Mode of action
Immunological effects
Avemar has multiple immunological effects.
Increase of blastic transformation: Concanavalin A-induced blastic transformation was examined in the spleen cells of 8 week-old C57B1/6 mice using a 3H-thymidine incorporation test. The animals in the test group received Avemar through gastric tubes for 6 weeks; those in the control group remained untreated. The increase in mitogen-induced 3H-thymidine in-corporation in the splenocytes of the group receiving Avemar was significantly higher than that in the animals of the control group: a finding which underlines Avemar's ability to enhance cellular immune response [4].
The effects of Avemar on the restitution of impaired immune response was modeled in co-isogenic skin transplant (GVHD) experiments on mice made partially immune deficient by thym-ectomy. The C57Bl/10 and B10LP mouse strains differ only in the 3rd locus, thus skin grafted from one strain to the other will be rejected after approximately three weeks unlike the custom-ary seven days. When the recipient underwent thymectomy, rejection time was increased to 50 days on average. Avemar treatment improved the maturation and differentiation of bone marrow lymphocytes and significantly reduced the rejection time of the skin graft, thus shortening the survival time of the skin grafts of mice subjected to both thymectomy and treatment.
This indicates that Avemar significantly reduces the immune deficiency caused by thymectomy [4], and provides further evidence of the stimulatory effect of Avemar on cellular immune response. This gains further significance from the fact that the organism's natural anti-tumor immune response is based largely on the functioning of the "cellular" immune system.
The observed immunological effects encouraged the re-searchers to test the effects of Avemar not only on anti-tumor immune response, but in other immunological models as well. The experimental induction of 'adjuvant' arthritis in rats is one of the most widely used models to test human rheumatoid arthritis. The efficacity of Avemar in these experiements was all but equal to that of the drugs indomethacin and dexa-methasone. Taking into account the fact that, as compared with non-steroid anti-inflammatory drugs (NSAID) and steroids, Avemar has no side effects, Avemar provides a promising alternative in the treatment of rheumatoid arthritis. This possibility is supported by the results of a pilot-scale clinical study.
The effect of Avemar on autoantibody levels was also measured in mice with experimentally induced SLE (systemic lupus erythematosus). The results demonstrated a significant decrease in the levels of all the antibodies tested, and the inhibitory effect of Avemar on autoantibody production was still detectable even one month after the completion of treatment - in fact, production continued to decrease in the case of several antibodies [17]. The same experiment provided further results, notably an observation of a change in the ratio of Th1/Th2 cytokine production with the reduction in autoantibody production in the background. Avemar caused a reduction in Th2 cytokine production while simultaneously increasing the production of Th1 cytokines. While Th1 cytokines help to regulate and 'ex-ecute' cellular immune response, Th2 cytokines are parts of humoral response, which may very well account for the effic-iency of Avemar in combatting both autoimmune diseases and human cancers. The inhibition of humoral immune response is beneficial in the treatment of autoimmune diseases, while the enhancement of the cellular immune response helps in defeating malignant tumors.
The effects of avemar on the metabolism of cancer cells
The cancer cell's modified genes constantly urge the affected cells to divide. In order to maintain the processes of cell division, cell metabolism must also be changed; the cell needs to adapt to an enhanced synthesis of nucleic acids (RNA/DNA) and other constituents. To fuel these processes, cancer cells need an ab-undance of precursors. Cancer cells adapt their metabolism in a way that enables them to utilize the most abundant resource in circulation: glucose. They do this not only to gain chemical en-ergy, but also to produce structural molecules and metabolically active ones. In order to maintain a continuous proliferation, it is crucial that glucose is utilized continuously for synthetic (ana-bolic) biochemical processes.
Another important fact which distinguishes the metabolism of cancer cells from that of normal cells is the considerably high rate of the non-oxidative steps of the anabolic processes. The fact that this process is typical of and limited to cancer cells makes it a primary target for research into new diagnostic and therapeutic approaches [23].
It is commonly observed that cancer patients experience ra-pid weight loss and a decrease in overall physical fitness. The declining resistance to infect-ions also makes them more vul-nerable.
