Antineoplastons are an experimental cancer therapy developed by S.R. Burzynski, MD, PhD. Chemically, antineoplastons are a mixture of amino acid derivatives, peptides, and amino acids found in human blood and urine.[1-4] The developer originally isolated antineoplastons from human blood and later found the same peptides in urine. Urine was subsequently used because it was less expensive and easier to obtain. Since 1980, antineoplastons have been synthesized from commercially available chemicals at the Burzynski Research Institute.[2,4]

According to the developer, antineoplastons are part of a biochemical surveillance system in the body and work as “molecular switches.” For the developer, cell differentiation is the key to cancer therapy. At the molecular level, abnormal cells that are potential cancer cells need to be “switched” to normal mode. Antineoplastons are the surveillance system that directs cancer cells into normal channels of differentiation. According to statements published by the developer, people with cancer lack this surveillance system because they do not have an adequate supply of antineoplastons.[1-3]

The notion of controlling tumor growth through a naturally occurring biochemical mechanism in the body that directs cancer cells into normal channels of differentiation is one of the theoretical foundations of antineoplaston therapy. In a complex organism like the body, cells are continuously differentiating. Groups of abnormal cells can arise under the influence of carcinogenic factors from outside or inside the body. The body must have a mechanism for dealing with these abnormal cells, or the organism will not live very long. The proposed components in the body that correct the differentiation problems of abnormal cells and send them into normal pathways have been given the name “antineoplastons.”[2]

The developer defines antineoplastons as “substances produced by the living organism that protect it against development of neoplastic growth by a nonimmunological process which does not significantly inhibit the growth of normal tissues.”[2]

The developer originally hypothesized the existence of antineoplastons by applying the cybernetic theory of information exchange in autonomous systems to the study of peptides in the blood.[2] The living cell is an autonomous cybernetic system connected to, and receiving, information from its environment through an energy pathway and an information pathway. It was postulated that a regulator within such a system would control the transfer of information and the expenditure of energy. Peptides were considered the information carriers in the body. Hypothesizing that peptides were the carriers of differentiation information to the cells, the developed began looking for peptides in the blood of cancer patients that might correct abnormal differentiation.[1-3,5]

To begin the search for antineoplastons, the developer used human blood, separating and removing the peptides found there. Later it was discovered that the same peptide fractions existed in human urine. Each peptide fraction was tested in vitro against various normal and neoplastic cell lines to gauge their effect on DNA synthesis and growth. The fractions that had little or no inhibitory effect on normal cells but a substantial inhibitory effect on neoplastic cell lines were separated into two classes: those that were effective against a specific cell line and those that were active against a broad array of neoplastic cell lines. Those with a broad spectrum of activity were grouped together and called “antineoplaston A.” Peptide fractions with specific antineoplastic activity were not investigated further.[2]

Antineoplaston A was further purified and yielded antineoplastons A1, A2, A3, A4, and A5. These mixtures of 7 to 13 peptides were patented in 1985.[6] In vitro tissue culture studies and in vivo toxicity studies in animal models were performed for antineoplastons A1 through A5. According to the developer, each individual fraction had a higher level of antitumor activity and lower toxicity level than antineoplaston A.[2]

Phase I trials of this antineoplaston group in patients with various advanced cancers showed A2 as contributing to the highest tumor response rate, so it was selected for further study.[2]

The active compound in A2 was found to be 3-phenylacetylamino-2,6-piperinedione, which was named antineoplaston A10.[7] From antineoplaston A10, three other compounds have been derived:

• AS2-5, which is phenylacetylglutamine (PAG).
• AS2-1, which is a 4:1 mixture of phenylacetic acid (PA) and PAG.
• A5, which is PA and an aromatic fatty acid.

Other antineoplastons (A3, A4, A10-1, AS5) were added to this group after further studies.[2-4]

There have been no independent analyses of which amino acids comprise the antineoplastons used in any of the reported studies.

