formation of blood vessels, and also curtails mitotic signal transduction receptors on the cellular membranes of cancer cells. This latter process affects receptor regions common to numerous tumor growth factors (TGFs). Thus this new modality not only can enhance conventional medicine, it also allows oncologists the option to treat cancer patients with less toxic therapies.
Introduction
In 2011, about 571,950 Americans are expected succumb to cancer in this country.5 Most deaths will occur in patients who develop inoperable, especially metastatic, cancers. Conventional medicine alone simply cannot save the lives of most cancer patients if their tumor(s) cannot be totally excised from their bodies.6,7,8 Therefore, what is urgently needed is some compound(s) or protocol(s) that can work synergistically with conventional medicine to manage inoperable cancers successfully.
Cancer science evolving over the past several years reports on the work of natural biological weapons to target specific sites on cancer cells. This promising research, which involves diet, nutrients, phytochemicals, and herbs, opens entirely new pathways to attack cancer cells at their weakest biological points.
It is now possible to design numerous biological and therapeutic protocols that can bolster the benefits of conventional therapy. This possibility allows oncologists an option to reduce the high, often toxic amounts of drugs or radiation therapy required to provide patients with maximum benefits.
Outlined here is a model, Controlled Amino Acid Therapy or CAAT for short, that can serve as a possible therapeutic biological protocol to combat cancer. This model reduces certain nutrients in the daily diet of cancer patients, such as specific amino acids, carbohydrates, vitamins B6 (pyridoxine) and folic acid, and phosphorus. The reasons prevailing science upholds the concept of a biological-deprivation diet to benefit cancer patients are elaborated below.
An Amino Acid–Deprivation Diet as the First Half of the CAAT Protocol
Amino acids are the building blocks of all proteins. Twenty amino acids are necessary to sustain human life:
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The ten amino acids appearing in bold face above are called essential amino acids because the body does not synthesize them and thus they must be supplied by the daily diet; the remaining ones are called nonessential amino acids because they are synthesized in the body. Our CAAT Protocol contains seven essential amino acids.
Genes and chromosomes dictate the kind of proteins each cell will manufacture, using different combinations of amino acids. Some proteins, such as glutathione, contain only three amino acids: glycine, glutamic acid, and cysteine. Other proteins may contain as many as a hundred or more amino acids in their molecules. These proteins not only form the major components of the human cell structure but, in the form of enzymes and hormones, control literally every chemical or metabolic reaction that occurs in cells during daily life.
Reasons Reducing Amounts of Certain Nutrients, Especially Amino Acids, Helps Fight Cancer
Before one cancer cell can grow and divide, it must first synthesize and double its DNA content. Four amino acids are essential to DNA synthesis: glycine, glutamic acid, aspartic acid, and serine.9 Many of the most effective chemotherapeutic drugs, such as 5-fluorouracil (5-FU or Adrucil®), work by preventing cancer cells from synthesizing normal DNA. An amino acid–deprivation diet, by decreasing the precursor pool of any of these four nonessential amino acids, can therefore work alone or synergistically with numerous chemotherapeutic drugs to inhibit DNA synthesis in cancer cells. However, because the body can synthesize each of the four amino acids mentioned above, it would be very difficult to reduce the precursor pool of all four at the same time simply by reducing their amounts in the daily diet.
The CAAT model therefore concentrates on the depletion in the body of only one of the four amino acids, glycine. A glycine deficiency alone can inhibit DNA synthesis. The CAAT model contains a formula of amino acids that replaces most regular protein foods at lunch and dinner. It creates a deficiency in the amino-acid precursor pool in the patient’s body. The diet, also low in carbohydrates and certain other nutrients, is adequate in calories to sustain desirable body weight. The amino-acid formula contains an additive, sodium benzoate, that further deprives cancer cells of glycine. The liver uses glycine to detoxify and eliminate sodium benzoate from the body.10 Therefore, when added to the CAAT amino acid formula in nontoxic but physiological quantities, sodium benzoate helps deplete glycine in the body.
An amino acid–deprivation diet can stop the growth of cancer cells because proteins are the major structural components of almost all cells, including cancer cells. Before a cancer cell can divide, it must double both its DNA and its entire protein content. Here again, reducing the precursor pool of certain amino acids—especially any of the essential amino acids—can impede the cancer cell’s ability to produce sufficient proteins to self-replicate. An amino acid–deprivation diet also inhibits the tumor's use of angiogenesis to grow. Depriving cancer cells of glycine affects the building of new blood vessels because blood vessels are composed primarily of proteins. One protein absolutely essential to the manufacture of new blood vessels is elastin.11
Elastin contains five amino acids—glycine, proline, leucine, isoleucine, and valine.12 Twenty-five percent of the elastin molecule consists of glycine. Cancer cells have an extra requirement for these five amino acids, compared with normal cells,13 indicating that they depend much more on angiogenesis for their growth and reproduction than normal cells do. This is understandable, since normal cells have a built-in system of blood vessels and do not need to build as many new ones as cancer cells do.