For patients with malignant tumors, death is almost always caused by the severe deterio-ration of one or more of the vital organs or by a severe and life-threatening weight loss which leads to metabolic col-lapse. The main question one needs to comprehend when dealing with malignant feature - one which is also crucial for understanding how Avemar works - is how tumor cells can maintain their continuous growth in a body which is rapidly and inexorably deteriorating as it ap-proaches death. This can only be possible if the tumor cells use certain essential substances or substrates to support their own growth, something that the body keeps in continuous supply because it is crucial for the survival. One such material, and one which the body attempts to maintain at normal physiological levels in all circumstances, is glucose. It was already known in the early 1930's that tumor cells can adapt to a glucose-based metabolism and are also capable of taking up enormous quantities of this molecule - up to 20-30 times more than normal cells do. One part of this glucose will be used for energy production, while another, significant part will be used for the syntesis of nucleic acids.
Another important fact crucial to the understanding the metabolism of tumor cells is the capability of these cells to pro-liferate and settle in an environment with low oxygen partial pressure, such as it is found in hypoxic conditions. This condition is fulfilled if cells prefer non-oxidative processes rather than oxidative ones during macromolecular synthesis. In tumor cells, these non-oxidative anabolic and catabolic processes are found in the pentose-cycle and in the early stages of glycolysis, where glucose is used to build lactate and ribose. As ribose molecules are the building blocks of RNA and DNA, tu-mor cells need to use their glucose for these processes. Transketolase and trans-aldolase, the two key enzymes capable of converting (6 carbon-atoms) phosphorilated glucose derivatives into ribose (5 carbon-atoms). What makes this process even more specific is that it is completely reversible and only slightly controlled. Moreover, it is also the most efficient way for the tumor cell to produce large quantities of nucleic acid precursors. Syn-thesizing ribose through oxid-ative processes produces re-ductive potential (reduced NADP) as well. The latter is not 'wasted' on fatty acid syn-thesis, but is used for con-verting ribonucleotides into de-oxyribonucleotides (DNA).
Obviously, cancer cells have a fairly primitive, undiffer-entiated structure; owing to reduced fatty acid and amino acid synthesis, cancer cells are unable to produce enough proteins and triglycerides to develop functional receptors, enzymes, structural proteins and membrane components. The cancer cell fulfills a single role, but does so quite efficiently: it multiplies at a phenomenal rate and produces primitive, seriously dysfunctional cells. The above-mentioned description is a basic characteristic of all cancer cells irrespective of their origin (genetic or chemical damage, abnormal response to signal transductory or growth hormones) [25].
As a result, it would seem logical to examine the metabolism of tumor cells by adding isotope-labeled sugar molecules to the cell culture in order to track the intracellular distribution of the isotope both in untreated cultures and in those treated with different doses of Avemar. These experiments were performed by our research team in the medical faculty at the University of California at Los Angeles (UCLA) using two cancer cell lines: aggressively growing pancreatic carcinoma and Jurkat-leuk-emia cells. The results were similar in both cell lines and demonstrated that Avemar significantly inhibits the cancer cells in their effort to phosphorilate glucose, thereby inhibiting its activation. This significantly reduces sugar consumption in tumor cells, with the be-nefit that the body will be capable of using this glu-cose to maintain its normal activities and provide en-ergy for organs still in good functional condition. Even more peculiar is the effect of Avemar on the ribose syn-thesis. Ribose is an essential key element of nucleic acids. Avemar prevents the cancer cells from syn-thesizing ribose - and thus RNA and DNA - from glucose using the non-oxidative pathways of the pentose cycle in a direct dose-dependent manner. In fact, since Avemar also blocks the reduced NADP synthesis of tumor cells, it holds back the de-oxy-ribonucleotide production, and thus DNA synthesis, in not one, but two channels. The cancer cells get bogged down in the S-phase and their division stops. Enzym-ology studies performed at the University of Barcelona have ascertained that these effects of Avemar are highly selective for cancer cells [30].
Dosages of Avemar pre-scribed in humans inhibit the activities of the enzymes hexokinase, glucose-6P-de-hydrogenase, transketolase and lactate-dehydrogenase, but only in tumor cells. Therefore, tumor cells become incapable of utilizing glucose reserves for ribose synthesis. Because of Avemar's interference, the tumor cell will be deprived from ribose and, without ribose or its reduced derivants, and thus without RNA and DNA, proliferation becomes impossible. In normal, healthy cells (as in peripheral lymphocytes), a dose at least 50 times higher is required to achieve the same inhibiting effect. Translating these figures onto a human scale, an average weighing adult would need to consume nearly 0,5 kg (!) of Avemar every day, instead of the usual 9 g, in order to diminish its beneficial selective action.
