Antineoplastons - Burzynski

Antineoplastons - Burzynski

Very expensive alternative treatment by an M.D. It is best known for its success at treating brain cancer.

Peer Review Research on Burzynski

Inhibitory Effect of Antineoplaston A-10 on Breast Cancer Transplanted to Athymic Mice and Human Hepatocellular Carcinoma Cell Lines

Hideaki Tsuda and the Members of Antineoplaston Study Group, Kurume University School of Medicine, Kurume, 830 Japan

Summary: The inhibitory effect of Antineoplaston A-10 was tested on the growth curve of human breast cancer (R-27) serially transplanted to athymic mice and on the cell growth of human hepatocellular carcinomas (KMCH-1, KYN-1, KIM-1). Approximately 1.25% of Antineoplaston A-10 in the regular mouse diet (CE2) inhibited the growth curve significantly after 35 days treatment (p<0.05). Seventy milligrams of daily intraperitoneal administration of Antineoplaston A-10 Injection also inhibited the growth curve of R-27 after 52 days treatment (p<0.01). Histological study of tumor showed no essential difference in structure but significant decrease in number of mitoses in the Antineoplaston A-10 treated groups. The cell growth of human hepatocellular carcinoma cell lines KMCH-1, KYN-1 and KIM-1 was inhibited by Antineoplaston A-10 Injection dose dependently.

Introduction

Antineoplastons are naturally occurring peptides and amino acid derivatives which show inhibitory effect on cancer cells isolated from human blood and urine by Burzynski (1973). It was hypothesized that organs have a naturally occurring biochemical defense mechanism to control neoplastic growth (Burzynski et al. 1976; Burzynski, 1976). It has been suggested that cancer is a disease of cell differentiation. Given the large number of differentiating cells and assuming the possibility of error in the program of differentiation the organism would not live long without a reliable mechanism for "normalizing" such erroneously developed cells. Burzynski looked for a substance which could perform this function. He was able to isolate substances from human blood and urine which inhibit neoplastic growth but not inhibit normal tissues significantly and named these substances Antineoplastons. He fractionated Antineoplastons further and identified Antineoplaston A-10 (3-phenylacetyl-amino-2, 6-piperidinedione, and succeeded in synthesizing it. (Burzynski et al. 1985).

Antineoplaston A-10 has been shown to have negligible toxicity in acute and chronic studies in animals. Antineoplastons did not exhibit any mutagenic activity in the standardized Ames test. Antineoplaston A-10 is quite insoluble in water and partly hydrolyzed in pancreatic juice to phenylacetylglutamine and phenylacetylisoglutamine in the ratio of 4:1. The sodium salt of phenylacetylglutamine and phenylatylisoglutamine was formulated as Antineoplaston A-10 Injection because both these two degradation products were found to have inhibitory effect on neoplastic cell growth in tissue culture study. Although Burzynski reported antitumor effects of both oral and injectable formulations of Antineoplaston A-10 in clinical studies (Burzynski et al. 1984, 1986), an antitumor effect of this substance has never been reported in an animal model. Thus, we designed animal experiments to test for an antitumor effect of Antineoplaston A-10 on human breast cancer (R-27) transplanted to athymic m ice (Nawata et al. 1981) as well as for an inhibitory effect on human hepatocellular carcinoma cell lines (KlM-1, KYN-1, KMCH-1) (Murakami, 1984; Yano et al. 1986; Murakami et al. 1987).

Discussion and Conclusion

Antineoplaston, first described by Burzynski, are naturally occurring peptides and amino acid derivatives in humans which show inhibitory effect on neoplastic cell growth. Antineoplaston A-10 is the first compound, isolated from urine, identified and synthesized. Antineoplaston A-10 (3-phenylacetylamino-2,6-piperidinedione) is a fine white stable crystal at room temperature, and quite insoluble in water. Antineoplaston A-10 is partly hydrolyzed by pancreatic juice to 4:1 of phenylacetylglutamine and phenylacetylisoglutamine which were proven to have also an antitumor effect in tissue culture study. Because of the insolubility of Antineoplaston A-10 in water, sodium salts of 4:1 of phenylacetylglutamine and phenylacetylisoglutamine was formulated as Antineoplaston A-10 Injection. Although Burzynski reported antitumor effects of oral and injectable formulations of Antineoplaston A-10 in clinical investigation, the antitumor effect of Antineoplaston A-10 has never been reported in animal experiment previously.

One of the reasons for the lack of studies in the experimental animals seems to be the rapid excretion of Antineoplaston A-10 by the kidney in animals. (Ashraf et al. 1987) reported orally administered Antineoplaston A-10 remained in the body longer in human than in animal. In addition, Antineoplaston A-10 does not naturally occur in mice.
Hendry et al. (1988) predicted by their stereoscopic structure study that 3-phenylacetylamino-2,6-piperidinedione (Antineoplaston A-10) would bind to DNA weakly and reversibly as well as phenylacetyglutamine and phenylacetylisoglutamine. Lehner et al. (1986) also showed that orally administered Antineoplaston A-10 possessed antitumorigenic activity as a result of competing with carcinogens for binding to DNA. Many researchers reported remarkable chemopreventive effects of Antineoplaston A-10 against tumor formation induced by various carcinogens such as benzo (a) pyrene (Kampalath et al. 1987), urethane (Eriguchi et al. 1988), DMBA and aflatoxin B1 (Kampalath et al. 1987). This could explain the fact that a small dose of Antineoplaston A-10 was sufficient to prevent tumor formation but not sufficient to inhibit already existing tumors and also the fact that a large dose of Antineoplaston A-10 could be required to inhibit the growth of already existing tumors in animals.