Antineoplastons are administered by different methods. Antineoplaston A has been given intravenously, intramuscularly, rectally, topically, intrapleurally, and by bladder instillation.[8] Presently, antineoplastons A10, AS2-5, AS2-1, A2, A3, and A5 are given orally or by injection.[8-20]

Critical opposition to antineoplaston therapy and its developer have appeared in the published literature.[4] A basic criticism of the developer’s work is that although he has put forth a theory of peptides inducing cell differentiation, there is no published evidence that he has experimentally tested the hypothesis that information-bearing peptides could normalize cancer cells. Although some articles attempt to demonstrate that antineoplastons (specifically, antineoplaston A10) can bind to DNA at certain sites, this is an extrapolation from three-dimensional molecular models of DNA and A10 and does not demonstrate that this binding actually occurs.[21-23]

Other criticism focuses on the form of antineoplastons. Although the active fraction, antineoplaston A10, is insoluble in aqueous solutions, the developer has stated that it is present in body fluids.[4]

Antineoplastons AS2-5 and AS2-1 are derived from A10. Antineoplaston AS2-5 is PAG, and AS2-1 is a 4:1 mixture of PA and PAG. Because it is a strong acid, PA would exhibit cytotoxicity in vitro if in high enough concentration and not neutralized.[4]

The active component of antineoplaston A10 is 3-phenylacetylamino-2,6-piperidinedione. Reagents necessary for the synthesis of this antineoplaston compound are readily available internationally from any chemical supply company.[24] The developer retains patents on antineoplaston compounds and their use when administered pharmaceutically to inhibit the growth of neoplastic cells.[6,25]

To conduct clinical drug research in the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). The FDA’s IND process is confidential, and the existence of an IND application can be disclosed only by an applicant.

There are currently several active clinical trials sponsored and administered by the developer of antineoplastons. Information on these trials can be accessed through the NCI Web site ¹. None of these trials are randomized controlled trials.

Although several possible mechanisms of action and theories about the activity of antineoplastons have been proposed, specifically for antineoplaston A10, none of the theories has been conclusively demonstrated.

One theoretical mechanism of action proposes that antineoplaston A10 is specifically capable of intercalating with DNA at specific base pairs and thereby might interfere with carcinogens binding to the DNA helix. This interweaving of A10 into the DNA helix may be capable of interfering with DNA replication, transcription, or translation.[21,23] The theory is based on the manipulation of molecular models of DNA and A10; however, no published evidence of the creation of this actual molecule or evidence of the properties ascribed to it exists in the medical literature.

Another theoretical mechanism of action is based on the structural similarities of antineoplaston A10 to other experimental anticancer drugs such as carmustine and 5-cinnamoyl-6-aminouracil. A10 has been proposed to bind to chromatin and therefore relate to other anticancer drugs such as doxorubicin that interact directly with DNA.[21,26,27]

At the cellular level, two other mechanisms of action have been proposed to explain inhibition of tumor growth. One theory involves the activity of PAG, a component of some antineoplastons. PAG appears to compete with glutamine for access to the glutamine membrane transporter and may inhibit the incorporation of glutamine into the proteins of neoplastic cells. Because glutamine is essential for the cell cycle transition from G1 to S phase where DNA replication occurs, antineoplastons may arrest cell cycle progression and stop cell division.[28] Another theory proposes that phenylacetic acid, also a component of several antineoplastons, inhibits methylation of nucleic acids in cancer cells. The hypomethylation of DNA in cancer cells may lead to terminal differentiation and prevention of tumor growth or progression.[28]

References

1. Burzynski SR: Antineoplastons: biochemical defense against cancer. Physiol Chem Phys 8 (3): 275-9, 1976.  [PUBMED Abstract]
   
   
2. Burzynski SR: Antineoplastons: history of the research (I). Drugs Exp Clin Res 12 (Suppl 1): 1-9, 1986.  [PUBMED Abstract]
   
   
3. Burzynski SR: Potential of antineoplastons in diseases of old age. Drugs Aging 7 (3): 157-67, 1995.  [PUBMED Abstract]
   
   
4. Green S: 'Antineoplastons'. An unproved cancer therapy. JAMA 267 (21): 2924-8, 1992.  [PUBMED Abstract]
   
   
5. Burzynski SR: The present state of antineoplaston research (1). Integr Cancer Ther 3 (1): 47-58, 2004.  [PUBMED Abstract]
   
   
6. Burzynski SR: Purified Antineoplaston Fractions and Methods of Treating Neoplastic Disease. US Patent 4558057. December 10, 1985. Washington, DC: US Patent and Trademark Office, 1985. Available online ². Last accessed October 16, 2007. 
   