Another effect observed in Avemar treated tumor cells is that these tumor cells utilized the glucose that they would have normally used for nucleic acid production for fatty acid synthesis. This process significantly improves the differentiation or the maturity grade of the cells, as the cancer cell modifies its metabolism to match that of normal cells and thereby becomes considerably less malignant.
The effects of avemar on the escape/survival strategies of cancer cells
Natural anticancer immune response is based on the activity of the "cellular" immune system. Primary anticancer cellular im-mune response depends on the activity of the NK cells. If we consider the model of the immune system as an army, then the NK cells are the soldiers in the front lines. A low level of MHC-I (major histocompatibility complex) antigens enhances the activity of these cells. In other words, a cell that carries a high concentration of MHC-I on its surface should not be attacked by NK cells. This serves as the basis for one of the main survival strategies of the tumor cell: by enhancing the synthesis of MHC-I (tumorous upregulation), the cells effectively 'camouflage' themselves from NK cells.
The second line of action in natural anticancer immune response is found in the activity of the macrophages (mononuclear phagocytes). Macrophages are present in every organ or tissue. Their main activity is phagocytosis and the production of biologically active molecules (free radicals, cytokines). TNFa (tumor necrosis factor alpha) is the most important cytokine produced by the macrophages and also plays an important role in local inflammatory and adhesion processes. What is more, TNFa can destroy tumor cells both directly (by inducing apoptosis or by producing free radicals) and indirectly (by inhibiting tumorous angiogenesis or by enhancing other cellular anti-tumor processes). In order to activate their own anti-tumor capabilities, macrophages need to reach and then pe-netrate into the tumor. They fulfill this by circulating through blood vessels and by migrating from the vas-cular system. The leukocytes are aided by the protein ICAM-I, an intracellular ad-hesion molecule, (CD54), which helps them cross the vessel wall and also to trans-port them to their target. Once a cancerous tumor reaches a size of 1mm3, it begins the intensive process of building up its own vas-cular system (tumorous angiogenesis). Vessels grown in tumors are charac-terized by an almost complete lack of ICAM-I.
This is one of the most specific escape techniques utilized by malignant tu-mors, as, even if the body activates the cellular com-ponents of anticancer immune response, if the cells cannot migrate through the walls of the tumorous vessel, they cannot reach the tumor cells.
The enzyme PARP-1 (poly-(ADP-ribose)-polymerase) is known as the 'guardian angel' by biochemists because one of this enzyme's functions is to repair damage at the genome level (DNS repair). Cancer cells possess a part-icularly enhanced PARP activity, as they need this to correct the steadily increasing number of gene defects such as nucleotide substitutions which accompany their abnormally escalated di-vision. They seek to be efficient at correcting these mistakes in order to survive.
Avemar inhibits the tumor cells in using of all of the three above mentioned escape/survival strategies. Treatment with Avemar decreases the concentration of MHC-I on the surface of cancer cells by up to 90%, thus making them primary targets for NK cells. On the other hand, Avemar does not interfere with the MHC-I levels of healthy cells [26].
Avemar is capable of increasing the level of ICAM-I molecules, an effect synergistic with its TNFa-like effect. In this way, Avemar enhances ICAM-I production in two distinct ways - on its own and through the enhancement of TNFa-production in macro-phages - thereby helping the leukocytes to reach tumor cells [35].
It has also been demonstrated that Avemar inactivates the en-zyme PARP through proteolytic cleavage. This action is medi-ated by the caspase-3 pro-tease system and it is prod-uced only in tumor cells. This explains why Avemar induces apoptosis (programmed cell death) only in cancer cells [30].
Cancer cells can be eliminated in a number of ways. In certain cases, cancer tissue can be re-moved surgically or destroyed by chemotherapy or radio-therapy. However, none of these therapeutic processes possesses Avemar's most important characteristics, namely selective action with-out side effects.
Avemar achieves this se-lectivity on the one hand by inhibiting metabolic processes used only by tumor cells for nucleic acid synthesis and, on the other hand, by blocking just those processes 'invented' by tumor cells to ensure their own survival.
Another property of Avemar is that it does not need a specific protein or genetic mutation to exert its anti-tumor effect. There are several newly developed anticancer agents available which are effective against a specific group of tumors and work by blocking a specific abnormal or altered protein found only in one particular tumor type. These proteins regulate the metabolic enzymes influenceable by Avemar resulting in anticancer effect.
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