We intended to keep high plasma levels of Antineoplaston A-10 in our animal experiments. We used a large amount of Antineoplaston A-10 and slow growing tumor to permit long and dense contact of the tumor with Antineoplaston A-10. The growth curve of R-27 was inhibited in both oral administration of Antineoplaston A-10 (70mg/day) and intraperitoneal administration of Antineoplaston A-10 Injection (70mg/day). Oral administration of Antineoplaston A-10 inhibited the growth curve significantly (p<0.02) after 39 days treatment and intraperitoneal administration of Antineoplaston A-10 Injection inhibited after 52 days treatment. (Hashimoto et al. 1990) The fact that oral administration of Antineoplaston A-10 showed significant inhibition on tumor growth earlier than intraperitoneal administration of Antineoplaston A-10 Injection suggests that a sufficient plasma level of these agents was maintained better by constant eating Antineoplaston A-10 contained food. In human the better resul ts can be expected when Antineoplaston A-10 Injection is continuously infused. The decrease in the number of mitoses in treated groups observed in the histological study suggests that Antineoplaston A-10 acts on tumor cell cytostatically rather than cytocidally at the dose used in these experiments. The reduction of AFP production in spite of increase in cell number in KIM-1 cell line would clearly indicate that there was some change in protein synthesis which might be related to DNA base change.

In conclusion, the discrepancy between animal and clinical results regarding antitumor effect of oral formula and injection formula of Antineoplaston A-10 could be at least partly explained as due to the dose of Antineoplaston A-10 administered and maintained. Because the effect of Antineoplaston A-10 is cytostatic, longer and careful observation is required to evaluate the antitumor effect of the agent especially in animals. The great potential of this agent in inducing change in protein synthesis by the tumor cells should be investigated from the point of view of application for the cancer chemotherapy.

Article copyright Townsend Letter for Doctors & Patients.

Share this with your friends

MEET THREE CHILDREN DENIED THE
BEST CANCER TREATMENT
Probably the single greatest motivator for me in trying to raise peoples awareness of the cancer racket
are the true stories of three children and what their family’s went through in trying to save them.
Thomas Navarro, Alexander Horwin and Crystin Schiff. Orthodox treatment for brain
cancer, especially Children's, is absolutely appalling. Chemotherapy and radiation treatment cause
horrific side-effects and permanent retardation. Very few survive for five years with this treatment. Their
quality of life is ghastly, constantly sick from the chemotherapy/radiation treatments, their immune
system wrecked by this barbaric treatment. But if this was the only treatment available, of course we
would do all we could to try and buy our child a few extra months or years, anything to try and save them.
The truth is however that it is definitely not the best treatment. Dr. Stanislaw Burzynski MD
(and Ph.D. in biochemistry) developed natural, nontoxic antineoplastons over 20 years ago.
They are incredibly effective for brain cancer and they have very few side-effects
that are temporary.

Thomas Navarro

Here is an excerpt form a report by Dr. Robert Burdick, oncologist and professor at the
University of Washington Medical School. Burdick based his report on 17 cases of brain
cancer that were treated with
antineoplastons as of April 1996. He writes,
"As a rough estimate, neurosurgeons do well to cure one in every 1,000-brain
cancer patients they operate on. Radiation therapy slows the growth of adult tumors,
gaining perhaps one month of life, and may result in a cure of only one in 500-1,000
patients. Similarly, chemotherapy, despite 30 years of clinical trials, has not resulted
in the development of a single drug or drug combination that elicits more than an
occasional transient response in primary brain tumors.’

After reviewing Burzynski’s cases Burdick wrote “I am very impressed with the number
of complete and partial responses…compared with the number of responses that I have
seen in my personnel experience. The responses here are far in excess of any prior series
of patients published in the medical literature…the response rate here is an astounding
81%, with an equally astounding 35% complete remission…It is very clear the responses
here are due to antineoplaston therapy and are not due to surgery, radiation or
standard chemotherapy.” (Daniel Haley, “Politics In Healing” p379/80)
These three family’s independently researched their child's cancer. After collectively studying
cancer treatments for many thousands of hours they all concluded that antineoplastons were by far the
best choice. But the FDA will not allow access to this treatment until the child has first undergone
chemotherapy/radiation treatment. At which time it is usually too late because the child's immune system
is destroyed and nothing can help. Raphaele and Michael Horwin researched their son’s treatment and
decided that antineoplastons were the best choice. The FDA refused and forced them to use
chemotherapy/radiation. On January 31 1999, two year old Alexander Horwin died in his mothers arms.

