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Topic 1: Angiogenesis and LCE
1. What is angiogenesis?
Angiogenesis is a natural physiological function by which new blood vessels form and grow to supply
oxygen and other vital nutrients to cells. Angiogenesis is a dynamic process regulated at the cellular level
through the maintenance of a delicate balance between pro- and anti-angiogenic factors. In normal,
healthy adult tissues, angiogenesis is restricted to episodic bursts related to reproduction, muscle growth,
increasing adipose mass, and wound healing.
2. How is angiogenesis triggered?
A limited set of events can trigger angiogenesis. Metabolic stress resulting from a low oxygen
environment is a potent inducer of vessel growth. Mechanical stress, inflammation, and oxidative stress
are other potential stimuli. Genetic mutations that occur in cancer can also stimulate angiogenesis by
activating or deleting genes involved in the control of angiogenesis
In the event of such stresses, affected cells react by producing pro-angiogenic factors such as vascular
endothelial growth factor (VEGF) that diffuse to neighboring established blood vessels and promote
their spread.
One of the first cellular events observed in response to VEGF is extravasation, which allows inflammatory
cells to migrate toward the signal source. Through the secretion of additional proangiogenic factors, these
inflammatory cells amplify the angiogenic signal. For their part, endothelial cells respond to the
angiogenic command by secreting specialized enzymes, called matrix metalloproteinases.
3. What are MMPs?
MMP’s are a special class of enzymes that target and cleave the fibrous proteins (collagen) of the
extracellular matrix. Upon activation, MMPs digest collagen fibers within the basement membrane that
constitute vessels walls. This creates a breach through which proliferating endothelial cells can migrate
toward the angiogenic signal. Along their path, endothelial cells produce extracellular matrix components
that assemble to form new vessel walls, leading to the formation of a functional blood vessel.
4. Which health conditions would be dependant on angiogenesis?
Antiangiogenic therapy was first developed to fight solid cancer, but when angiogenic factors were
determined to also contribute to non-solid tumor development, the concept was extended to include
hematologic malignancies such as leukemia, lymphoma, and myeloma. Although cancer is still the main
focus of antiangiogenic therapies, dozens of other diseases have also been associated with overactive
blood vessel growth. Psoriasis, rheumatoid arthritis, macular degeneration, atherosclerosis, as well as
obesity are good candidates for antiangiogenic therapy.
5. How does angiogenesis contribute to the development of hematologic malignancies?
It came as a surprise that angiogenesis could also contribute to the development of leukemia, lymphoma
and myeloma. The link was made with the report of increased bone marrow vascularization, high levels of
VEGF, and increased MMP activity in most hematologic malignancies.
As with solid tumors, increased angiogenesis in hematologic malignancies may feed and sustain cancer
cells.
Unlike with solid tumors, VEGF may directly stimulate malignant cell survival in non-solid tumors because
blood derived cancer cells expressed the receptor for this growth factor.
As for MMP activity, it correlates strongly with the dissemination of cancer cells out of their normal
environment.
6. I understand that angiogenesis is involved in the development of cancer, however, you also
mentioned angiogenesis is a normal process involved in wound healing. Does it mean that
targeting angiogenesis may compromise normal body functions?
No, because there are striking differences between vessels forming in physiological versus pathological
conditions.
In normal angiogenesis, new vessels rapidly mature and develop in an orderly structure with regular
branching at defined angles. Blood flows regularly in these vessels. Normal vessels are stabilized as long
as they are needed.
By contrast, in pathological angiogenesis growing vessels never mature completely. Vessels grow
tortuously, are disorganized, dilated, and leaky. This creates high interstitial pressure that hampers blood
flow. Due to persistence of pro-angiogenic factors, pathological vessels never fully stabilize.
This difference in stability may be exploited to specifically prune those vessels that grow in pathological
conditions.
7. Is there anything that we can rely on to maintain a healthy angiogenesis balance?
Several antiangiogenic drugs are being developed targeting specific facets of the angiogenic process.
