Antineoplastons (PDQ®)

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of antineoplastons in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Overview

This cancer information summary provides an overview of the use of antineoplastons as treatments for people with cancer. The summary includes a brief history of the development of antineoplastons; a review of laboratory, animal, and human studies; and possible side effects associated with antineoplaston use.

This summary contains the following key information:

• Antineoplastons are drugs composed of chemical compounds that are naturally present in the urine and blood. They are an experimental cancer therapy that is purported to provide a natural biochemical substance that is excreted and therefore lacking in people with cancer.
• Antineoplastons were first proposed as a possible cancer treatment in 1976.
• Antineoplastons were originally isolated from human urine but are now synthesized from readily available chemicals in the developer’s laboratory.
• Antineoplastons are not approved by the U.S. Food and Drug Administration for the prevention or treatment of any disease.
• No randomized controlled trials showing the effectiveness of antineoplastons have been published in the peer-reviewed scientific literature.
• Antineoplaston side effects can include serious neurologic toxicity.
• Nonrandomized clinical trials investigating the anticancer efficacy of antineoplastons are underway at the developer’s institute.

Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

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” by the developer.[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 developer 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 its 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 website. 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] In one in vitro study, human colon cancer cells were exposed to antineoplaston AS2-1 at high concentration and reported to normalize hypermethylation status at the promoter region of various tumor suppressor genes that are silenced in colon cancer.[29] However, this effect was noted at an AS2-1 concentration of 2 mg/mL, which is approximately four times higher than the mean steady state concentration previously reported in cancer patients treated with AS2-1,[20] and thus the clinical relevance of these findings is questionable.

History

As noted in the General Information section, Burzynski first proposed antineoplastons as a naturally occurring biochemical defense against cancer in 1976 as a result of his study of cybernetic systems and information theory. The search for information-bearing peptides in body fluids led him to separate peptides from human blood and subsequently from human urine. He called these substances antineoplastons and categorized them according to their general and specific anticarcinogenic potential. In 1980, the developer characterized the chemical structures of antineoplastons and began preparing them synthetically rather than isolating them from human urine. Preparations now used in clinical studies to treat cancer are antineoplastons A10, AS2-5, AS2-1, A2, A3, and A5.

From 1991 to 1995, the National Cancer Institute (NCI) initiated phase II clinical trials of antineoplastons A10 and AS2-1. Protocols for two phase II clinical trials were originally developed by investigators from several cancer centers, with review and input from both the developer and NCI. The National Institutes of Health (NIH), Office of Alternative Medicine, now known as the National Center for Complementary and Integrative Health, provided funding for the trials. Three centers (Memorial Sloan-Kettering Cancer Center, the Mayo Clinic, and the Warren Grant Magnuson Clinical Center at NIH) began accruing participants for these NCI-sponsored studies in 1993. However, by August 1995 only nine patients had entered the trials. Despite efforts by the developer, NCI staff, and investigators to reach agreement on proposed changes to increase patient accrual and dose, these agreements could not be reached, and the studies were closed prematurely in August 1995.[1,2]

The developer and investigators in Japan have reported several case series showing varying results using antineoplastons as a clinical therapy against several different types of cancer, alone or in combination with standard chemotherapy.[3-14] These studies are described in more detail in the Human/Clinical Studies section of this summary. Most of these studies were phase I trials or their equivalent; therefore, the only objective of these trials was safety.

Other uses of antineoplastons suggested by the developer include treatment of conditions such as Parkinson’s disease, sickle cell anemia, and thalassemia.[15]

Laboratory/Animal/Preclinical Studies

In vitro studies using a variety of human cell lines have been used to assess the effectiveness of antineoplastons as antineoplastic agents. Burzynski states that antineoplaston A is species-specific because it had no therapeutic effect when the human preparation was tested on animal tumor systems. Although this finding limits the usefulness of animal model testing, the developer has suggested that a “marked” therapeutic effect was produced in a xenograft bearing human tumor tissue.[1] This claim is made only for antineoplaston A. Other formulations of antineoplastons have not been tested in animal models.

Japanese scientists have tested antineoplastons A10 and AS2-1 in vitro for cell growth inhibition and progression in several human hepatocellular cell lines.[2,3] Tests were performed in a dose-dependent manner at concentrations varying from 0.5 to 8 µg/mL for A10 and AS2-1, and growth inhibition was generally observed at 6 to 8 µg/mL. This dose level is considered excessively high and generally reflects a lack of activity. Growth inhibition of one of the cell lines (KIM-1) was observed at low concentration for a mixture of cisplatin (CDDP) and A10, but this result was probably caused by the cisplatin, which was effective at concentrations of 0.5 to 2.0 μg/mL when tested alone.[4] AS2-1 was reported to induce apoptosis in three of the cell lines at concentrations of 2 and 4 μg/mL.