Alexander Horwin

Then we have the particularly nefarious and very well documented case of 4 year old Crystin Schiff. On January 21, 1992, Crystin was diagnosed with malignant rhabdoid tumor in her brain and spinal cord, the most deadly of all childhood cancers. Her parents,Ric and Paula, were beside themselves with worry. Crystin immediately underwent surgery at the University of California at San Francisco Medical Center (UCSF).This was a temporary measure that would buy a little time. The only other options open to Crystin was chemotherapy and radiation treatment that may extend her life by a few months. Ric and Paula asked many of the oncologists at UCSF if there were any other alternatives apart from immune wrecking chemotherapy/radiation that causes appalling side-effects. The unanimous answer was "no".

So trusting the doctors, Crystin went through 6 months of devastating chemotherapy and radiation treatment. Ric and Paula describe this barbaric treatment best,

"Over the next 6 months, we literally tortured our little girl. Crystin’s urine burned her from the poisons, and we had to use rubber gloves to change her diapers. She threw up constantly and lost weight rapidly. We played a constant game of trying together to eat more than she lost. Every little cold was life-threatening, and no comfort from us could ease her suffering. I doubt whether Crystin had a comfortable night's sleep ever again."

During this time Ric and Paula started investigating different cancer treatments. They found Dr.Burzynski's antineoplastons and asked Crystin's oncologist about it. All the doctors at UCSF were very negative about it. Ric and Paula write,

"Crystin's oncologist was concerned and asked us to speak to a colleague of his who supposedly knew all about Dr. Burzynski. I met with Dr. Prados, head of neuro-oncology at UCSF. He told me that Dr.Burzynski’s medicine did not work and that he had testified against Burzynski in court. He suggested other experimental and toxic therapies, but by then we were weary of chemotherapy."

After investigating Burzynski and listening to his patient's candid opinions the Schiff's decided to give antineoplastons a try. The Schiff's continue,

Within months, Crystin became cancer free. Eighteen months after starting on Dr. Burzynski’s treatment Crystin was still cancer free. My wife and I had been living a miracle as each successive MRI showed Crystin improving. Strangely, our doctors continued to remain unexcited about Crystin’s improvement.

It is of little surprise that the oncologists at UCSF were unexcited about Crystin's remission after antineoplastons. These doctors are not allowed to prescribe Antineoplastons. They also couldn't bare to face the fact that Crystin's only health issues now were a result of their barbaric treatments that included 10,000 rads of radiation to her still-developing brain/spinal cord, and highly toxic chemotherapy drugs. As Dr. Whitaker writes in his February 1996 "Health and Healing" Newsletter,

"Miraculously, Cryssie's malignant cancer did not come back as the medical staff at UCSF expected, which was cause for consternation among them. They had counted on Cryssie's dying, because her type of cancer had never responded to any treatment for long. With Cryssie in remission, they were forced to watch the effects of their toxic therapies eat away at a four-year-old girl."

Although the antineoplaston's had put Crystin into remission from cancer, her body had been too badly damaged by the radiation and chemotherapy.The Schiff's continue,

"On July 29, 1995, the bravest and strongest little girl I have ever known died absolutely cancer free. Her autopsy revealed the ultimate cause of death was brain damage as a result of radiation and chemotherapy."

Several months after Crystin's death Dr. Julian Whitaker contacted Ric and Paula. Whitaker told theSchiffs that Dr. Prados had followed an earlier case of brain cancer treated with antineoplsatons. From Whitaker's February 1996 issue of "Health and Healing,"

"Dr. Prados followed this case closely. From 1989 through 1993, he sent Dr. Burzynski 14 two-page letters documenting Jeff Keller's condition on his follow-up visits at UCSF. All these letters were signed or initialed by Michael Prados. On September 6,1991, with Jeff Keller now in complete remission, Dr. Prados wrote, "We are very pleased that Mr. Keller's clinical and adiographic status is stable. He seems to be having an excellent response to antineoplaston therapy."

This information was derived from Ric and Paula Schiff's letter (linked at the bottom) and Dr.Julian Whitaker's February 1996 "Health and Healing" newsletter. I e-mailed the Schiff's and verified the accuracy of the information.

Crystin Schiff

Starting about a year and a half ago, the Navarro’s fought the FDA tooth and nail to have their son,
Thomas, treated with antineoplastons. They waged a large media campaign supported by Alan Keyes,
then Texas governor George W. Bush, Senator Orin Hatch, Senator John McCain and Chairman of the
Committee for Government Reform, Congressman Dan Burton. Nothing had an effect on the FDA.
Protecting the drug companies profit margins was far more important than saving a little boys life.
Finally, after 18 wasted months the FDA finally allowed Thomas the treatment of his parents choice.
The reason they allowed this was because a recent MRI had shown multiple new tumors in his head
neck and spine. This was all caused by the chemotherapy Thomas was forced to undergo.
He was now considered terminal by conventional medicine so it was okay to allow him to use the
so-called alternative treatment.Once his doctors had virtually killed him and the drug
companies had made their blood money. I have spent many hours reading about the blatant
conflict of interests between the FDA and pharmaceutical companies. A few years ago the FDA
director left for a 2 million a year job at a pharmaceutical company. One hand washes the other.