One way to interfere with angiogenesis is through neutralization of VEGF activity. This can be done
by trapping the VEGF molecule, by preventing it from binding to receptors at the surface of endothelial
cells, or by reducing the number of such receptors. Avastin, the only antiangiogenic drug to have
reached the market so far, falls in this category.
Another approach uses small molecules that act inside endothelial cells by inhibiting the intracellular
signaling pathway normally triggered when VEGF binds to its receptor.
A third approach is aimed at restraining endothelial cell proliferation. Among other mechanisms, this can
be done through the inhibition of MMPs. Because these proteases are involved in breaking down the
extracellular matrix walls surrounding blood vessels, it is believed that inhibiting their activity may contain
blood vessels within their normal environment.
A fourth approach targets a specific subset of integrins, which are anchor proteins involved in vessel
persistence.
Finally, vascular targeting agents are also being developed that attack the vasculature structure causing
it to collapse.
8. Are there any natural products that can do the same thing?
There are natural alternatives for the modulation of angiogenesis. Cartilage extract, flaxseed, garlic,
ginseng, green tea, milk thistle, Noni juice, pomegranate, soy, tomatoes, and tumeric are among natural
sources of antiangiogenic molecules presently under NCI evaluation in clinical trials for cancer patients.
Among natural products with antiangiogenic activity, LCE, a liquid cartilage extract derived from a marine
source, is the one at the most advanced stage of clinical evaluation.
9. How does LCE differ from shark cartilage powder?
Both products are derived from shark cartilage. However, they are very different. Cartilage powder is a
crude extract with very little antiangiogenic activity per gram of proteins. Moreover, its fabrication
generally involves high temperatures that might alter this activity. By contrast, LCE is a concentrate of
active antiangiogenic molecules processed under conditions that preserve their biological activity. Only
LCE is supported by positive clinical studies.
10. How is LCE made? Where?
LCE is obtained through a patented manufacturing process that involves breaking up cartilage cell
membrane in purified water to liberate active molecules. The homogenate is then centrifuged and the
supernatant retained for serial steps of ultrafiltration allowing for the selection of molecules with
antiangiogenic activity. LCE is concentrated and purified at low temperature in a natural process. Atrium
Biotechnologies, located in Quebec City, Canada, has manufactured LCE for more than 10 years.
11. What is the state of the research on LCE?
Over the last 10 years, the therapeutic potential of LCE has been investigated in various angiogenesisrelated conditions including cancer, with clear signs of efficacy. In the course of clinical trials, over 900
patients have been treated with LCE in Canada, the United States, and Europe, some for several years.
Among the most significant results of those studies:
A significant survival advantage was seen for patients receiving a high dose of LCE in two Phase I/II
studies for lung and kidney cancers.
In a double-blind, placebo-controlled phase III trial involving 305 patients with refractory metastatic kidney
cancer, LCE doubled life expectancy (from 12.6 to 26.3 months) for a pre-planned cohort of patients
with clear cell histology, an ECOG=0, and a single metastatic site.
Recent characterization of LCE has documented its potential to sustain blood parameters (red blood cells
counts, hematocrit and hemoglobin values) within a human cancer population.
Topic 2: Anemia and cancer
1. How are anemia and cancer related?
Anemia is a frequent complication of cancer that can occur as a direct effect of the tumor or indirectly as a
result of its treatment.
Anemia has important detrimental consequences for cancer patients.
Cancer-related anemia is associated with intense debilitating fatigue that affects the QOL of patients and
may require postponement of treatments, an increase in the intervals between treatments, or a reduction
in dosages. Moreover, the general tissue hypoxia that results from anemia interferes with the
effectiveness of radiation therapy and chemotherapy. Tissue hypoxia also promotes angiogenesis, which
further sustains cancer growth.
The presence of anemia in cancer patients has been reported to increase the relative risk of death by
65%.
Topic 3: Comitris™
1. What is ComitrisTM?
ComitrisTM is a frozen marine liquid cartilage extract obtained through cutting-edge ultrafiltration
technology using only pure water as a solvent. Comitris TM is a dietary supplement.