   
7. Revelle LK, D'Avignon DA, Wilson JA: 3-[(Phenylacetyl)amino]-2,6-piperidinedione hydrolysis studies with improved synthesis and characterization of hydrolysates. J Pharm Sci 85 (10): 1049-52, 1996.  [PUBMED Abstract]
   
   
8. Burzynski SR, Stolzmann Z, Szopa B, et al.: Antineoplaston A in cancer therapy. (I). Physiol Chem Phys 9 (6): 485-500, 1977.  [PUBMED Abstract]
   
   
9. Tsuda H, Hara H, Eriguchi N, et al.: Toxicological study on antineoplastons A-10 and AS2-1 in cancer patients. Kurume Med J 42 (4): 241-9, 1995.  [PUBMED Abstract]
   
   
10. Burzynski SR: Toxicology studies on antineoplaston AS2-5 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 17-24, 1986.  [PUBMED Abstract]
    
    
11. Burzynski SR, Burzynski B, Mohabbat MO: Toxicology studies on antineoplaston AS2-1 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 25-35, 1986.  [PUBMED Abstract]
    
    
12. Burzynski SR, Kubove E: Toxicology studies on antineoplaston A10 injections in cancer patients. Drugs Exp Clin Res 12 (Suppl 1): 47-55, 1986.  [PUBMED Abstract]
    
    
13. Burzynski SR, Kubove E, Burzynski B: Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1. Drugs Exp Clin Res 16 (7): 361-9, 1990.  [PUBMED Abstract]
    
    
14. Burzynski SR, Kubove E, Burzynski B: Phase I clinical studies of antineoplaston A5 injections. Drugs Exp Clin Res 13 (Suppl 1): 37-43, 1987.  [PUBMED Abstract]
    
    
15. Burzynski SR, Kubove E: Phase I clinical studies of antineoplaston A3 injections. Drugs Exp Clin Res 13 (Suppl 1): 17-29, 1987.  [PUBMED Abstract]
    
    
16. Burzynski SR, Kubove E: Initial clinical study with antineoplaston A2 injections in cancer patients with five years' follow-up. Drugs Exp Clin Res 13 (Suppl 1): 1-11, 1987.  [PUBMED Abstract]
    
    
17. Sugita Y, Tsuda H, Maruiwa H, et al.: The effect of Antineoplaston, a new antitumor agent on malignant brain tumors. Kurume Med J 42 (3): 133-40, 1995.  [PUBMED Abstract]
    
    
18. Tsuda H, Sata M, Kumabe T, et al.: Quick response of advanced cancer to chemoradiation therapy with antineoplastons. Oncol Rep 5 (3): 597-600, 1998 May-Jun.  [PUBMED Abstract]
    
    
19. Kumabe T, Tsuda H, Uchida M, et al.: Antineoplaston treatment for advanced hepatocellular carcinoma. Oncol Rep 5 (6): 1363-7, 1998 Nov-Dec.  [PUBMED Abstract]
    
    
20. Buckner JC, Malkin MG, Reed E, et al.: Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma. Mayo Clin Proc 74 (2): 137-45, 1999.  [PUBMED Abstract]
    
    
21. Lehner AF, Burzynski SR, Hendry LB: 3-Phenylacetylamino-2,6-piperidinedione, a naturally-occurring peptide analogue with apparent antineoplastic activity, may bind to DNA. Drugs Exp Clin Res 12 (Suppl 1): 57-72, 1986.  [PUBMED Abstract]
    
    
22. Hendry LB, Muldoon TG, Burzynski SR, et al.: Stereochemical modelling studies of the interaction of antineoplaston A10 with DNA. Drugs Exp Clin Res 13 (Suppl 1): 77-81, 1987.  [PUBMED Abstract]
    
