The Use of Free Radicals in the Treatment of Disease - Literature review Example

?The use of free radicals in the treatment of disease The ground is the most stable form of the molecule existence. If for a particular atom every electron in the outermost shell has a complementary electron spinning in the opposite direction then that atom is in the ground state. A free radical can be defined as a particle with at least one unpaired electron occupying the outermost shell, capable to exist independently (Karlsson, 1997). In other words, there is at least one electron without a pair. The presence of unpaired electrons usually makes free radicals highly reactive. For example, they can react with other molecules (M1) and steal an electron from them. The reacting radical (R1.) transforms into a ground state molecule (M2) and the formation of a new radical takes place (R2.)(Scheme 1) ( Fieser and Fieser, 1966 ). Scheme 1: Typical reaction of radicals (Nesmeianov and Nesmeianov, 1970). The first type of free radicals is thermodynamically unstable particles. These are the molecular fragments similar in structure to CH3. ,C2H5. and their derivatives. Next, atoms with one unpaired atom also fall under the definition of radicals. For example, H. ,Na. ,Cl. . And the last group of radicals are the thermodynamically stable radicals. As an example of this group triarylmethyl (a) and semiquinones (b) can be put forward (Scheme 2). Stabilisation of the radical in these structures are realised through delocalisation of the unpaired electron. Nitrogen oxides (NO, NO2) can also be classified as radicals as they possess an unpaired electron. Odd electron of the hydrogen atom is an s electron. In case of chlorine, or any carbon based radical it is a p radical. Scheme 2: Triarylmethyl and semiquinones based radicals (Nesmeianov and Nesmeianov, 1970). If the radical is stable then it usually does not participate in the reactions described on scheme 1. Such radicals cannot sustain chain reactions but can stop them. They have the ability to remove free radicals from the system and consequently serve as inhibitors of chain reactions. All the described particles are paramagnetic due to their uncompensated spin, what can be detected using magnetic balance (in case of stable particles) or electron paramagnetic resonance (if the concentration of the studied compound is too small or it is unstable) (Nesmeianov and Nesmeianov, 1970). Free radicals have the ability to damage cells. Respiration and the immune system reaction to the infection are the ways which lead to generation of free radicals in the body. Environment factors, such as food, pollutants and drugs that are used, also contribute to the formation of radicals. Once produced, radicals damage lipids, proteins, nucleic acids and other tissue macromolecules. They also have been proven to play a major role in aging and lead to a series of diseases, including cancer. The amount of free radicals in the body is regulated through the use of antioxidants which donate an electron, thereby transform a free radical into a stable molecule. A number of enzymes are able to act as antioxidants, including catalase, superoxide dismutase and glutathione peroxidase. The list of antioxidants can be continued by mentioning selenium, beta-carotene and both vitamins C and E (Brown, 1999; Huang, 2000). Because of the mentioned destructive properties of free radicals they can be used to treat cancer. A number of methods utilises free radicals. The method that has been used for decades is radiation therapy. The first case of using radiation therapy in the USA is dated 1896 when Emil Grubbe used X-rays to treat cancer. The discovery of radium and polonium in the end of the nineteenth century gave radiotherapy a push for further advancement. In the mid-1900s radium was substituted by radioactive caesium and cobalt. Later, with the development of various forms of tomography it became possible for physicians to selectively target tumours. This led to fewer side effects and more effective treatment. Depending on the position of the radiation source there are three types of radiotherapy. In teletherapy (External beam radiation therapy) radiation source is outside the body. Systematic radioisotope therapy takes advantage of the possibility of oral ingestion or infusion of radioisotopes. In the last type of radiotherapy, sealed source radiation therapy, radiation source is implanted inside the body temporary or permanently (Jongmans, 1999). Regardless of the type of radiotherapy, it is vital that free radicals are formed in cancer cells and normal cells are left unharmed. A balance between eliminating cancer and protecting normal cells should be reached. The radiation therapy is used to eradicate cancer cells and to relieve pain connected with metastasis development. The main goal of radiotherapy is to maximise DNA damage in cancer cells, thus stopping cancer cells from reproducing. Another important course of action is to affect cellular homeostasis, alter transduction pathways along with red ox states. High energy radiation is used to form free radicals that will stimulate the described processes. But, in many cases, tumour cells are resistant to radiation. Because cancer cells are poorly supplied by blood they are low in oxygen. As a consequence, the quantity of the produced free oxygen radicals is not enough to damage the tumour. There are two types of radiation capable of producing free radicals. These are gamma and X-rays or irradiation with particles, such as neutrons, protons and electrons that also lead to free radicals formation. Both types are used in radiation oncology with electron radiation employed at greater extent (Harrison, 2002). Radiation destroys cancer cells primarily by ionisation of DNA and indirectly through the formation of reactive oxygen species. Oxygen based free radicals are produced as a consequence of exposure to ionising radiation. Such radicals include superoxide anion radicals, hydroxyl, hydrogen peroxide and a number of other which form only in trace amounts. These particles take part in chemical interactions, thus producing a series of other damaging radicals (Ben-Yoseph, 1994). Approximately two thirds of gamma and X-rays damage is caused by indirect action. Heavy particles usually damage cells by direct ionisation. One of the major disadvantages of using reactive oxygen species is the fact that not only