2. What does it do?
ComitrisTM helps maintain a healthy angiogenic balance*, as well as healthy hematocrit and erythrocyte
levels*.
3. What does the name stand for?
Comitis is the ethymologic root of the word “concomitant” or adjuvant.
4. How does it work?
In vitro, ComitrisTM competes with vascular endothelial growth factor (VEGF) for receptor binding on
endothelial cells (EC). VEGF is a key regulator of the angiogenic process and Comitris TM prevents VEGF
action on EC. In vitro, ComitrisTM also inhibits specific matrix metalloproteinase (MMP-2 and MMP-9)
activities involved in the angiogenic process.
ComitrisTM is also involved in the modulation of blood parameters. It healps maintain healthy hematocrite
and erythrocyte levels. The mechanism responsible for the support of healthy blood parameters by
ComitrisTM is unknown at this point but may involve cytokine modulation.
5. Is ComitrisTM bioavailable and active when ingested?
ComitrisTM given orally was shown to control excessive angiogenesis1 and support healthy blood
parameters2 in healthy human volunteers. Such results attest of its bioavailability in humans.
6. What are the active molecules in this product?
No specific active molecule has been singled out in ComitrisTM. The product is a natural blend of selected
molecules that work in concert to sustain its complementary beneficial activities.
7. Is it safe to take ComitrisTM?
ComitrisTM has an outstanding profile of safety demonstrated through extensive in vitro and animal
toxicological studies. Importantly, ComitrisTM does not alter normal dermal wound healing. ComitrisTM is
suitable for long term intake.
8. Will ComitrisTM interfere with the medications I take?
We recommend discussing ComitrisTM supplementation with your health care provider. ComitrisTM is a
safe all natural product. No interference with marketed drugs has been documented.
9. How is the product supplied?
ComitrisTM is provided in 30 mL and 60 mL units of a frozen oral suspension in polypropylene bottles.
Each box of ComitrisTM contains 30 units that need to be kept frozen until use.
10. What dosage do you recommend?
We recommend discussing dosage with your healthcare practitioner. Support of blood parameters and
inhibition of angiogenesis have been documented with as little as 7 mL/day of cartilage extract in healthy
human volunteers. However, people with a pre-existing condition related to angiogenesis imbalance may
need a more substantial intake. Dosage should be adjusted to account for the severity and the duration of
the exposure to angiogenesis imbalance. For people with a severe or chronic angiogenesis imbalance,
we suggest up to 60 mL/day as a dietary supplement. As the angiogenesis imbalance improves, intake
may be downsized to 30 mL/day for maintenance, as long as needed.
11. How long should I take ComitrisTM?
Based on experience, a minimum of 4 months supply is usually needed for people with angiogenesis
imbalance.
12. Are there other liquid cartilage extracts on the market?
Atrium Biotechnologies has been granted a worldwide patent over the production of liquid cartilage
extracts. ComitrisTM is the newest addition to the line of innovative supplements developed by Atrium
Biotechnologies. The company also carries other liquid cartilage extracts commercialized as CarTCellTM,
and CarTCell+30TM. ComitrisTM is the result of the commitment of Atrium Biotechnologies to constantly
improve the quality of its products.
13. What are the distinctive features of ComitrisTM?
ComitrisTM has the highest level of anti-angiogenic activity per unit of volume. It is 30% more potent then
CarTCellTM, and 20% more potent then CarTCell+30TM. ComitrisTM is processed on a new industrial scale
facility that allows for the production of a more concentrated product at a better price. ComitrisTM is
intended for use by people with severe angiogenesis imbalance when daily high volumes are requested.
This concentrated and potent version should facilitate compliance. The final product’s molecular weight is
between 0 and 500 kDa.
Topic 4: PHYTOSTATIN
1. Is there such a thing as resistance to chemotherapy?
Chemotherapy is a tool of choice to slow down the evolution of most cancers. Successful chemotherapy
should track and kill all cancer cells while avoiding attacking the healthy cells of one’s organism.
Unfortunately this therapeutic ideal is seldom attained because cancer cells naturally have certain means
to resist the action of chemotherapeutic agents.
In fact, cancer cells generally react well to a first round of chemotherapy. Their number decreases to a
level where their presence cannot be detected anymore and the patient is then considered in remission.
This more or less long calm spell unfortunately is still too often followed by a relapse. However, some
cancer cells more resistant than average can indeed survive the first offensive of chemotherapy. Being
very few, they are not easily detectable up to the moment when, having recovered from chemotherapy
insults, they start dividing at a fast pace. Reapplying the initial therapeutic protocol generally turns out to
be ineffective on these cells and increasing doses may exacerbate side effects to an unacceptable level.
Even opting for a different arsenal of chemotherapeutic agents may not make it possible to break this
resistance. The cancer cells have now developed resistance to multiple chemically and functionally
unrelated anti-tumor compounds. This phenomenon is called multi-drug resistance.
2. What is the molecular mechanism underlying this drug resistance?
A major reason for such drug resistance is the presence of proteins called P-gp within the membrane of
the cancer cells. P-gp proteins are pumps that actively extrude the “activated” chemotherapeutic agents
from the interior of the cancer cells to the extracellular space where they can no longer exert their antitumor action. By preventing accumulation of drugs inside the cancer cells, P-gp pumps action seriously
impairs the efficacy of treatments. Moreover, this pump is not very selective and will expel the vast
majority of chemotherapeutic agents encountered, leaving very few therapeutic options whenever the
cancer cells express much P-gp.
One of the negative effects of chemotherapy is the selection for survival of cancer cells overexpressing Pgp from an initially heterogeneous population for P-gp expression. The cells overexpressing P-gp pumps
indeed manage to survive the initial chemotherapy to possibly form a new clonal population of cancer
cells from now on refractory to most chemotherapeutic agents. Chemotherapy resistance is established.
3. What is PHYTOSTATIN?
PHYTOSTATIN is an all-natural vegetarian formula acting as a chemosensitizer and an inhibitor of matrix
metalloproteinase activity (MMP) as well. Phytostatin is a combination of extracts from green tea,
curcumin, milk thistle, selenium-enriched yeast, soy, and flaxseed, plus an organo-mineral complex
(AOMC).
All ingredients were judiciously selected for their synergistic action in order to achieve optimal support for
chemotherapy. Inclusion of Atrium Organo-Mineral Complex (AOMC) proprietary ingredient makes
PHYTOSTATIN a unique formula. Moreover, the various levels of solubility of PHYTOSTATIN
ingredients make it possible to saturate simultaneously both aqueous and lipidic pools of the human
body.
4. How does PHYTOSTATIN work at the molecular level?
P-gp inhibition
The main strength of PHYTOSTATIN resides in its ability to inhibit P-gp pumps activity in cells. In vitro
studies showed that the binding properties of P-gp toward a representative substrate were inhibited by
86% in the presence of PHYTOSTATIN as detected by a photoaffinity technique. This result suggests
that PHYTOSTATIN binds to P-gp. Another in vitro experiment showed that PHYTOSTATIN was able to
inhibit chemotherapeutic drug extrusion in P-gp overexpressing cells.
Based on these results, PHYTOSTATIN is expected to act as a valuable therapeutic support. By
inhibiting P-gp pumps activity, PHYTOSTATIN will allow chemotherapeutic agents to accumulate within
the cancer cells to better exercise their anti-tumor action. It is expected that PHYTOSTATIN should help
preserve the sensitivity of cancer cells towards chemotherapeutic agents.
MMP inhibition
Sensitizing tumor cells to chemotherapeutic agents is not the only mode of action of PHYTOSTATIN. This
multipotent product also has the potential to antagonize the action of some metalloproteinases, as shown
in an in vitro assay for MMP-2 activity. As mentioned earlier, cancer cells subvert MMPs activity to
promote invasion of the surrounding tissues as well as metastasis to distant ones. Thus by opposing
MMP-2 activity, PHYTOSTATIN shall prevent tumor progression and metastasis.
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