ANTINEOPLASTONS: AN ALTERNATIVE CURE AGAINST MALIGNANT BRAIN TUMOURS

ANTINEOPLASTONS: AN ALTERNATIVE CURE AGAINST MALIGNANT BRAIN TUMOURS

Dr Evangelos Kontargiris,

Bsc, Biomedical Sciences, PhD in cellular and molecular physiology

In oncology many years ago existed the so-called “alternative cures” which were applied to cancer patients and were completely different to the typical anti-cancer treatments. The alternative cures were characterized as “unproved” by their opponents because according to their opinion, the appropriate clinical tests were not done and therefore the therapeutic value of these treatments is unknown. One of these alternative cures is the so called therapy with antineoplastons. There are several clinical case studies that were done and especially in the tumors of the brain, which could be characterized valid.

“The body itself has its own treatment against cancer”, according to Stanislaw R. Burzynski a medical doctor and a biochemist born in Poland who works in Huston, Texas. Dr Burzynski discovered that mixtures of peptides, amino acids and other simple organic substances that appear naturally in the whole of the human body inhibit the development of cancer cells. These substances are part of a biochemical defense system that is completely different from the immune system. The immune system protects the human organism by destroying the “foreign invaders” or the defective cells. On the other hand this biochemical defense system reprograms or repairs the defective cells by transferring “correct” information in defective cells which receive the “order” to develop naturally afterwards.^{1, 2}

Dr Burzynski named these specific peptides antineoplastons because of their ability to stop the development of the neoplastic (cancer) cells. He discovered that cancer patients have drastic decrease of these peptides in their organism. Therefore, by simply inserting antineoplastons into the blood of the patients orally or intravenously, results in shrinking or in a complete recession of the malignant tumor. Nevertheless Dr Burzynski stated that the therapy with antineoplastons is not effective for all types of cancer and for all cancer patients, but patients with brain cancer, prostate cancer, certain types of lung cancer, urine bladder cancer and cancer of the pancreas responded well in this therapy, which is safe and non-toxic. The human organism has a very good tolerance in antineoplastons, which are natural substances, even in high doses. Moreover antineoplastons do not cause any of the disastrous side effects which are induced by chemotherapy and radiotherapy in the organism.^1,2 Some side effects that could be mentioned are anemia and hypernatraemia in patients in percentages of 1.4% and 0.5% respectively. Furthermore some mild side effects are skin rashes in a percentage of 0.76% and slurred speech in a percentage of 0.9%. Most patients experience increased diuresis, which may lead to dehydration and thirst. In general, however, adverse reactions observed during treatment with antineoplastons have usually been transient and mild.³

The current theory of the mechanism of action of antineoplastons is their function as “molecular switches,” which turn on tumor suppressor genes and turn off oncogenes. Such molecular switches should theoretically control cancer because they deal directly with its biochemical causes: increased activity of oncogenes and decreased expression of tumor suppressor genes. It is known that there are accelerators and brakes in the cancer process. Oncogenes are the accelerators, and normal tumor suppressor genes serve as brakes. ³ The research that was done many years ago about the therapy with antineoplastons in malignant tumors of the brain and especially with the antineoplastons named A10 (or Α10-Ι) and AS2-1 is published by Dr Burzynski himself and is referred to case studies of patients.³

The first case study concerned a young man who was 10 years old and was diagnosed with low-grade astrocytoma in October 1997. Because his tumor grew in a difficult area of involvement, including the thalamus and brain stem, he was not a candidate for surgery and did not receive any standard treatment. He began treatment with antineoplastons A10 and AS2-1 in April 1998 and also he was partially paralyzed in a wheelchair. His contrast-enhancing tumor decreased and finally could no longer be seen on magnetic resonance imaging (MRI) in March 1999 (Figure 1). Repeated positron emission tomography (PET) scans did not show tumor ecurrence. This patient has made a complete recovery. ³

Figure 1: Treatment of low-grade glioma with antineoplastons A10 and AS2-1 in a 10-year-old male. Magnetic resonance imaging (MRI) of the head with gadolinium. Images in the upper row show a large tumor before treatment. Images in the lower row confirm disappearance of the tumor after 11 months of treatment (Burzynski, 2004).

According to another case study one patient presented one of the most difficult brain stem glioma cases ever treated in the Burzynski clinic. She arrived at the clinic in October 1998, when she was less than 3 months old. The patient was diagnosed with a large intrinsic diffuse brain stem glioma, measuring approximately 7 cm across its largest diameter. Unfortunately, there was no conventional treatment available for her. Her parents were told she would almost certainly die within 1 month. She came to Burzynski clinic in terminal condition and began treatment immediately. After 4 months of treatment with antineoplastons A10 and AS2-1, her contrast-enhancing tumor was no longer visible on MRI (Figure 2). She had been near death at the beginning of antineoplaston treatment and was being kept alive only by large dosages of corticosteroids. Pre-treatment photographs showed the child with facial nerve paralysis and extensive swelling of the face resulting from the corticosteroids. Six months later, her symptoms decreased and disappeared. Now, 5 years from her diagnosis, she is a completely normal and healthy child. ³

Figure 2: Treatment of progressive intrinsic diffuse brain stem glioma with antineoplastons A10 and AS2-1 in 3-monthold female, for almost four years. Patient was diagnosed shortly after birth with large inoperable brain stem glioma and presented for treatment with antineoplastons in terminal condition. Magnetic resonance imaging of the head with gadolinium shows decrease and disappearance of contrast-enhancing tumor (Burzynski, 2004).

Another case study refers to a 54-year-old male diagnosed with high-grade malignant glioma (mixed astrocytoma, oligodendroglioma) on February 23, 1996. At the time of diagnosis, he underwent subtotal tumor resection and did not receive any standard treatment. He was treated with antineoplastons A10 and AS2-1 from March 27, 1996, to August 27, 1997. He had a large tumor in the right temporal lobe, which gradually decreased and disappeared (Figure 3). He has been tumor free for more than 6 years.³

Figure 3: Treatment of high-grade glioma with antineoplastons A10 and AS2-1. After the treatment with antineoplastons A10 and AS2-1 from March 27, 1996, to August 27, 1996, his tumor gradually decreased and disappeared. Magnetic resonance imaging of the head with gadolinium shows gradual decrease and disappearance of the tumor (Burzynski, 2004).

One more case study was a good example of a rapid response. The patient was 41 years old when on April 18, 2000, he underwent a partial resection of a brain tumor and was diagnosed with anaplastic astrocytoma. After the surgery, he received radiation therapy, which was completed in June of 2000. On December 1, 2000, he underwent a second craniotomy for tumor recurrence, which confirmed the same diagnosis. After he developed a second recurrence, he began treatment with antineoplastons A10 and AS2-1 on February 22, 2001. His follow up MRI on April 25, 2001, did not show a contrast enhancing tumor (Figure 4). The treatment with antineoplastons was discontinued on August 5, 2001. A follow-up PET scan on January 22, 2003, did not show any tumor recurrence (more than 3 years after his diagnosis).³

According to another case study 26-year-old female was diagnosed with glioblastoma multiforme and underwent subtotal resection of the tumor on July 28, 1994. She received initial treatment with radiation therapy and chemotherapy with BCNU (bis-chloroethylnitrosourea). In January of 1995, due to tumor recurrence, she received chemotherapy with procarbazine. After the second recurrence of her tumor, she received treatment with antineoplastons A10 and AS2-1 from April 2, 1996, to July 29, 1996. The tumor decreased and was no longer seen on repeated MRIs (Figure 5). She survived and now is in good health more than 9 years from tumor diagnosis.³

Figure 4: Rapid response to treatment with antineoplastons A10 and AS2-1 in patient with high-grade glioma. The patient is a 41-year-old male treated with antineoplastons after his anaplastic astrocytoma progressed after partial resection, radiation therapy, and a second resection. MRI of the head with gadolinium shows disappearance of contrast-enhancing tumor after the treatment with antineoplastons (Burzynski, 2004).

Figure 5: Treatment of glioblastoma multiforme with antineoplastons A10 and AS2-1 in a 27-year-old female. The patient was diagnosed with glioblastoma multiforme on July 28, 1994. She started antineoplastons A10 and AS2-1 on April 2, 1996, after tumor recurrence postsubtotal resection, radiation therapy, and 2 types of chemotherapy. Magnetic resonance imaging of the head with gadolinium shows gradual decrease and disappearance of the tumor. This patient’s survival is more than 9 years (Burzynski, 2004).

In the same article information is given about the action mechanism of the antineoplastons A10 and AS2-1. The antineoplaston AS2-1 via its active ingredient phenylacetic acid (PN) causes downregulation of the oncogene Bcl-2 and also activates the tumor suppressor gene p53. In most cases the protein p53 activates the p21 gene which directs the synthesis of the p21^WAF1/Cip1 protein. Induction of p21^WAF1/Cip1 suppresses human glioma cell proliferation. This protein activates promoter sequences of the tumor suppressor gene p53, which is undergoing demethylation. DNA methylation of tumor suppressor genes is a common mechanism of silencing the genes. Removal of methyl groups (demethylation) activates the gene,

which causes malignant cells to die through apoptosis. The main ingredient of A10-I is phenylacetylglutamine (PG). It was found that PG inhibits the uptake of growth-critical amino acids, such as 1-glutamine and 1-leucine, in neoplastic cells.³

One article published also in 2004 by Dr Burzynski and his colleagues is referred to a 40-year-old man diagnosed with recurrent brainstem glioblastoma multiforme who received antineoplastons. The patient underwent a left suboccipital craniotomy with subtotal resection of the pontine tumor on June 2, 1999. Between June 18, 1999, and August 2, 1999, he underwent radiation therapy and 51 days after completion of radiation therapy, tumor recurrence was confirmed. Treating physicians informed the patient that his tumor could not be cured and he may have no longer than 6 months to live, with or without chemotherapy. Approximately 2 months after completion of radiation therapy, he was admitted for administration of intravenous antineoplastons A10 and AS2-1 over 655 consecutive days with the exception of a few short interruptions. On several occasions, antineoplaston treatment was discontinued due to some side effects such as mild hypernatremia, fatigue, decreased white blood cell count (2,5 x 10³ /μl) and elevation of transaminases. When the symptoms of the side effects were not observed in the patient, the treatment was continued. Follow-up MRIs of the head at 8-week intervals showed a continuous decrease of the size of the tumor after antineoplaston treatment for 4 months and for 3 years (Figure 6). The most recent clinical evaluation of December 1, 2003, showed the patient in good condition and complaining only of minor symptoms including slight balance difficulties, decreased lacrimation in the left eye, left-sided facial muscle weakness, and slight short term memory deficit. The patient is able to carry on normal activities and works full-time. ⁴

Figure 6: MRI image of the head of a 40-yerar-old patient with recurrent brainstem glioblastoma multiforme. Images in the upper row show a large tumor that progressed after radiation therapy and prior to antineoplaston administration. Images in the middle and lower rows show a marked decrease in the tumor size after administration of antineoplastons (Burzynski, et al, 2004).

According to the results of another study antineoplastons AS2-1 and A10 contributed in the survival of more than 5 years of one small group of patients with recurrent, diffuse, intrinsic brainstem glioblastoma and anaplastic astrocytoma. In this article one case was of special interest because it represents successful treatment of a patient with recurrent, diffuse, intrinsic brainstem glioblastoma. This patient was a 40-yearold man diagnosed with glioblastoma of the brainstem in May 1999, underwent subtotal tumor resection and standard radiation therapy. Subsequent MRI and PET scans documented tumor recurrence. Two months after completion of radiation therapy, he started antineoplastons, which were administered over 650 days with the exception of a few short interruptions. Complete response was documented after approximately 1 year of treatment. He continues to be tumor free more than 5 years from the start of antineoplaston therapy (Figure 7).⁵

Figure 7: Treatment with antineoplastons of glioblastoma multiforme of the brainstem in a 40-year-old man. MRI image before and more than 5 years after the start of treatment. The image on the left side shows a large tumor that progressed after radiation therapy and prior to antineoplastons treatment, and the image on the right side shows resolution of the tumor 5 years and 5 months later, after administration of antineoplastons (Burzynski, et al 2006).

The same article states the proposed mechanism of anti-tumor activity of antineoplastons in high-grade glioma pathology (HBSG). Phenylacetic acid (PN) which is the active ingredient of antineoplaston AS2-1, inhibits farnesylation of protein p21 of the RAS oncogene, inhibits RAS and BCL-2, and activates the tumor suppressor genes TP53 and p21 through demethylation of their promoters. Phenylacetylglutamine (PG) which is the main ingredient of antineoplaston A10  restores global methylation of DNA, inhibits the oncogenes AKT2 and MYCC, activates the tumor suppressor genes PTEN and MAD, and restores activity of the mutated INI1 protein through normalization of nuclear transport. Both PN and PG promote apoptosis: PN through inhibition of BCL-2 and PG through deamidation of the BCL-XL protein. (Figure 8). ⁵

Another interesting article by Dr Burzynski and his colleagues refered to the effectivity of antineoplaston therapy in patients with primitive neuroectodermal tumors. According to the study thirteen children, either with recurrent disease or high risk, were treated in phase II studies with antineoplastons. The median age of patients was 5 years, 7 months. Medulloblastoma was diagnosed in 8 patients, pineoblastoma in 3 patients, and other primitive neuroectodermal tumors in 2 patients. Previous treatments included surgery in 12 patients, chemotherapy in 6 patients, and radiation therapy in 6 patients. Six patients had not received prior chemotherapy or radiation. The treatment consisted of intravenous infusions of the antineoplastons, A10 and AS2-1, and was administered for an average of 20 months. Complete response was accomplished in 23%, partial response in 8%, stable disease in 31%, and progressive disease in 38% of cases. Six patients (46%) survived more than 5 years from initiation of antineoplastons; 5 were not treated earlier with radiation therapy or chemotherapy. The serious side effects included single occurrences of fever, granulocytopenia, and anemia. The study is ongoing and accruing additional patients.⁶

Figure 8: Suggested mechanisms of the action of the antineoplastons AS2-1 and A10 in the pathology of glioma pathology (Burzynski, et al 2006).

In this study 2 patients were of the greatest interest. The first patient was a 1-year-old female who, in December 1996, was diagnosed with a brain tumor and underwent partial resection on December 18, 1996. The pathology diagnosis was pineoblastoma. The patient did not receive any further treatment, and her follow-up MRIs of January 7, 1997, and February 26, 1997, revealed a recurrent and progressive tumor. She began antineoplastons on February 27, 1997. Follow-up MRIs have shown a decrease of the tumor size, and PET scans of the brain on September 16, 2002; September 25, 2003; and December 4, 2003, did not reveal any hypermetabolic lesion, confirming a complete response. The patient has recovered completely from her symptoms, including blindness, and has been living a normal life for more than7½years since antineoplastons were started (Figure 9). The second patient was a 2-year-old white male who, on February 13, 1994, underwent a subtotal tumor resection and was diagnosed with medulloblastoma of the cerebellum and brainstem. He did not receive any further conventional treatment. On April 11, 1994, the patient began antineoplastons. The pre-treatment MRI of the head on March 8, 1994, showed residual enhancing tumor measuring 1.8 Χ 0.8 cm. After 6 weeks of treatment, the tumor was no longer visible, indicating complete response. On March 15, 1997, the treatment with antineoplastons was discontinued. The patient now lives a normal life, more than 10 years, 4 months since the start of treatment (Figure 10).⁶

Figure 9: Treatment of a 1-year-old girl with pineoblastoma .The patient’s tumor progressed after partial resection and was not treated with radiation and chemotherapy.T1-weighted gadolinium magnetic resonance imaging of the head shows decrease of the tumor size (left).Positron emission tomography (PET) scan confirms complete response (right).The patient has been living a normal life for 7½ years since initiation of antineoplastons (Burzynski, et al, 2005).

The study also examines the anti-cancer mechanisms of the antineoplastons A10 and AS2-1 in a molecular level in medulloblastoma. The antioneoplaston AS2-1 via its active ingredient PN interrupts signal transmission through the RAS pathway by decreasing farnesylation of the RAS protein, and the antineoplaston A10 via PG decreases expression of AKT2 in a dose-dependent fashion. This removes inhibitory effects of AKT2 on the pro-apoptotic protein BAD (Bcl-2-associated death promoter). Furthermore the antineoplaston AS2-1 via PN down-regulates anti-apoptotic Bcl-2, and the antineoplaston A10 via PG may also inactivate anti-apoptotic protein BCL-XL through deamidation. BCL2 and BCL-XL reside in the outer mitochondrial membrane and suppress apoptosis by blocking mitochondrial outer membrane permeabilization through the sequestration of activated BAX (Bcl-2–associated X protein) Inactivation of BCL-XL allows MYC to release cyctochrome c from mitochondria and trigger apoptosis  (Figure 11).⁶ It is also obvious that some of the mechanisms of action of antineoplastons A10 and  AS2-1 in the medulloblastoma cells ⁶ are similar to the ones that are referred to the pathology of glioma (Figures 8 and 11).⁵

Figure 10: Successful treatment of a 2-year-old male diagnosed with medulloblastoma of the cerebellum and brainstem. After subtotal resection, the patient did not receive radiation therapy or chemotherapy. T1-weighted gadolinium magnetic resonance imaging of the head shows disappearance of the tumor size after treatment with antineoplastons. The patient is now alive and well more than 10 years, 4 months since the start of treatment (Burzynski, et al, 2005).

Figure 11: Induction of apoptosis in medulloblastoma by PN and PG. (Burzynski, et al, 2005).

The results of this study show that the percentage of patients’ response is lower than for standard treatment of favourable primitive neuroectodermal tumors, but long-term survival in poor-risk cases and reduced toxicity makes ANP promising for very young children, patients at high risk of complication of standard therapy, and patients with recurrent tumors. ⁶

References

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Integr Cancer Ther 2004 3: 47-58.

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Jurida, Mohammad Khan, Chymbeelyn B. Larisma, Jaroslaw Paszkowiak and

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