THE EVIDENCE IS OVERWHELMING THAT ANTINEOPLASTONS
ARE FAR BETTER THAN CHEMOTHERAPY/RADIATION
TREATMENT FOR BRAIN CANCER. THE FDA ARE KILLING OUR
KIDS TO PROTECT THE DRUG COMPANIES PROFITS AND
DESTROY ANY COMPETITION. WE MUST HAVE MEDICAL
FREEDOM OF CHOICE.

http://www.cancerinform.org/kids1.html

Antineoplastons: An Investigational Cancer Therapy

As a paid consultant to those formerly in litigation against me, Saul Green, author of the June 3 article in JAMA "`Antineoplastons' - An Unproved Cancer Therapy,"( 1) can scarcely be considered an impartial reviewer of my work. Not surprisingly, Green seriously misrepresents over 20 years of research on antineoplastons. The combination of 1) severe distortion of the literature reviewed, 2) selective omission of the most relevant and recent literature, 3) reliance upon comments of subordinates completely contradicted by written documents of their superiors, and 4) a grave misunderstanding of some of the basic science involved conspire to mislead the reader.

To begin with, Green's title is incorrect. Antineoplastons are an investigational cancer therapy, in the process of approval in a number of countries throughout the world. Permission to conduct clinical trials with antineoplastons has been given in the U.S., Germany, Japan, Poland, and Czecho-Slovakia. On March 16, 1989, permission was given by the FDA to proceed with a Phase II clinical trial in advanced breast cancer using Antineoplaston A10 capsules. This spring the National Cancer Institute will conduct four Phase II clinical trials in brain tumors using antineoplastons A10 and AS2-1. Would this be happening if Saul Green's conclusion were correct: "None of the independent tests carried out with antineoplastons in experimental tumor systems have shown anticancer activity."? Either the government agencies and researchers of the U.S., Germany, Poland, and Czecho-Slovakia know something Saul Green doesn't know, or Green chooses not to acknowledge all the research available. As the reader will see, this lack of acknowledgement is a pattern common to his review of the literature on antineoplastons.

Educational Background

Green disputes my claim to a Ph.D. degree in biochemistry and asserts my bibliography does not identify a dissertation. He further questions whether I did independent research in the Department of General Chemistry at the Medical Academy in Lublin, Poland. The informant Green quotes from Lublin was never a Chairman of the Department during the term of my employment. He was better known as the second in command of the local communist party. In contradiction to Green's allegations, my doctoral dissertation( 2) is always listed in my bibliography. Furthermore, the sworn statement and affidavit of Professor Zdzislaw Kleinrok, President, Medical Academy of Lublin states:
"As President of the Medical Academy of Lublin, Poland, I am the person in charge of all transcripts and records of former medical students. Dr. Stanislaw Burzynski graduated with Distinction and received a diploma of Medical Academy Doctor on June 30, 1967 from our Medical Academy. Our records also reflect that...on October 16, 1968, Dr. Stanislaw Burzynski also received a Ph.D. degree from the Medical Academy in Lublin, Poland for his studies in biochemistry." (written communication, May 25, 1990).

According to Green's paper, I worked in the Department of General Chemistry only from December 15, 1966 to September 30, 1967. However, in this same paper, Green refers to my articles which were published from 1964 to 1969. It is written in each of these articles, usually on the first page, that the publication came from the Department of General Chemistry.
Theory of Antineoplastons
It is postulated by the author that the human body possesses a biochemical defense system (BDS), which parallels the immune system.( 3-9) Whereas the main purpose of the immune system is protection against the invasion of microorganisms, the BDS protects against defective cells.
According to the definition published in 1976, antineoplastons are substances produced by the living organism that protect it against the development of neoplastic growth by a nonimmunological process which does not significantly inhibit the growth of normal tissues.( 3) Contrary to Green's statement that I "concluded that antineoplastons must be peptides," my initial statement was "Peptides are ideal compounds to participate in the system." As the research expanded we found that not only peptides, but amino acid derivatives and certain organic acids are components of the BDS.( 4, 5, 7-9) When the term "hormone" was introduced by William Hardy in 1905, nobody dreamed that the field of endocrinology would be born and that chemicals with hormonal activity would have such diverse structures as steroids and polypeptides.

The BDS is the system of differentiation inducers. The mechanism of action is based not on a cytotoxic effect, but on the "reprogramming" of defective cells through the induction of differentiation. Cancer patients were found to have a deficiency of antineoplastons.( 6, 10, 11) The administration of antineoplastons to cancer patients should offer a new treatment modality which will be discussed later. The protective effect of antineoplastons against the development of lung, breast and liver cancer in animals has been proven by a number of investigators.( 12-23)

Chemistry of Antineoplastons

Green mistakenly concludes that A10 is insoluble in aqueous solutions and as such "cannot be part of the normal anticancer system." In support of this assertion, Green cites one of my U.S. patents,( 24) but nowhere in this patent is A10 described as insoluble in aqueous solutions. The solubility of A10 in water is within the range of solubility of amino acids - more soluble in fact than tyrosine and tryptophan. Many important biological substances, such as steroid hormones, have solubility lower than A10.

Green suggests that A10 is an artifact formed in urine, not elsewhere in the human body, from phenylacetylglutamine (PAG) because its formation requires only the acidification of urine. Contrary to Green's assertion, the actual process of A10 synthesis requires not only acidification, but also a high temperature of 160øC for an extended period of time in order to cyclise the molecule of PAG.( 25, 26)

Green's next set of false statements concerns antineoplaston A10 injections. During pharmacokinetic studies of A10 administered orally, there was no substantial hydrolysis in simulated gastric juice, but 30% of A10 was hydrolyzed when exposed to simulated pancreatic juice for 3 hours. Two products of hydrolysis were identified as PAG and phenylacetylisoglutamine (isoPAG). The ratio of these two compounds was similar to the ratio of the products obtained during alkaline hydrolysis of A10 equal to 4:1.( 27) As indicated in the preceding article, "A decision was therefore made to produce a formulation of antineoplaston A10 injections, 100 mg/ml as a 4:1 mixture of sodium salts of PAG and isoPAG."( 27) Green refers to the same article, but distorts the truth saying that A10 is a sodium salt of only PAG. Subsequently, Green alleges that Chinese researchers came to the same conclusion. In fact, however, these researchers concluded that "Antineoplaston A10 injection is a mixture of sodium salts of PAG and isoPAG."( 28)
Further in his communication, Green tries to convince the reader that the A10 molecule is similar to the molecules of thalidomide and glutethimide. It doesn't take more than an elementary chemical education to determine that these structures are quite different. Of course, neither glutethimide nor thalidomide contains a peptide bond. For some reason, Green fails to notice that A10 resembles the most nucleic bases, uracil and thymine.( 29-32) The absence of mutagenic effects of antineoplastons A10, AS2-1, and AS2-5 has already been reported.( 33) The study which indicated the lack of teratogenic effect of A10 was submitted to the NCl last year (written communication dated October 17, 1991).
Green next alleges the identical composition of antineoplastons A1, A2, A3, A4, and A5, and as evidence he cites one of my U.S. patents.( 24) Yet in this same patent the differences in composition of A1-A5 are clearly evident even to the layperson. The chromatographic characteristics of A10, which allowed it to be located on chromatograms of A1-A5, are also given in the referred patent.

Manufacturing

Green does correctly state that over 95% of patients are being treated with synthetic preparations of antineoplastons. He also refers to the production of antineoplastons from urine as described in the patent.( 24) However, he misleads the reader by suggesting that antineoplastons isolated from urine consist solely of filtered urine. It is thoroughly described in the referenced patent that highly purified peptide fractions were used to prepare antineoplastons A1A5. The process is extremely complex and involves, in addition to filtration and ultrafiltration, two different chromatographic separations.
Green's next accusation concerns the alleged lack of "specific information about the methods used for sterilization of antineoplastons." Apparently Green is unaware that the only information filed in a patent is limited to descriptions of novel procedure. It is not necessary to describe well known procedures. Therefore in my patent it was only appropriate for me to reference the U.S. Pharmacopoeia regarding sterilization and depyrogenation,( 24) rather than to give, in Green's words, "specific information about the methods used for sterillization of antineoplastons."

The manufacturing facilities of Burzynski Research Institute, Inc. (BRI), including facilities for sterilization and depyrogenation, have been inspected by the NCI, and numerous bottles of injections were submitted to the NCl for their evaluation (written communication dated October 17, 1991). These samples were found sterile and not pyrogenic.
Green alleges that "the FDA will not confirm that it stated in writing that it considered the manufacturing plant at BRI to be operating in accordance with the FDA's good manufacturing guidelines." Perhaps Green's informant from the FDA, Houstonbased S. Miller, was too low in the ranks to be aware of the FDA's letter to us confirming BRI's compliance with Good Manufacturing Procedures (GMP) (Stephen Terman, FDA Offices, Rockville, Maryland, October 30, 1985).

Animal Toxicology and Pharmacokinetics

Among all the formulations of antineoptastons mentioned by Green, only one, AS2-1, is the subject of criticism because of alleged toxicity. AS2-1 is a mixture of two metabolizes of A10, sodium salts of PAG and phenylacetic acid (phenylacetate sodium, PA) in the ratio of 1:4.

Contrary to Green's statement, "In 1969, Burzynski recognized that metabolically produced PA was toxic in humans," the publication referenced by Green does not even mention PA.( 34) Acute and chronic toxicity studies of AS2-1 in mice, among other studies overlooked by Green, confirmed negligible toxicity.( 35) Green asserts that the toxicity of PA has been associated with brain damage. However, the publications cited by him deal with the vulnerability of the immature rat brain, not the human brain.( 36, 37) On the other hand, Green is very well aware that the metabolism of PA in humans is completely different than in rats. According to Green, "PAG is a waste product that is only found in the urine of humans." Apparently Green is unaware that since 1980 PA has become an investigational new drug approved for human use by the FDA and has already been established as safe and effective in the treatment of hyperammonemia.( 38-40) It is important to note that PA has been successfully used in the treatment of children a few months to a year old.( 38) In fact the government study cited above reported in Cancer Research that PA is a "novel nontoxic inducer of tumor cell differentiation," and concluded "we propose that its use may be extended to cancer prevention and therapy."( 40)
It is difficult to understand why Green distorts printed data regarding the pharmacokinetics of antineoplaston A10. According to him, "Burzynski has reported that insoluble A10 that is ingested is rapidly converted to PAG by alkaline digestive juices in the small intestine." To the contrary, there is nothing about a rapid conversion of A10 into PAG in the reference cited by Green.( 41) As explained earlier, it takes 3 hours to digest 30% of A10 to PAG and isoPAG.( 27) In spite of the extensive literature on the bioavailability and pharmacokinetics of A10 and AS2-1, which clearly demonstrate absorption, organ distribution, and excretion of A10 and AS2-1,( 42-48) Green dares to say, "It is PAG, and not A10 that is absorbed into the circulation from the small intestine."

Mechanisms of Action

There are three main possible mechanisms of action of antineoplastons. AS2-1 and AS2-5 inhibit the incorporation of glutamine into the proteins of neoplastic cells. A2, A3, and A5 decrease the methylation of nucleic acids, and A10 works through specific intercalation with DNA.

In spite of numerous publications in this area, Green seems to notice only one mechanism of action which is associated with A10. Green admits that A10 intercalates with DNA, but he asserts that this was merely an assumption based on theoretical considerations. This is far from the truth. Research done by Hendry, Muldoon, et al. at the Medical College of Georgia involved both computer modeling and in vitro studies regarding intercalation. In addition, there were numerous studies on anticancer activity in animals and tissue culture.( 14, 16, 17, 20, 21, 23, 25,49-65)

Anticancer Activity

Published research data documents anticancer activity in tissue culture, animal experiments, and treatment of patients. According to Green, there is no published evidence that antineoplastons can induce differentiation in cancer cells. To the contrary, there are 26 articles and presentations at international conventions which clearly demonstrate induction of differentiation of cancer cells by antineoplastons and their components.( 40,66-90) Three of these publications were authored by five researchers from the National Cancer Institute.( 40,89,90)

As mentioned earlier, Green concludes that none of the antineoplastons has been proven to be active against cancer in experimental tumor test systems. Somehow he chose to ignore 63 papers which clearly demonstrate anticancer activity. In addition to 26 reports dealing with the induction of cellular differentiation, there are 19 studies which document the anticancer activity of antineoplastons in tissue culture, and 18 which demonstrate anticancer activity in animals.( 12-16, 18-23, 28,61-63,65,91-111)

Green refers to tests done by the NCI as "compelling evidence of the lack of efficacy of antineoplastons against experimental cancer." It is quite obvious that any drug can be found inactive if it is tested in the wrong model and at the wrong dosages. Prior to the first series of tests, I informed the NCI that "I do not believe the compound will display significant activity in the prescreen P388" (written communication to V.L. Narayanan, Ph.D.,NCI, June, 1984). In spite of the suspected lack of activity against P388 leukemia, the NCI tested antineoplastons in this tumor model and, as predicted, found no activity. (In 1985 the NCI abandoned the P388 screen because of its insensitivity to agents active in solid tumors.)

The NCI's second series of tests in 1990 were conducted at a dosage level 10,000 times smaller than the recommended dosage of A10. Still, Green concludes that these test results are "compelling evidence of the lack of efficacy of antirneoplastons." Green's most serious omission in this matter, however, concerns a third series of NCI tests. The reader never learns from Green that his series, performed by the NCI in 1992 for the first time at a correct dosage level and in a proper model, did demonstrate the anticancer activity of both A10 and AS21 (written communication, M.R. Grever, M.D., Acting Associate Director Developmental Therapeutics Program, Division of Cancer Treatment, NCI, 1992).

Another U.S. government agency which has witnessed the antitumor effect of antineoplaston A10 is the FDA. In December, 1988, two FDA inspectors made a site visit to the University of Kurume Medical School in Japan. Regarding this site visit, the director of the Antineoplaston Study Group at the Kurume Medical School wrote December 20, 1988: "We believe that the FDA inspectors had a good impression of our study." Shortly after this site visit, the FDA gave its approval for a clinical trial with A10 to begin in this country.

Apparently biochemist Green attempted to evaluate the clinical results of antineoplastons. For some reason, he mentioned only two out of 28 studies dealing with clinical results.( 24, 41,79,112-136) Each of these reports show clear evidence of anticancer activity in the treatment of cancer patients. In reference to one paper, Green alleges that according to my study, PAG was ineffective against cancer cells, despite the fact that this same publication describes two cases of cancer which went into complete remission as a result of treatment with PAG.( 24) Further he alleges that I cited the work of Israeli researchers who obtained the same results.(137) Contrary to that, my statement was that Israeli researchers confirmed a slight effect on the growth of murine tumors, but they did not report the use of PAG in the treatment of human cancer.

Green quotes a Japanese researcher (now in his third year of conducting clinical trials with antineoplastons) completely out of context: "We do not think that you are going to pick up any biological effect of antineoplaston A10 in our study." The Japanese physician's intended point was that Green, not an M.D., does not have sufficient qualifications to evaluate the biological effects of A10 in clinical studies (written communication, H. Tsuda, June, 1992).

Regarding clinical studies in Poland, Green quotes A. Danysz as saying that the Institute of Drug Research and Control is not supervising such studies. And yet, in direct contradiction, Professor Danysz wrote to me December 22, 1989:
"On behalf of the Polish Ministry of Health and Social Welfare, as well as myself as Director of the Institute for Drug Research and Control, I have the honor to thank you very much for your donation of Antineoplaston A10 and AS2-1 for the treatment of breast cancer, prostate cancer and tumors of CNS."

