Hackett 1 WO 2007015837 A2 Antineoplaston (ANP) is a name used byStanislaw Burzynskifor a group of chemical compounds and mixtures for which he claims anti-canceractivity. These compounds have been sold and administered by Burzynski to cancer patients since 1986; clinical efficacy has not been demonstrated and several fatal side effects have occurred. [1] The practice is considered quackery by critics. [2] Burzynski maintains corporate offices and operates a clinic in Houston, Texas where he treats patients with antineoplastons. At a nearby facility in Stafford, Texas he conducts research and manufactures the pharmaceutical ingredients used in the medications and other products that he produces. AdvertisementContents 1 Background 2 Treatment with Antineoplastons 3 Proposed mechanisms 4 References Background In 1967 Stanislaw Burzynski began investigating the use of antineoplastons after noting significant peptide deficiencies in the blood of cancer patients as compared with a control group [3] . Burzynski initially derived antineoplastons from human blood. Since similar peptides had been isolated from urine, in 1970 Burzynski switched to urine as a cheaper source of antinoeplastons. Since 1980 he has been reproducing his c ompounds synthetically. [4] Since his initial discovery, Burzynski has isolated dozens of peptide fractions from urine, some of which have been reportedly found to be active against cancer with low toxicity.
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Antineoplaston (ANP) is a name used by Stanislaw Burzynski for a group of chemical compounds andmixtures for which he claims anti-cancer activity. These compounds have been sold and administered byBurzynski to cancer patients since 1986; clinical efficacy has not been demonstrated and several fatal sideeffects have occurred.[1] The practice is considered quackery by critics.[2] Burzynski maintains corporate officesand operates a clinic in Houston, Texas where he treats patients with antineoplastons. At a nearby facility inStafford, Texas he conducts research and manufactures the pharmaceutical ingredients used in themedications and other products that he produces.
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Contents
1 Background
2 Treatment with Antineoplastons
3 Proposed mechanisms
4 References
Background
In 1967 Stanislaw Burzynski began investigating the use of antineoplastons after noting significant peptidedeficiencies in the blood of cancer patients as compared with a control group[3]. Burzynski initially derivedantineoplastons from human blood. Since similar peptides had been isolated from urine, in 1970 Burzynskiswitched to urine as a cheaper source of antinoeplastons. Since 1980 he has been reproducing his compoundssynthetically.[4] Since his initial discovery, Burzynski has isolated dozens of peptide fractions from urine, someof which have been reportedly found to be active against cancer with low toxicity.
The first active peptide fraction identified was called antineoplaston A-10 (3-phenylacetylamino-2,6-piperidinedione). From A-10, antineoplaston AS2-1, a 4:1 mixture of phenylacetic acid andphenylacetylglutamine, was derived [5]. The active ingredient of antineoplaston A10-I isphenylacetylglutamine [6].
Phenylacetic acid is a toxic compound that the body produces during normal metabolism. It is detoxified inthe liver to phenylacetyl glutamine. The "antineoplaston A-10" compound is an isolation artifact resulting fromheating the urine under acidic conditions. The "antineoplaston AS2-1" mixture is the result of an alkalinehydrolysis of "antineoplaston A-10". All compounds are widely available cheap chemicals.
Treatment with Antineoplastons
For legal reasons Burzynski currently sells his treatments only in the context of clinical trials. Patients receivingcancer treatment with antineoplastons must first qualify for one of the currently available clinical trials. In order to qualify for most of the trials, a patient must have first failed standard treatment for the condition beingtreated, or it must be a condition that is unlikely to respond to currently available therapy and for which nocurative therapy exists. Antineoplastons may be administered intravenously or orally. Patients who respondpositively to initial treatment with intravenous antineoplastons sometimes transition to the oral form.Intravenous antineoplastons are administered continuously with a portable programmable pump that the patientcarries on a shoulder strap in a canvas bag.
Treatment with antineoplastons can be very costly to patients without insurance coverage, exceeding $100,000for the first year of intravenous treatment. Many insurance companies consider antineoplaston therapy to beinvestigational and unproven and will not cover the cost.[7][8] The administered "antineoplastons" are very cheapand widely available chemicals that cost no more than 80 cents per treatment [9].
Proposed mechanisms
Antineoplastons have never shown to be effective in treating human cancer. Independent tests at atthe National Cancer Institute have never been positive.[10] The drug company Sigma-Tau Pharmaceuticalscould not duplicate Burzynski's claims for AS-2.1 and A-10. The Japanese National Cancer Institute hasreported that antineoplastons did not work in their studies. No scientific coauthor of Burzynski publications has
endorsed his use of antineoplastons in cancer patients.[9]
Burzynski suggest that antineoplastons A10 and AS2-1 both work by inhibiting oncogenes,promoting apoptosis, and activating tumor suppressor genes [6]. Several other mechanism of action have beenproposed.
One of the factors that allows some cancers to grow out of control is the presence of abnormal enzymes, abyproduct of DNA methylation. In the presence of these enzymes, the normal life cycle of the cells is disruptedand they replicate continuously. Antineoplastons have been shown in the laboratory to inhibit theseenzymes [11].
Recent studies have shown that inhibiting histone deacetylase (HDAC) promotes the activation of tumor suppressor genes p21 and p53. Phenylacetic acid contained in the AS2-1 mixture has been shown to be a
weak HDAC inhibitor [12]
.
References
1. ^ (1998) "Burzynski probe finds unflattering picture". NCRHI News 21 (5).2. ^ Goldberg P (1998). "The Antineoplaston Anomaly: How a Drug Was Used for Decades in Thousands
of Patients, With No Safety, Efficacy Data". The Cancer Letter 24 (36): –.3. ^ Burzynski SR (1986). "Antineoplastons: history of the research (I)". Drugs under experimental and
clinical research 12 Suppl 1: 1-9. PMID 3527634.4. ^ Ralph Moss (1996), The Cancer Industry ISBN 1881025098
5. ^ NCI Drug Dictionary, Definitions of antineoplastons A10 and AS2-16. ^ a b S.R. Burzynski, The Proposed Mechanism of Antitumor Activity of Antineoplastons (ANPs) in High
Grade Glioma Pathology (HBSG) Integrative Cancer Therapies 2006; 40-477. ^ Aetna Clinical Policy Bulletin, Antineoplaston Therapy and Sodium Phenylbutyrate8. ^ Blue Cross/Blue Shield Medical Policy, Antineoplaston Therapy9. ^ a b Saul Green, Stanislaw Burzynski and "Antineoplastons", adapted from a talk at the American
Association for Clinical Chemistry Symposium, Atlanta, 1997.
10. ^ Burzynski SR (1999). "Efficacy of antineoplastons A10 and AS2-1". Mayo Clin. Proc. 74 (6): 641-2.PMID 10377942.
11. ^ Liau MC, Burzynski SR (1986). "Altered methylation complex isozymes as selective targets for cancer chemotherapy". Drugs under experimental and clinical research 12 Suppl 1: 77-86. PMID3743383.
12. ^ Jung M (2001). "Inhibitors of histone deacetylase as new anticancer agents". Curr. Med.Chem. 8 (12): 1505-11. PMID 11562279.
In this experiment, we converted 1,4-dimethoxybenzene into 1,4-di-t-butyl-2,5,-
dimethoxybenzene. This reaction illustrates the Friedel-Crafts alkylation of an activated benzene
molecule with a tertiary alcohol in the presence of sulfuric acid as the Lewis acid catalyst. The
overall reaction is shown below:
The first step of the reaction involves the protonation of tert-butyl alcohol, followed byloss of water. Thus, an electrophilic tert-butyl carbocation is generated through the reaction of
tert-butyl alcohol with sulfuric acid acting as the dehydrating agent. This reaction is shown
below:
The advantage of this method for generating the electrophile is that the tertiary butyl
cation is a stable carbocation and will not undergo rearrangement. In the next step, 1,4-
dimethoxybenzene reacts with the carbocation generated from tert-butyl alcohol, and a
trisubstituted product, 1-tert-butyl-2,5-dimethoxybenzene is formed. This involves the addition
of the electrophilic carbocation to the electron-rich aromatic system. Benzene uses two of its π
electrons to react with the electrophile, forming a σ-complex or arenium ion. The σ-complex
subsequently loses a proton to reconstitute the aromatic system, while also regenerating the
catalyst. The arenium ion, intermediate carbocation, is stabilized by resonance, which delocalizes
its charge. This alkylation occurs quite readily because the aromatic ring is activated toward
electrophilic aromatic substitution by the two electron-donating (activating) methoxy groups.
Because the methoxy groups are ortho-para directors, alkylation occurs ortho to the methoxy
group present. This reaction and the three resonance structures represented in this process are
shown below:
Formation of Tert-butyl Carbocation via Dehydration of Protonated Alcohol
The limiting reagent for this Friedel-Crafts alkylation reaction is 1,4-dimethoxybenzene.
OBSERVATIONS AND R EMARKS During experimentation many notable observations were
made. First, the product obtained directly after addition of slow sulfuric acid addition had a
slightly pinkish color. The flask become noticeable warm upon the addition of sulfuric acid,
signifying this was an exothermic reaction. Also, a yellowish color was observed during
recrystallization, which possibly indicated impurities. Lastly, the resulting product, 1,4-di-t-
butyl-2,5,-dimethoxybenzene was obtained, which was a white crystalline solid, feathery in
texture. The low percent yield (52%) could be due to the fact that many of the crystals were
stuck in the reaction tube and could not be removed for weighing.
Name StructureMol. Wt.
(g)
Amt
Used
Mol
UsedEq.
b.p/m.p
(°C)
Density
1, 4-
dimethoxybenzene 138.16 6.0 g 0.0434 1.00213
55-59
1.053
g/cm3
t-butyl alcohol 74.12 10 mL 0.1053 2.0082.8
25-26
0.775
g/mL
Concentrated H2SO
4 98.08 30 mL 0.5628 -290-335
10
1.84
g/mL
1,4-di-t-butyl-2,5,-
dimethoxybenzene250.37 - - -
104-105
336.3 0.924g/cm3
Solubility data: 1, 4-dimethoxybenzene- Soluble in acetone. Very soluble in ether, benzene.
t-butyl alcohol: Miscible in ester, aromatic and aliphatic hydrocarbons. Soluble in water. Miscible in alcohol andether. 1,4-di-t-butyl-2,5, dimethoxybenzene: very low solubility in water and methanol
Concentrated H2SO
4: Soluble in acetic acid water,proportions in ethanol.