Antineoplaston A10 was also shown to inhibit prolactin or interleukin-2 stimulation of mitogenesis in a dose-dependent manner in rat Nb2 lymphoma cell line. The addition of A10 (1–12 mM) to prolactin-stimulated cells inhibited growth but was reversible when A10 was removed, suggesting a cytostatic rather than cytotoxic mechanism of action. A10 also showed no toxicity in a chromium release assay. DNA synthesis was also inhibited by A10.[5]

The ability of antineoplaston A3, isolated from urine and not an analog, to inhibit the growth of the HBL-100 human breast cancer cell line in vitro was investigated in a study that also examined the toxicity of A3 in Swiss white mice. Antineoplaston A3 inhibited colony formation in a dose-dependent manner over a dose range of 0.05, 0.1, 0.2, and 0.4 µg/mL.[6]

A somewhat different approach to the use of A10 was taken by researchers in Egypt. Taking the developer’s initial ideas about the presence of A10 in the urine of patients, this study looked for the amount of A10 in the urine of 31 breast cancer patients and compared this to the amount in 17 healthy controls. They found significantly (P < .001) less A10 in the urine of breast cancer patients than in controls, suggesting that the amount of A10 in urine has a potential use as a screening tool.[7]

The same researchers looked at the immunomodulating potential of A10 by examining the inhibition of neutrophil apoptosis induced by A10 in vitro. Neutrophils from 28 breast cancer patients and 28 controls were obtained from blood samples. Urine samples were obtained from the same patients and tested for the presence of A10. Cancer patients had significantly (P < .001) higher levels of neutrophil apoptosis and significantly lower levels of A10. Neutrophil apoptosis was assessed by adding A10 at a dose of 10 µg/mL to the cellular suspensions of 42 breast cancer patients. Nontreated samples were used as controls. A10 was found to significantly inhibit neutrophil apoptosis (P < .0001).[8]

In a 2014 study done in Japan, human colon cancer cells were exposed to antineoplaston AS2-1 at high concentration and reported to normalize hypermethylation status at the promoter region of various tumor suppressor genes that are silenced in colon cancer.[9] However, this effect was noted at an AS2-1 concentration of 2 mg/mL, which is approximately four times higher than the mean steady state concentration previously reported in cancer patients treated with AS2-1,[10] and thus the clinical relevance of these findings is questionable.

Several analogs of antineoplaston A10 have been synthesized and their antineoplastic activity tested against various cell lines. These include aniline mustard analogs of antineoplaston A10 and Mannich bases of antineoplaston A10.[11,12] These analogs showed improved in vitro antitumor activity over that of antineoplaston A10.

Human/Clinical Studies

To date, no phase III randomized, controlled trials of antineoplastons as a treatment for cancer have been conducted. Publications have taken the form of case reports, phase I clinical trials, toxicity studies, and phase II clinical trials. Phase I toxicity studies are the first group discussed below. The studies are categorized by the antineoplaston investigated. The second group of studies involves patients with various malignancies. Table 1 is a summary of dose regimens for all human studies. Table 2 summarizes the following clinical trials and appears at the end of this section.

Adverse Effects

Adverse effects of antineoplaston therapy have ranged from mild and short-lasting symptoms to severe neurologic toxicity necessitating discontinuation of therapy in some patients.[1]

Table 3 summarizes the adverse effects in the referenced studies.

Summary of the Evidence for Antineoplastons

To assist readers in evaluating the results of human studies of integrative, alternative, and complementary therapies for cancer, the strength of the evidence (i.e., the "levels of evidence") associated with each type of treatment is provided whenever possible. To qualify for a level of evidence analysis, a study must:

• Be published in a peer-reviewed scientific journal.
• Report on a therapeutic outcome or outcomes, such as tumor response, improvement in survival, or measured improvement in quality of life.
• Describe clinical findings in sufficient detail that a meaningful evaluation can be made.

Antineoplaston therapy has been studied as a complementary and alternative therapy for cancer. Case reports, phase I toxicity studies, and some phase II clinical studies examining the effectiveness of antineoplaston therapy have been published. For the most part, these publications have been authored by the developer of the therapy, Dr. S.R. Burzynski, in conjunction with his associates at the Burzynski Clinic. Although these studies often report remissions, other investigators have not been successful in duplicating these results. (Refer to the Human/Clinical Studies section of this summary for more information.) The evidence for use of antineoplaston therapy as a treatment for cancer is inconclusive. Controlled clinical trials are necessary to assess the value of this therapy.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis of integrative, alternative, and complementary therapies for cancer, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Changes to This Summary (06/20/2018)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary