Alternative
Medicine Cancer Treatments:
Antineoplastons
National Cancer Institute Report
The antineoplastons have been considered
an unconventional method of cancer treatment because there have been very
few independent interpretable scientific data on their potential clinical
efficacy.
Based on a recent report of observed
responses in brain cancer patients treated with antineoplastons at the
Burzynski Research Institute (founded by Dr. S.R. Burzynski) in Houston,
Texas, the Cancer Therapy Evaluation Program (CTEP) conducted a site visit
to review a "best case" series of clinical responses to antineoplastons
in the treatment of brain tumors at that institute. This case series does
not constitute a clinical trial; the cases were selected on the basis
of positive response from many different studies of antineoplaston treatment
at the Institute.
The site visit team determined that antitumor
activity was documented in this best case series and that the conduct
of Phase II trials was indicated to determine the response rate. The antineoplastons
were presented as DN Stage IV candidates for the conduct of Phase II trials
in glioblastoma multiforme, anaplastic astrocytoma, pediatric brain tumors,
and low grade gliomas, to confirm the observations in brain tumors at
the Burzynski institute.
It was proposed that the same treatment
regimen as that used at the institute would be used in the Phase II trials.
A decision regarding subsequent trials (e.g., other tumors, additional
Phase I development, Phase III trials in brain tumors) would be deferred
until the results of these initial trials were known. Dr. Burzynski presented
background on antineoplaston research. His research is based on the hypothesis
that antineoplastons are components of a biochemical defense system against
cancer. The antineoplastons are medium and small size peptides and amino
acid derivatives that form the defense against cancer by inducing differentiation
in neoplastic cells. Initial study on antineoplastons was concentrated
on isolation of peptides in blood and urine of healthy people.
Two main groups of antineoplastons have
been isolated -- one including compounds with broad spectrum activity
in many different cell lines and the other with a narrow spectrum of activity
against single cell lines. Of the broad-spectrum antineoplastons, five,
including antineoplastons Al, A2, A3, A4, and A5, have been isolated from
normal human urine. Antineoplaston A10 was the first active ingredient
that has been reproduced synthetically. Antineoplaston AS2-1 and AS2-5
are metabolites of antineoplaston A10 that have also been synthesized.
Dr. Burzynski cited experiments that
have shown that antineoplaston A10 intercalates In a stereospecific manner
between base pairs in double-helical DNA. The main mechanism of action
of antineoplaston AS2-1 appears to be inhibition of incorporation of glutamine
into proteins in cancer cells. The other antineoplastons all seem to have
different mechanisms of action involving inhibition of methylation of
RNA and DNA. The potency of the antineoplastons has been confirmed in
tissue cultures, but with relatively low specificity. No significant activity
was seen in NCI tissue culture studies when low concentrations were used.
Tests in various models for induction
of cell differentiation (e.g., human promyelocytic leukemia, fibrosarcoma)
showed that antineoplastons can induce cell differentiation. Antineoplastons
also showed activity against human breast cancer in athymic mice. Acute
and chronic toxicity studies of antineoplastons showed that antineoplastons
A10 and AS2-l have extremely low toxicity. The LD50 of antineoplaston
A10 was greater than 10 g/kg in mice and rats; the LD50 of AS2-1 was approximately
3 g/kg in mice and rats. There was no apparent toxicity in mice given
daily injections of 1 g/kg/day for 1 year. The compounds were not found
to be mutagenic. PK studies of both the oral and injectable forms of antineoplastons
A10 and AS2-1 showed that both compounds are absorbed rapidly. The maximum
concentration of AS2-1 can be detected in urine approximately 3 hours
after oral administration. A10 is absorbed somewhat slower, reaching the
highest concentration in blood approximately 3 hours after oral administration.
The compounds are cleared more rapidly after i.v. administration; A10
cannot be detected in the blood approximately 2 hours after i.v. administration.
Thus, frequent dosing or continuous
infusions is indicated for clinical studies. From studies in mice, it
was also noted that antineoplaston A10 is retained in brain tissue. A
concentration of approximately 500 micrograms/g of brain tissue in mice
was reached about 1 hour after oral administration; however, the concentration
dropped to a negligible amount within about 6 hours.
A review of the best case series of seven
patients with brain tumors was provided by the neuroradiologist at the
NIH Clinical Center who participated in the NCI site visit to the Burzynski
Institute. All patients received a combination of antineoplastons A10
and AS2-l. Some patients initially progressed on a study using oral antineoplastons
with low-dose methotrexate.
All of the responses were seen after
i.v. antineoplaston administration, and, therefore, the proposed Phase
II studies would be conducted using the i.v. regimen (i.e., 1 g/kg/day
of A10 and 0.5 g/kg/day of AS2-1).
The results of the review were presented
as follows, with case histories distributed to all committee members:
Marked decrease in tumor size and possible
complete response (CR) of approximately 4- months' duration in a 46-year-old
female with glioblastoma multiforme. Possible CR, thus far of 2-years'
duration, in a 36-year-old female with anaplastic astrocytoma. Partial
response, or possible CR, in a 47-year-old male with aggressive, infiltrating
glioma (astrocytoma or mixed astrocytoma/oligodendroglioma).
Substantial decrease in tumor size in
7-year-old male with well-differentiated astrocytoma. Decrease in tumor
size in a 40-year-old female with an unusually large glioblastoma multiforme
tumor. CR, thus far of approximately 1-1/2-years' duration, in a 10-year-old
male with anaplastic astrocytoma. Good response, possible CR, in a 30-year-old
male with anaplastic astrocytoma. It was noted that several of the patients
received antineoplaston treatment shortly after taking radiation therapy,
and the question of the possibility of a confounding effect of residual
continued improvement following radiotherapy on evaluating response to
antineoplastons was raised.
However, complete resolution of both
postradiation edema and tumor enhancement was demonstrated on CT scans
in several cases, therefore negating the possible problem of differentiating
between progression of tumor and postradiation edema.
In discussion, it was clarified that
the proposed Phase II trials would utilize the combination of antineoplastons
A10 and AS2-l, without any other therapy. No problems were foreseen with
filing the INDA on the pharmaceutical preparation provided by Dr. Burzynski.
The primary rationale for using a mixture of the two antineoplastons in
the proposed trials is to duplicate exactly the regimen used in the studies
at the Burzynski Institute. http://www.cancermed.com/brochure.htm
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