    
23. Michalska D: Theoretical investigations on the structure and potential binding sites of antineoplaston A10 and experimental findings. Drugs Exp Clin Res 16 (7): 343-9, 1990.  [PUBMED Abstract]
    
    
24. Choi BG, Seo HK, Chung BH, et al.: Synthesis of Mannich bases of antineoplaston A10 and their antitumor activity. Arch Pharm Res 17 (6): 467-9, 1994.  [PUBMED Abstract]
    
    
25. Burzynski SR: Purified Antineoplaston Fractions and Methods of Treating Neoplastic Disease. US Patent 4559325. December 17, 1985. Washington, DC: US Patent and Trademark Office, 1985. Available online ². Last accessed October 16, 2007. 
    
    
26. Wood JC, Copland JA, Muldoon TG, et al.: 3-phenylacetylamino-2,6-piperidinedione inhibition of rat Nb2 lymphoma cell mitogenesis. Proc Soc Exp Biol Med 197 (4): 404-8, 1991.  [PUBMED Abstract]
    
    
27. Tsuda H: Inhibitory effect of antineoplaston A-10 on breast cancer transplanted to athymic mice and human hepatocellular carcinoma cell lines. The members of Antineoplaston Study Group. Kurume Med J 37 (2): 97-104, 1990.  [PUBMED Abstract]
    
    
28. Sołtysiak-Pawłuczuk D, Burzyński SR: Cellular accumulation of antineoplaston AS21 in human hepatoma cells. Cancer Lett 88 (1): 107-12, 1995.  [PUBMED Abstract]
    
    

Glossary Terms

Not normal. An abnormal lesion or growth may be cancerous, premalignant (likely to become cancer), or benign.

In medicine, the act of giving a treatment, such as a drug, to a patient. It can also refer to the way it is given, the dose, or how often it is given.

Cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment.

One of several molecules that join together to form proteins. There are 20 common amino acids found in proteins.

An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models.

A substance that blocks the formation of neoplasms (growths that may become cancerous).

A substance isolated from normal human blood and urine that is being tested as a type of treatment for some tumors and AIDS.

Having to do with stopping abnormal cell growth.

Having to do with water.

Having an odor, which often is pleasant or spicy.

The organ that stores urine.

A tissue with red blood cells, white blood cells, platelets, and other substances suspended in fluid called plasma. Blood takes oxygen and nutrients to the tissues, and carries away wastes.

A term for diseases in which abnormal cells divide without control. Cancer cells can invade nearby tissues and can spread to other parts of the body through the blood and lymph systems. There are several main types of cancer. Carcinoma is cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma is cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is cancer that starts in blood-forming tissue such as the bone marrow, and causes large numbers of abnormal blood cells to be produced and enter the blood. Lymphoma and multiple myeloma are cancers that begin in the cells of the immune system. Central nervous system cancers are cancers that begin in the tissues of the brain and spinal cord.

Any substance that causes cancer.

An anticancer drug that belongs to the family of drugs called alkylating agents.

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

The process during which young, immature (unspecialized) cells take on individual characteristics and reach their mature (specialized) form and function.

Having to do with the examination and treatment of patients.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called a clinical study.

In science, a substance that is made up of more than one ingredient.

A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all.

The beliefs, values, and behaviors that are shared within a group, such as a religious group or a nation. Culture includes language, customs, and beliefs about roles and relationships.

Cells of a single type (human, animal, or plant) that have been adapted to grow continuously in the laboratory and are used in research.

Cell-killing.

In chemistry, a compound produced from or related to another.

In cancer, refers to how mature (developed) the cancer cells are in a tumor. Differentiated tumor cells resemble normal cells and tend to grow and spread at a slower rate than undifferentiated or poorly differentiated tumor cells, which lack the structure and function of normal cells and grow uncontrollably.

Deoxyribonucleic acid. The molecules inside cells that carry genetic information and pass it from one generation to the next. Also called deoxyribonucleic acid.

A drug that is used to treat many types of cancer and is being studied in the treatment of other types of cancer. Doxorubicin comes from the bacterium Streptomyces peucetius. It damages DNA (the molecules inside cells that carry genetic information) and stops cells from growing. Rapidly growing tumor cells that take up doxorubicin may die. It is a type of anthracycline antitumor antibiotic. Also called doxorubicin hydrochloride, Adriamycin PFS, Adriamycin RDF, and Rubex.

