The Role Of Glyoxalase System In Cell Metabolism And Its Reaction To Radiation Effect On Cancer Cells And Other Serum Enzymes
Nyandieka, Hezron Syekei
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Since the inception of radiobilogical experimentation on animal tumors, typified by the studies of (crabtree and cramer (1933), many workers have turned their attention to related problems. But it was not until about the present decade that most workers have turned their attention to the probabilities of radiation inactivation of the cells which populate a tumor and, consequently the biochemical function of those vital substances so essential to the body's total chemistry, such as the enzymes, their importance lies in the fact that no metabolic or anabolic change can take place in the cell without their help. At the same time they are substances which allow of quantitative determination of radiation effects. Furthermore, enzymes are, apart from their prosthetic groups, proteins and results obtained with them are one aspect of the response to radiation of molecules of high molecular weight and intricate camposition. It has long been known that cells contain a powerful enzymic system for the transformation of methylglyoxal to lactic acid, a reaction in which CBH is involved as a co-factor. This enzymic system consists of two catalytic proteins known as glyoxalase I and glyoxalase II which are involved in the formation and hydrolysis of lactoyl-glutathione complex. Since its discovery by Neuberg in 1913, its regulatory mechanism has occupied many workers without, however, anybody being able to fit it into the framework of metabolism. But it was not until 1965 that Szent- Qiorgyi and his associates have 'proposed that the role of the enzyme may be to regulate cell division. Since cancer involves the uncontrolled proliferation of cells, this theory is intriguing in that it implies a possible relationship between glyoxalase, ketoaldehyde and malignancy. Present studies were therefore directed to examine this problem in an attempt to determine the role of this system in cellular proliferation and its relation to radiation effects on cancer cells and other serum enzymes whose diagnostic usefulness are known. As a first approach to this problem, a simple method to follow continuously and colorimetrically the activity of the glyoxalase system was designed and developed. The method is suitable to detect changes related to the mass of the neoplastic tissues and can be applied to serum and other biological tissue extracts. Further studies on this enzyme indicated an exceedingly wide distribution of this cell constituent in a variety of solid human tumors and among male and female population. Several studies were directed to determine changes in the activity of this system in regressing tumors following radiation therapy of cancer victims. Radiation therapy was administered to over 200 patients referred from different parts of Kenya, Uganda and Tanzania. The radiation facility was a 60CO unit (SiemensCall1rratron).The irradiation was usually performed 5 days each week, a part from a few exceptions when it was given 6 days a week. The immediate effect of the radiation is, naturally, difficult to assess. The radiation effect on hemoglobin and white blood cell and platelet counts was moderate and never led to discontinuance of the treatment. Although the kind of criterion to be used in the evaluation of radiation effect indicates the manner in which a tumor must be irradiated, current findings indicate that tumor "cure"(regression) and local control can be used as criteria at least in respect with glyoxalase activity changes. Studies which were directed to determine changes in this system in tumors following gamma - irradiation indicated that tumor regression is heralded by a decrease in glyoxalase activity over the first 24 hours, then subsequently increases over the next few days of radiation therapy, and finally decreases progressively with the tumor response to the treatment. In view of the normal values which were also obtained on other serum enzymes such as LDH, COT, GPT and MDH in parallel experiments, one can conclude, with a fair degree of certitude, that normalization of glyoxalase activity observed towards the end of treatment suggests tumor responsiveness to the therapeutic agent. It is, therefore, suggested that this activity can be used as a therapeutic guide indicating an early objective sign of tumor response to treatment. The role of this activity in cell growth regulation would also seem to be effected here. The observed increased levels in the activity of this system on the fourth and twelfth days of treatment, followed by a decrease before the end of treatment, suggest that the system becomes activated in the affected organ whilst normal tissues proliferate to replace tumor tissues ren10vedby radiation. In reviewing the experimental evidence discussed in the main text, it becomes apparent that gamma- rays have been used successfully, at least in cases analyzed, to cure all malignant sarcomas and carcinomas by way of inhibition or suppression. It has also been demonstrated that tumor inhibition is accompanied by inactivation of enzymes which would otherwise promote cellular growth. The inactivation of enzymes by radiation therapy effecting tumor suppression is probably caused by different chemical reactions since the enzymes studied were of different classes. Glyoxalase which belongs to the class of SH-group of – enzymes may have been rendered inactive by the oxidation of - SH groups, necessary for its activity, to -S-S- bond by peroxides generated in the presence of oxygen during ionization process. Ionizing radiation can also inactivate enzymatic activities by destroying either their prosthetic groups or their specific protein. From the standpoint of present knowledge , at any rate, this criteria was employed to quantitate the degree of radiation effect on tumors and thus provided a basis for the advancement of a working hypothesis on the mechanism of tumor growth inhibition by ionizing radiation. Various doubts may therefore be raised about the increased therapeutic use of radiation. If radiation does not harm the cell, but only prevents its division, how can one hope for a cure? While it may be true that medical progress has frequently preceded scientific understanding, there should not be an emotional basis for employing radiotherapy for both the determination of objective signs to tumor response and the treatment of tumors which could have been determined or cured by other means. The activity of glyoxalase system could be considered as a therapeutic guide indicating the necessity for switching to other agents. A well constructed scientific rationale with medical progress may still be missing. After all cancer is not necessarily autonomous and essentially self - perpetuating. Its growth can be sustained and propagated by hormonal, function, in the host which is not, unusual in kind or exaggerated in rate but which is operating at normal or even at subnormal levels (Rous, 1966). From the immunological aspects of view, absence of satisfactory evidence for the role of glyoxalase in bleed lyrnphocytes has involved disappointment to those interested in this system and immunology. However this should not discourage further work in this field. The acceptance of this document which has left. many problems open for further work may be excused: for cancer in Africa with the multitude of problems posed by infectious diseases and nutritional disorders, is often viewed by medical administrators as low priority in health planning and certainly so when a claim is made on the limited funds available for medical research.