Green's most glaring omission is with regard to the NCI site visit to our Institute. It is of special interest that he omits the official statement of the NCI: "The National Cancer Institute reviewed 7 cases of primary brain tumors that were treated by Dr. Burzynski with antineoplastons A10 and AS2-1 and concluded that antitumor responses occurred." (NCI, Office of Cancer Communications, January 6, 1992).

In conclusion, the reader must be left with the same question I have. How did such an article, by an author with such grave conflicts of interest, ever pass peer review?
Correspondence:
Stanislaw R. Burzynski, M.D., Ph.D.
Burzynski Research Institute, Inc.
6221 Corporate Drive
Houston, TX 77036

References

(1.) Green S. `Antineoplastons' - an unproved cancer therapy. JAMA 1992;2672924-2928.
(2.) Burzynski S. Investigations on amino acids and peptides in blood serum of healthy people and patients with chronic renal insufficiency. 1968, 274 pages, Lublin, Poland.
(3.) Burzynski SR. Antineoplastons: Biochemical defense against cancer. Physiol Chem Phys. 1976; 8:275279.
(4.) Burzynski SR. Antineoplastons - History of the research (I). Drugs Exptl Clin Res. 1986; 12 (suppl 1):1-9.
(5.) Burzynski SR. Synthetic antineoplastons and analogs. Drugs of the Future. 1986;11:679-688.
(6.) Liau MC, Szopa M, Burzynski B, Burzynski SR. Chemosurveillance: A novel concept of the natural defense mechanism against cancer. Drugs Exptl Clin Res. 1987;13(supl 1):71-76.

(7.) Burzynski SR. Antineoplastons: Basic research and clinical applications. Adv Exptl Clin Chemother. 1988;2:1-9.
(8.) Burzynski SR. Isolation, purification and synthesis of antineoplastons. Internat J Exptl Clin Chemother. 1989;2:63-69.
(9.) Burzynski SR. Novel differentiation inducers. Presented at the 17th International Congress of Chemotherapy. June 1991; Berlin, Germany.

(10.) Liau MC, Szopa M, Burzynski B, Burzynski SR. Quantitative assay of plasma and urinary peptides as an aid for evaluation of cancer patients undergoing antineoplaston therapy. Presented at the 13th Annual Meeting of the International Society for Oncodevelopmental Biology and Medicine; September 1985; Paris, France.
(11.) Liau MC, Szopa M, Burzynski B, Burzynski SR. Quantitative assay of plasma and urinary peptides as an aid for the evaluation of cancer patients undergoing antineoplaston therapy. Drugs Exptl Clin Res. 1987;13(suppl 1): 61-70.
(12.) Kampalath BN, Liau MC, Burzynski B, Burzynski SR. Chemoprevention by antineoplaston A10 of benzo(a)pyrene induced pulmonary neoplasia. Presented at the 5th Mediterranean Congress of Chemotherapy; October 1986; Cairo, Egypt.

(13.) Kampalath BN, Liau MC, Burzynski B, Burzynski SR. Chemoprevention by antineoplaston A10 of benzo(a)pyrene induced pulmonary neoplasia. Drugs Exptl Clin Res. 1987;13 (suppl1): 51-55.

(14.) Muldoon TG, Copland JA, Hendry LB. Antineoplaston A10 activity in rodent mammary tumors. Presented at the 10th international Congress of Pharmacology; August 1987; Sydney, Australia.
(15.) Kampalath BN, Liau MC, Burzynski B, Burzynski SR. Protective effect of antineoplaston A10 in hepatocarcinogenesis induced by aflatoxin B1. Presented at the 4th European Conference on Clinical Oncology and Cancer Nursing; November 1987; Madrid, Spain.

(16.) Muldoon TG, Copland JA, Lehner AF, Hendry LB. Inhibition of spontaneous mouse mammary tumour development by antineoplaston A10. Drugs Exptl Clin Res. 1987;13(suppl 1): 83-88.
(17.) Muldoon TG, Copland JA, Hendry JB. Aspects of the mechanism by which A10 prevents carcinogen-induced tumorigenesis in the rat. Presented at the 8th International Symposium on Future Trends in Chemotherapy; March 1988; Pisa, Italy.

(18.) Yoshida H, Eriguchi N, Nichida H, et al. Chemopreventive effect of antineoplaston A10 on urethane induced pulmonary neoplasma formation in mice. Presented at the 8th International Symposium on Future Trends in Chemotherapy; March 1988; Pisa, Italy.
(19.) Eriguchi N, Hara H, Yoshida H, Nishida H, Nakayama T, Ohishi K. Chemopreventive effect of antineoplaston A10 on urethane-induced pulmonary neoplasm in mice. J. Jpn. Soc. Cancer Ther. 1988; 23:1560-1565.
(20.) Hendry LB, Muldoon TG. Actions of an endogenous antitumorigenic agent on mammary tumor development and modeling analysis of its capacity for interacting with DNA. J Steroid Biochem. 1988;30:325-328.
(21.) Muldoon TG, Copland JA, Hendry LB. Actions of antineoplaston A10 on the genesis and maintenance of specific subpopulations of rodent mammary tumor cells. Adv Exptl Clin Chemother. 1988;2:15-18.
(22.) Kampalath BN, Liau MC, Burzynski B, Burzynski SR. Protective effect of antineoplaston A10 in hepatocarcinogenesis induced by aflatoxin B1. Internat J Tissue Reactions, 1990;12 (suppl): 43-50.
(23.) Muldoon TG, Copland JA, Hendry LB. Antineoplaston A10 activity on carcinogan-induced rat mammary tumors. Internat J Tissue Reactions, 1990;12 (suppl):51-55.