The amino acid–deprivation diet also thwarts the growth of cancer cells by inhibiting their production of various TGFs. Almost every malignant tumor requires these TGFs for growth and metastasis; normal cells do not have the same necessity. With the exception of steroid hormones, almost all TGFs, such as epithelial growth factor, hepatocyte growth factor (HGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), and the Ras gene protein growth factor, are proteins composed of amino acids. Again, reducing any essential amino acid in the daily diet can affect protein synthesis and therefore the production of TGFs in the body as well.14,15
Trials of the amino acid–deprivation diet to reduce cancerous tumor growth have taken the therapy far beyond the theory stage. Over the years, besides in vitro studies, numerous studies with laboratory animals and humans have reported reduced tumor size and improved quality of life for most subjects treated with deprivation diets.
Earliest studies with amino-acid deprivation diets occurred in the early 1940s. In 1944, Kocher 16 reported in Cancer Research that a lysine-deprivation diet failed to stop the growth of cancers in laboratory animals. White,17 working with cysteine, also reported no benefits in treating cancer in laboratory animals with the amino-acid deprivation diet. In those days, all of the amino acids had not been isolated in pure form, and scientists could study only the ones available at the time.
However, in 1965, Lorincz reported in the Nebraska Journal of Medicine a reduced tumor size in cancerous animals treated with a phenylalanine-deprivation diet.18 In 1966, he reported similar findings in the Federation Proceedings19 In 1967, in the Journal of the American Medical Association, Lorincz published a further study showing the benefits to cancer patients taking a diet low in phenylalanine.20 In 1969, he reported the benefits of treating advanced cancer patients with a diet restricted in the amino acids phenylalanine and tyrosine.21
During these same years, numerous studies, published by Demopoulos and other investigators, showed benefits of treating cancer patients with diets low in phenylalanine and tyrosine.22, 23, 24, 25 In the early 1980s, Meadows and other researchers (probably unaware of studies undertaken by the scientists mentioned above) also reported the benefits of treating cancerous animals with amino acid–deprivation diets.26
A Carbohydrate-Deprivation Diet as the Second Half of the CAAT Protocol
The second part of the CAAT model includes a carbohydrate-deprivation diet. Lee27 and Spitz28 and their teams list more than 20 studies supporting their discovery that a glucose-deprivation diet causes apoptosis (cell death) in cancer cells. Consider also that use of the positron emission tomography (PET) scan to detect or monitor cancer is based on the fact that cancer cells feed almost exclusively on glucose for their major source of energy.
The benefits that can be derived by reducing the amount of carbohydrates in the diets of cancer patients are now compelling because it has been established that most cancers depend largely on carbohydrates or glucose as their major fuel source.29 A paper in Medical Hypotheses 30 details why cancer cells cannot burn carbohydrates or fats in their mitochondria, as do normal cells, but must rely almost exclusively upon glycolysis and the metabolism of glucose for their daily energy. Most energy for normal cells comes from the burning of fats, carbohydrates, and amino acids in the Krebs cycle. Cancer cells, however, must extract almost all their energy from glycolysis, a process that utilizes only glucose. Lee and others have shown that cancer cells enter apoptosis when deprived of glucose.
Several other studies have reported the therapeutic action of caloric reduction on malignant tumors in animals. Kritchevsky, for example, reports that in laboratory animals, cancerous tumors regress when their caloric intake is reduced by 10 percent—and are even eliminated from the body when the carbohydrates are reduced by 40 percent.31
Another means to impair the metabolism of cancer cells and deprive them of energy is to inhibit the working of phosphofructokinase, an enzyme that plays a key role in glycolysis.32, 33 Citric acid and ketones have been reported in textbooks to inhibit the activity of this enzyme. The addition of citric acid in nontoxic but physiological amounts to the CAAT amino acid formula can help impair glycolysis and increase the benefits of the CAAT protocol. A diet low in carbohydrates can increase the amount of ketones in the blood and thus helps inhibit the workings of phosphofructokinase and glycolysis, robbing cancer cells of their energy needs.34
Prevailing science now shows that numerous phytochemicals and herbs can also serve as biological weapons to combat cancer. These are included in the CAAT model. Such biological weapons include tocotrienols, limonene, curcumin, and green tea.
Specific areas targeted with such weapons include receptor regions common to numerous TGFs. Cancer cells use these receptor regions to transmit mitogenic signals into their nuclei. Some TGFs are tyrosine kinase (TK), the Ras protein, EGF, and IGF-1.35
Tocotrienols, found in certain vegetable oils and olive oil, belong to the vitamin E family. In cancer cells, they exert their antimitogenic effects by impairing a process called isoprenylation (also called prenylation or lipidation, is the addition of hydrophobic molecules to a protein in order to facilitate its attachment to the cell membrane), 36 which is essential to activate the receptor regions of EGF, TK, and the Ras protein.37 D-Limonene contained in citrus fruits, can also curtail the activity of these three mitogens. 38 Curcumin, the active substance in the herb turmeric, is reported to have a powerful inhibitory effect on the activity of TK and protein kinase.39 Green tea contains a compound called epigallocatechin-3-gallate (EGCG). This substance shuts down the maleate–aspartic acid shuttle, a major function involved in conversion of glucose into energy during glycolysis.40
Dietary deprivation or restriction of the vitamins B6 and folic acid and phosphorus are further valuable components of the proposed CAAT model. Because folic acid is essential to DNA synthesis, its deprivation in the diet can help inhibit DNA synthesis in cancer cells. The chemotherapeutic drug, Trexall or Rheumatrix (methotrexate), works similarly by preventing cancer cells from utilizing folic acid, thereby inhibiting DNA synthesis.
The body utilizes pyridoxine to synthesize nonessential amino acids, including glycine. Its restriction in the diet can also help impair the synthesis of DNA and the amino acids necessary for cancer cells’ growth and reproduction. Phosphorus is an essential constituent of adenosine triphosphate (ATP), guanosine 5′-triphosphate (GTP), uridine 5′-triphosphate (UTP) and cytidine triphosphate (CTP), all of which together control the function of every metabolic reaction that occurs in every cell of the human body.41 A low phosphorus diet, resulting when animal proteins, which are among the richest sources of phosphorus, are reduced in the diet, helps create a deficiency of ATP. Consequently, glycolysis is impaired, and cancer cells find it difficult to grow, reproduce, or even to stay alive.
A discussion of the possible role that antioxidants play in cancer treatment may be deferred because results of studies reported to date are contradictory. However, evolving evidence suggests that the benefits, or lack of benefits, of antioxidant supplementation depend upon the oxidative stages the cancer cells are in. If they are in a state of high oxidative stress, then antioxidants may protect them against apoptosis.42 The fact that many drugs, including Adriamycin (doxorubicin) and Mitomycin C (mitomycin), as well as radiation therapy, cause apoptosis by increasing production of pro-oxidants suggests that antioxidants should be withheld until the oxidative status of malignant tumors is ascertained.
References
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- A.B. Lorincz, “Tumor Response to Phenylalanine-Tyrosine-Linked Diets,” Journal of the American Dietetic Association (Feb. 1968): 198–205.
- C.V. Dang, A.L. Simons, D.M. Matson, K. Dornfeld, and D.R. Spitz.” “Glucose Deprivation–Induced Metabolic Oxidative Stress and Cancer Therapy,” Journal of Cancer Research Therapy 5 (2009) Supplement 1: 52–56.
- M. Rabinovitz, “Evidence for a Role of Phosphofructokinase and tRNA in the Polyribosome Disaggregation of Amino Acid Deficiency,” Federation of European Biochemical Societies Letters 283 (2) (1991): 270–2. ———, “The Pleiotypic Response to Amino Acid Deprivation is the Result of Interactions between Components of the Glycolysis and Protein Synthesis Pathways,” Federation of European Biochemical Societies Letters 302 (2) (1992): 113–16. ———. “The Phosphofructokinase-Uncharged tRNA Interaction in Metabolic and Cell Cycle Control: an Interpretive Review,” Nucleic Acids Symposium Series 33 (1995); 182–89.
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- R.A. Kocher, “Effects of a Low Lysine Diet on the Growth of Spontaneous Mammary Tumors in Mice and on Nitrogen Balance in Man,” Cancer Research 4 (1944): 251.
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- A.B. Lorincz and R.E. Kuttner, “Response of Malignancy to Phenylalanine Restriction,” Nebraska Medical Journal 50 (1965): 609.
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- A.B. Lorincz, E. Kuttner, and M.B. Brandt, “Tumor Response to Phenylalanine-Tyrosine Limited Diets,” Journal of American Dietetic Association 54 (1968): 198–205.
- H.B. Demopoulos, “Selective Inhibition of Human Pigmented Melanomas, in Vitro and in Vivo, through Tyrosinase Inhibition,” Federation Proceedings 24 (1965): 494.
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- Y. Lee, “Dominant-Negative Jun N-Terminal Protein Kinase (JNK-1) Inhibits Metabolic Oxidative Stress during Glucose Deprivation in a Human Breast Carcinoma Cell Line,” Free Radical Biology and Medicine 28 (2000): 575–84.
- D.R. Spitz, “Glucose Deprivation-Induced Oxidative Stress in Human Tumor Cells,” Annals of the New York Academy of Sciences 899 (2000): 349–62.
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