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Review 3
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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