USING ENZYME THERAPY TO
DEAMINIZE ARGININE AND STARVE
CANCER
DR. KEVIN CONNERS
Conners Clinic | 1654 County Road E E, Vadnais Heights, MN 55110 |
www.ConnersClinic.com
CONTENTS
Section One
The Role of Arginine in Normal Tissue
Section Two
Arginine’s Role in Cancer Growth
Section Three
Novel Ways to Reduce Arginine in Patients
DATA……………………………………………..
CONCLUSION……………………………………
Conners Clinic | 1654 County Road E E, Vadnais Heights, MN 55110 |
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SECTION ONE – The Role of Arginine in
Normal Tissue
Arginine is a non-essential amino acid found in normal tissue in humans. It
is non-essential because it is normally synthesized in the cell; however,
many consider it semi-essential since studies have proved that both
children and diseased adults have hindered abilities to produce adequate
amounts. The concentration of studies regarding the physiological need for
arginine, in particular, L-arginine, center around its role in nitric oxide (NO)
production. NO has been identified as an important intra- and trans-cellular
signaling molecule involved in the regulation of many physiological and
pathophysiological processes. The most common rational for
supplementing L-arginine is to stimulate NO production in endothelial cells
which can aide in vasodilation, vascular proliferation, and other essential
functions.
However, it should be noted, that NO is synthesized through several
pathways in the body that then produce very different results depending on
the origin of tissue effected. The nitric oxide production occurs through
precursors called nitric oxide synthases named aptly after their unique
roles. Endothelial nitric oxide synthase (eNOS) is usually the desired target
of NO production for patients with heart disease. Studies have shown that
supplemental L-arginine coupled with citrulline has direct effects in the
endothelial cell in reducing inflammation and decreasing tone of vascular
smooth muscles. This outcome can be extremely beneficial reducing a
variety of morbidities known to cardiovascular disease (CVD).
Unfortunately, there are other effects of NO in tissues that may be less
desirable especially in those suffering from other disorders. It is the opinion
of this author that indiscriminately stimulating NO production by
supplementation with L-arginine must be cautioned. NO is also used in the
immune process through Inducible nitric oxide synthase (iNOS). Here it
aids in production of Th1 cytokines, which, in autoimmune individuals, may
not be a desired outcome.
Neuronal nitric oxide synthase (nNOS), working primarily in the central
nervous system, is the third subset in the NO cascade that will also be
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upregulated when one manipulates NO synthesis. Though this paper is not
suggesting that dietary stimulation of NO is contraindicative, it is
suggesting that, depending on the diagnosis of the patient, stimulation of
NO should be questioned due to the difficulty in discriminating between
eNOS, nNOS and iNOS, the three key enzymes generating nitric oxide
(NO) from the amino acid l-arginine and their distinct effects on local
tissue.
iNOS-derived NO plays an important role in numerous physiological (e.g.
blood pressure regulation, wound repair and host defense mechanisms)
and pathophysiological (inflammation, infection, neoplastic diseases, liver
cirrhosis, diabetes) conditions. iNOS is the synthase isoform most
commonly associated with malignant disease. Nevertheless, the role of
iNOS during tumor development is highly complex, and incompletely
understood. Both promoting and deterring actions have been described,
presumably depending upon the local concentration of iNOS within the
tumor microenvironment. In particular, pivotal effects such as malignant
transformation, angiogenesis, and metastasis are modulated by iNOS.
Both iNOS and eNOS stimulate angiogenesis which prove to be a horrible
outcome for patients with cancer and iNOS may stimulate a tumor’s own
production of self-defense immune cells.
There are several mechanisms by which L-arginine may be transported
into the cells. First, there is a family of specific cationic amino acid
transporter (CAT) proteins consisting of four members (CAT-1, -2A, -2B
and 3). Most interestingly, pro-inflammatory mediators such as
lipopolysaccharides (LPS) or interferon- (IFN-), which stimulate iNOS,
consume L-arginine to considerable extent, causing an up-regulation of
cellular L- arginine uptake.
From a cancer perspective, increased LPS expression from gram-negative
bacteria destruction increases iNOS and L-arginine uptake of surrounding
cancer cells. This is important for cancer patients with either concurrent
gram-negative bacterial infections (such as Lyme or h. Pylori) or a cancer
caused by gram-negative bacteria. For instance, Helicobacter Pylori is the
number one cause of stomach cancer worldwide.
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So, while upregulating NO may be extremely important in patients with
CVD proving clinical outcomes such as decreased blood pressure and
increased angiogenesis, it has much less desired effects on patients with
cancer.
SECTION TWO – Arginine’s Role in
Cancer Growth
Normal, adult human cells are able to synthesize arginine from metabolic
precursors via the urea cycle (see lower image). One of the steps in this
pathway involves the argininosuccinate synthase (ASS) catalyzed
conversion of citrulline to argininosuccinate. Some cancer cells from
tumors such as melanoma, hepatocellular carcinoma, pancreatic cancer,
prostate cancer, mesothelioma, and others are deficient in ASS and must
instead obtain arginine from the blood for growth and survival. Therefore,
depleting arginine from the blood can control tumor growth and even
eliminate arginine-requiring cancers without damage to normal tissue cells.
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Understanding this pathway, studies prove that Arginine deprivation
therapy has been shown to be an effective means for the treatment of
some forms of cancer. Recent clinical trials have found that human
hepatocellular carcinomas (HCC) cell lines that require arginine for growth
have been effectively reduced in size with the use of arginine reducing
medication. Therefore, selective elimination of arginine from the circulation
may be a means of treating patients with metastatic melanoma or nonresectable HCC. Unfortunately, the medication used in the trials is still
years away from FDA approval so this paper is suggesting some novel
approaches to achieve similar ends.
The enzyme arginine deaminase (ADI) metabolizes arginine into citrulline.
However, ADI is only found in microbes and not in humans. ADI is
therefore, highly immunogenic and has a short serum half-life following
injection. These potential drawbacks (microbial source and thus viewed as
foreign by the human immune system, and a short serum half-life) can be
overcome by covalent attachment of polyethylene glycol (PEG) to
argininedeiminase in a drug termed this ADI-PEG 20. However, promising
clinical trials do not equate to widespread use, perhaps, in part to other
natural, less-expensive avenues to achieve similar outcomes.
SECTION THREE – Novel ways to
Reduce Systemic Arginine in Cancer
Patients
This paper defends that there may be both a novel explanation to the
benefits of protein reduction diets as well as appropriate use of specific
proteases in treating cancer patients.
A protease is an enzyme that breaks down proteins. The body makes
specific proteases for unique purposes that can both assist in the spread of
cancer or hinder its growth. Matrix metalloproteinases (MMP), for example
are zinc-dependent proteolytic enzymes capable of breaking down
basement membranes and most extracellular matrix (ECM) components.
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Understand, degradation of such tissue allows the facilitation of
metastasis. MMP expression and activation are normally under careful
regulation in physiological conditions in order to prevent uncontrolled
destruction of body tissues but this regulation can be modified or disrupted
in pathological processes, including cancer. MMP inhibitors have been
used with only mixed results in clinical trials.
MMPs and other proteases, together with various co-operating factors,
cause degradation of the normal tissue surrounding the cancer cells and
enable them to invade into normal tissue and spread in the body.
Moreover, some proteases catalyze activation of growth factors and thus
regulate growth of primary tumors and metastases. High tumor levels of
components of one protease system, the plasminogen activation system
(PAS), are strong markers for a poor prognosis.
Numerous current studies are focusing on finding new types of protease
inhibitors, and testing the inhibitors in animal tumor models. One proposal
focuses on utilizing competing proteases and catabolizing bacteria that
neither increase tumor growth nor pave the way for expansion to decrease
arginine availability to cancer cells.
A suggested avenue of approach may be to utilize products that may help
clear tissue arginine levels. L-Arginine is known to be catabolized by some
lactic acid bacteria as well as some enzyme systems. The correlation
between the occurrence of arginine deiminase pathway enzymes and the
ability to catabolize arginine was examined in a recent study. There exists
three arginine deiminase pathway enzymes, arginine deiminase (explained
above), ornithine transcarbamylase, and carbamate kinase. All these were
measured in cell extracts of 35 strains of wine lactic acid bacteria.
Lactic acid bacteria from both strains of wine and sourdough contain
strains such as Lactobacillus sanfranciscensis CB1; Lactobacillus brevis
AM1, AM8, and 10A; Lactobacillus hilgardii 51B; and Lactobacillus
fructivorans DD3 and DA106 which showed all three enzyme activities.
Lactobacillus plantarum B14 did not show CK activity while L.
sanfranciscensis CB1 showed the highest activities. Unfortunately, the
author can find no products currently on the market that contain high
amounts of the above desired bacteria.
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Combining lactic acid bacteria with fermented strains of proteolytic
enzymes may also help to increase ADI and reduce tissue arginine levels.
If the clinical goal is to reduce tissue arginine levels thereby reduced risks
of growth and metastasis in arginine-driven cancers, concentrating on
increasing arginine deiminase (ADI), ornithine transcarbamoylase (OTC),
and carbamate kinase (CK) activities, which comprise the ADI (or arginine
dihydrolase) pathway may include a protocol such as this:
 Vegetarian-like diet with reduced protein intake
 NO added protein supplementation
 Supplement probiotic consisting of at least one or more
of the above listed strains
 Supplement fermented Nattokinase and Catalase
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