(24.) Burzynski SR. Purified antineoplaston fractions and methods of treating neoplastic disease. U.S patent 4558057; December 10, 1985.

(25.) Burzynski SR, Hendry LB, Mohabbat MO, Liau MC, Khalid M, Burzynski B. Purification, structure determination, synthesis and animal toxicity studies of antineoplaston A10. Proceedings of the 13th International Congress of Chemotherapy, 1983; 17, PS. 12.4. 11-4; Vienna, Austria.

(26.) Burzynski SR, Hai TT. Antineoplaston A10. Drugs of the Future. 1985;10:103-105.
(27.) Ashraf AQ, Liau MC, Mohabbat MO, Burzynski SR. Preclinical Studies of antineoplaston A10 injections. Drugs Exptl Clin Res. 1986;12 (suppl 1):37-45.

(28.) Xu W, Yu R, Gao C, Yuan Y, Wang H. The preliminary antitumor assay of antineoplaston A10 against the S180 and the effects on cAMP levels in tumor and liver tissues of mice. Adv Exptl Clin Chemother. 1988; 2:41-44.
(29.) Williams DJ. The crystal and molecular structure of antineoplaston A10. Presented at the 10th International Congress of Pharmacology; August 1987; Sydney, Australia.

(30.) Michalska D. Theoretical investigations on the structure and potential binding sites of antineoplaston A10 and experimental findings. Presented at the 9th International Symposium on Future Trends in Chemotherapy; March 1990; Geneva, Switzerland.

(31.) Michalska D. Theoretical investigations on the structure and potential binding sites of antineoplaston A10 and experimental findings. Drugs Exptl Clin Res. 1990;16:342-349.
(32.) Michalska D. MNDO studies on the structure of antineoplaston A10, glutarimide and piperidine. J Molec Struct. 1991;341:357-366.
(33.) Gingold E., Sear CHJ, Smith RN. Mutagenicity studies on antineoplaston A10, AS2-1 and AS2-5 in cultures of Salmonella typhimurium (Ames test). Presented at the 15th International Congress of Chemotherapy; July 1987; Istanbul, Turkey.

(34.) Burzynski S. Bound amino acids in serum of patients with chronic renal insufficiency. Clin Chim Acta. 1989;25:231-237.
(35.) Burzynski SR, Mohabbat MO, Lee SS. Preclinical studies of antineoplaston AS2-1 and antineoplaston AS2-5. Drugs Exptl Clin Res. 1986;12(suppl 1): 1116.

(36.) Loo YH, Fulton KA, Miller KA, Wisniewski HM. Vulnerability of the immature rat brain to phenylacetate intoxication: postnatal development of the detoxication mechanism. J Neurochem 1979;32:1699-1705.

(37.) Wen GY, Wisniewski HM, Shek JW et al. Neuropathology of phenylacetate poisoning in rats: an experimental model in phenylketonuria. Ann Neurol. 1980;7:557-566.
(38.) Brusilow SW, Danney M, Waber LJ, et al. Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis. N Eng J Med 1984;310:1630-1634.

(39.) Mendenhall CL, Rouster S, Marshall L, Weesner R. A new therapy for portal systemic encephalopathy. Am J Gastroenterol. 1986;81:540-543.
(40.) Samid D, Shack S, Sherman LT. Pheylacetate: a novel nontoxic inducer of tumor cell differentiation. Cancer Res. 1992;52:1988-1992.

(41.) Burzynski SR. Phase I clinical studies of antineoplaston AS2-5 injections. In: Recent Advances in Chemotherapy: Proceedings of the 14th International Congress of Chemotherapy, Kyoto, Japan; 1985:586-587.
(42.) Ashraf AQ, Kampalath BN, Liau MC, Burzynski SR. Pharmacokinetic study of radioactive antineoplaston A10 following oral administration in rats. Presented at the 7th International Symposium on Future Trends in Chemotherapy; May 1986: Pisa, Italy.
(43.) Ashraf AQ, Liau MC, Kampalath BN, Burzynski SR. Pharmacokinetic study of radioactive antineoplaston A10 following oral administration in rats. Drugs Exptl Clin Res. 1987;13(suppl 1): 45-50.

(44.) Ashraf AQ, Kampalath BN, Burzynski SR. Pharmacokinetic analysis of antineoplaston A10 injections following intravenous administration in rats. Presented at the 8th International Symposium on Future Trends in Chemotherapy; March 1988, Pisa, Italy.

(45.) Ashraf AQ, Kampalath BN, Burzynski SR. Pharmacokinetic analysis of antineoplaston A10 injections following intravenous administration in rats. Adv Exptl Clin Chemother. 1988;6:33-39.
(46.) Xu W, Wang H, Yuan Y. Pharmacokinetic study of radioactive antineoplaston A10 in rats and mice. Drug Exptl Clin Res. 1990; 16:351-355.
Article copyright Townsend Letter for Doctors & Patients.
~~~~~~~~
By Stanislaw R. Burzynski