Any substance, other than food, that is used to prevent, diagnose, treat or relieve symptoms of a disease or abnormal condition. Also refers to a substance that alters mood or body function, or that can be habit-forming or addictive, especially a narcotic.

In clinical trials, refers to a drug (including a new drug, dose, combination, or route of administration) or procedure that has undergone basic laboratory testing and received approval from the U.S. Food and Drug Administration (FDA) to be tested in human subjects. A drug or procedure may be approved by the FDA for use in one disease or condition, but be considered experimental in other diseases or conditions. Also called investigational.

A major component of fats that is used by the body for energy and tissue development.

Liquid.

FDA. An agency in the U.S. federal government whose mission is to protect public health by making sure that food, cosmetics, and nutritional supplements are safe to use and truthfully labeled. The Food and Drug Administration also makes sure that drugs, medical devices, and equipment are safe and effective, and that blood for transfusions and transplant tissue are safe. Also called FDA.

An amino acid used in nutrition therapy. It is also being studied for the treatment of diarrhea caused by radiation therapy to the pelvis.

A tentative proposal made to explain certain observations or facts that requires further investigation to be verified.

In the laboratory (outside the body). The opposite of in vivo (in the body).

In the body. The opposite of in vitro (outside the body or in the laboratory).

Use of a syringe and needle to push fluids or drugs into the body; often called a "shot."

In medicine, a method used to put a liquid into the body slowly or drop by drop.

IM. Within or into muscle. Also called IM.

Within the pleural cavity.

Into or within a vein. Intravenous usually refers to a way of giving a drug or other substance through a needle or tube inserted into a vein. Also called I.V.

A substance that has been tested in a laboratory and has gotten approval from the U.S. Food and Drug Administration (FDA) to be tested in people. A drug may be approved by the FDA for use in one disease or condition but be considered investigational in other diseases or conditions. Also called experimental drug.

A very thin layer of tissue that covers a surface.

In medicine, the rules and procedures for doing research and evaluating results.

The smallest particle of a substance that has all of the physical and chemical properties of that substance. Molecules are made up of one or more atoms. If they contain more than one atom, the atoms can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms.

By or having to do with the mouth.

A living thing, such as an animal, a plant, a bacterium, or a fungus.

Any compound consisting of two or more amino acids, the building blocks of proteins.

The first step in testing a new treatment in humans. These studies test the best way to give a new treatment (for example, by mouth, intravenous infusion, or injection) and the best dose. The dose is usually increased a little at a time in order to find the highest dose that does not cause harmful side effects. Because little is known about the possible risks and benefits of the treatments being tested, phase I trials usually include only a small number of patients who have not been helped by other treatments.

In medicine, action taken to decrease the chance of getting a disease or condition. For example, cancer prevention includes avoiding risk factors (such as smoking, obesity, lack of exercise, and radiation exposure) and increasing protective factors (such as getting regular physical activity, staying at a healthy weight, and having a healthy diet).

In medicine, the course of a disease, such as cancer, as it becomes worse or spreads in the body.

A molecule made up of amino acids that are needed for the body to function properly. Proteins are the basis of body structures such as skin and hair and of substances such as enzymes, cytokines, and antibodies.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

By or having to do with the rectum. The rectum is the last several inches of the large intestine closest to the anus.

The percentage of patients whose cancer shrinks or disappears after treatment.

In medicine, the ongoing collection of information about a disease, such as cancer, in a certain group of people. The information collected may include where the disease occurs in a population and whether it affects people of a certain gender, age, or ethnic group.

Treatment.

A group or layer of cells that work together to perform a specific function.

On the surface of the body.

The extent to which something is poisonous or harmful.

In biology, the process by which a cell makes an RNA copy of a sequence of DNA that is a gene.

An abnormal mass of tissue that results when cells divide more than they should or do not die when they should. Tumors may be benign (not cancerous), or malignant (cancerous). Also called neoplasm.

Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra.