9432 Katy Freeway, Suite 200, Houston, TX 77055 Phone: (713) 335-5697, Fax: (713) 935-0649 ANTINEOPLASTONS – HOW THEY WORK BACKGROUND Antineoplastons are naturally occurring peptides and amino acid derivatives, which control neoplastic growth. Research on peptides involved in cell-to-cell communication has grown at an impressive pace. Most of the effort has been concentrated in identification of the peptide growth factors, which by 1995 led to the discovery of approximately a hundred growth factors. Much less activity has focused on the isolation of peptide growth inhibitors. Thirty years ago, when the research on antineoplastons was started, very few researchers was interested in biologically active peptides and only a few such peptides had been identified, including pituitary hormones, plasma kinins, and angiotensins. Neoplastic process is a disease of cell differentiation. Given the large number of differentiating cells and assuming the possibility of error in the program of differentiation, groups of abnormally growing cells can arise very often under the influence of carcinogenic factors. Without a reliable mechanism, which can induce normal differentiation in cancer cells, chances for the survival of the organism will be very small. Such a corrective system can reprogram the growth of newly developed neoplastic cells and direct them into normal differentiation pathways. In the case of failure of this line of defense, the organism will not be able to defend itself against chemical and physical carcinogens, viruses and other neoplastic growth inducing agents, and will develop cancer. We have proposed the name "antineoplastons" for the components of such a redifferentiation system, which exists in the human organism. According to our definition, antineoplastons are the substances produced by the living organism which protect it against the development of neoplastic growth by a non- immunological process that does not significantly inhibit the growth of normal tissues. Based on theoretical grounds, it is very likely that antineoplastons have a peptide or amino acid derivative structure. Assuming that an error in the program for normal cell differentiation is responsible for neoplastic growth, the components of such a biochemical defense system against cancer should be information carrying molecules. Because of their high information content, peptides are ideal compounds to participate in such a line of defense. The theory of antineoplastons was conceived through the application of the cybernetic theory of autonomous systems to studies of peptides in human blood. The ideal cancer treatment should provide a large amount of information and a small amount of energy. Such a treatment may control neoplastic growth by directing the cancer cells into normal channels of differentiation. The practically infinite variety of peptides that can be formed by the combination of the twenty common amino acids indicates the possibility of the existence of a peptide system carrying information from cell to cell that is able to correct errors in the program for differentiation. The study of antineoplastic peptides existing in human blood and urine began in 1967. During the analysis of peptides and amino acids in the blood of healthy people and of patients suffering from various diseases, including cancer, it was noticed that there are significant differences in the peptide content in serum of cancer patients as compared with the control group. In the next few years, it was found that similar peptide fractions SRB Approved SI-001 BRI-IRB Approved Page 1 of 2 exist in urine. It was postulated that these peptides are probably synthesized in the tissues and passed into the blood and urine. Urine was proposed as the most economic source for their isolation and, therefore, a research program was established for the isolation and identification of antineoplastic peptides from human urine. Medicinal use of urine and urine extracts has been known for centuries. Serapion from Alexandria (III c.B.C.) was probably the most famous Greek physician to apply medicines derived from urine, but his experience was based on earlier Egyptian knowledge. Greek physicians practicing in ancient Rome were also very familiar with this type of treatment. Such therapy was described by Galen who is credited with the first medical description of cancer and also introducing the name "cancer." However, the most famous Greek in Rome in the second century A.D. to use urine therapy was Xenokrates. Medicinal use of urine was also known in ancient India, the importance of which is well described in a Sanskrit text entitled "Shivambu-kalp". Specifically, it should be mentioned that the treatment of cancer with urine was also then known in India. The interest in urine from both the therapeutic and diagnostic points of view persisted during the Middle Ages in Europe. "Essentia urinae " was commonly used at that time, and the vessel for urine "matula" was as widely shown by painters as an emblem of the practice of medicine as a cane with a snake in antiquity and the stethoscope in modern time’s. Medicine men in North and Central America were also quite familiar with urine treatment for various conditions, including cancer. In modern times, the first approach to the study of growth inhibiting substances in urine was conducted in 1937. Rohdenburg and Nagy, after studying samples from 541 cases, described the method of isolation of growth inhibiting agents from human urine. Floyd C. Turner in 1939 went one step further and tested the effect of Rohdenburg and Nagy's preparation on tumors in mice. He was able to find that a growth inhibiting substance derived from human urine prevented the formation of tumors in mice following injections of carcinogens, but the urinary derivative had little specific inhibiting effect on transplanted or spontaneous tumors in mice. Magnelia, Kaplan, and Hyson in 1943 were among the first who tried to treat human cancer by urine injections. In several cases of inoperable cancer, treated by daily urine injections and observed up to 18 months, they noticed marked relief of symptoms with no side effects. Von Wollheim prepared in 1948 an ether extract from human urine, which showed an inhibitory effect on cancer in mice. Considerable research, both basic and clinical, was done in England and Germany on a polypeptide of unknown structure named H-11, which was isolated from urine. In the initial clinical studies, 16 cases of inoperable lung cancer were treated by injections of urine extract. Relief of symptoms, e.g., cough, improvement of the general condition and prolongation of life in comfort was observed in most cases without any significant side effects. In more extensive trials described in 1968 by von Klose and Below, 49 cases of inoperable lung cancer were treated by injections of H-11 extract in combination with chemotherapy. Combination therapy gave better results than treatment with urine extract or chemotherapy alone. H-11 extract contained polypeptides, which were chemically different from antineoplastons, as proved by our research and the analysis done by the manufacturer of H-11. Antineoplastons are also completely different from peptides and amino acid derivatives isolated from urine by the other authors. Investigations on peptides in urine began 97 years ago and were initiated by Polish researcher Bondzynski. Further studies were continued by Bondzynski's former assistants in the University of Lwow and University of Warsaw. These compounds, initially named oxyproteic acids, were proven to be a wellcharacterized group of peptides by Skarzynski and Sarnecka-Keller. SRB Approved SI-001 BRI-IRB Approved Page 2 of 2