tumour cells are destroyed. The method lack selectivity and damages normal cells as well (Ikeda, 2000). Cells behave depending on the dose of radiation. But mostly it depends on the property of tissue to repair itself, sensitivity, intercellular factors, amount of antioxidants and concentration of oxygen. The amount of oxygen is extremely important as it determines the amount of damage done to DNA by gamma-radiation or X-rays. In order to effectively damage DNA reactive oxygen species must be present during 10-5 s which is the time of a free radical existence or during radiation. Without oxygen, damaged DNA strands can be repaired. Oxygen has the ability to bind to the damaged parts of DNA (Scheme 3). These parts have an unpaired electron, therefore a chemical reaction with reactive oxygen species is easy and the damage is preserved. Thiols have the opposite function, they repair the damage, competing with reactive oxygen (Scheme 4). Scheme 3: Damage of DNA by oxygen based particles and binding of oxygen to the damaged parts of DNA (Fieser and Fieser, 1966). Scheme 4: Thiol based repair enzyme (Fieser and Fieser, 1966) Radiotherapy can be an extremely effective method of eradicating cancer cells. Taking into account different kinds of radiation it is possible to change tactics depending on each individual case. However, among disadvantages of the therapy side effect should be mentioned (Guren, 2003). The irradiation is painless, however, due to nerve compression in the irradiated area short-term pain outbursts are possible. Side effects can manifest themselves immediately after treatment or during the following month or even years. In practice the type of side effect depends on each patient individually, the type of organ treated and the intensity of treatment. In many cases side effects are localised only in the treated area. One of the common side effects is skin irritation or burns. It manifests almost immediately and lasts for weeks after the treatment is finished. The damaged part of the skin will regenerate but will permanently lose its flexibility. For these reasons there is a drive to help patients live with unavoidable side effects and reduce them to a minimum level where possible (Uno, 2002). Radiotherapy is not the only method that uses free radicals to treat diseases, in particular cancer. For example, it is possible to produce drugs effective against hypoxic tumour cells (Wardman, 2002). Usually, such drugs are initially prepared by producing a prodrug. It consists of “trigger” and “effector” groups. Once inside the body, this inactive prodrug is reduced to a free radical by enzymes. In healthy cells the produced free radical reacts with oxygen and breaks down into inactive molecules. In contrast to oxygen rich normal cells, in hypoxic tumour cells the free radical collapses to form an active drug and the “trigger” residue. As an example of the drug that uses this mechanism tirapazamine can be mentioned (Harrison, 2002). It has the ability to selectively kill tumour cells leaving normal cells unharmed. The effectiveness of this drug can be elevated if used in conjunction with radiotherapy or chemotherapy (Hayakawa, 2001). Another perspective method to treat cancer using free radicals is to use a photodynamic therapy. In this kind of treatment initially a photosensitizer drug is administered. It has the ability to selectively accumulate in the cancer cells. Once the required concentration is reached, the organ is irradiated using laser and the activated drug reacts with oxygen transforming it into a highly toxic singlet state. The produced this way singlet oxygen destroys the cancer cells. It was also established that elevated concentration of glutathionone peroxidase protects cells against singlet oxygen (Weiss, 2009). It is also possible to produce prodrugs based on indole acetic acid (Scheme 5). Such drugs were developed in Gray Cancer Institute and all are produced from oxidation of an indol acetic acid based prodrug. The acid has the ability to accumulate in tumour cells and produce radical intermediates that can damage DNA (Gray Laboratory, 2000). Scheme 5: Indole acetic acid (Wardman, 2002) The initial stage of the treatment using indole acetic acid derivatives it the introduction of the prodrug. The prodrug is then activated by the peroxidase enzyme. It is also possible to activate the prodrug by introducing the peroxidase enzyme gene into the tumour cells. The final method of activating the prodrug is using a photodynamic therapy. Red light activates the photosensitizer which in turn transforms the prodrug into the activated state (Scheme 6) (Greco, 2001). The last method that utilises free radical to treat cancer is the inhibition of superoxide dismutase. It was established that cancer cells are very active and grow rapidly, they produce high amount of free radicals. They are also usually low in superoxide dismutase. Taking into account these factors a promising method was developed that allows to selectively kill tumour cells by inhibiting superoxide dismutase (Wang, 2001). Scheme 6: indole acetic acid action mechanism (Wardman, 2002). In conclusion, according to epidemiological studies there is a direct correlation between the amount of antioxidant taken with food and reduction in the risk of cancer. But, many questions remain unanswered. For example, it is not clear which antioxidant is the most effective along with its ideal amount. Moreover, the effects of antioxidants on patients who have been diagnosed cancer should be investigated. Among physicians there is no consent whether or not a person should consume antioxidants during radiation therapy. For these reasons the question should be investigated further. References Ben-Yoseph, O., 1994. Oxidation therapy: The use of a Reactive Oxygen Species-Generating Enzyme System for Tumour Treatment. British Journal of cancer, 70, pp.1131- 1135. Borek, C., 2004. Antioxidants and Radiation Therapy. The journal of nutrition, 134, pp. 3207S-3209S. Brown, M., 1999. Cancer Treatment Development. Interviewed by… Norman Swain. [broadcast] ABC, 22 March 1999, 8:30. Guren, M., Dueland, S., Skovlung, E., Fossa, S., Poulsen, J. and Tveit, K., 2003. Quality of life during radiotherapy for rectal cancer. European Journal of Cancer. 5, pp. 587-594 Gray Laboratory, 2000. Gray Laboratory Cancer Research Trust Report: Molecular Mechanisms. Edinburg: Gray Laboratory. Greco, O., 2001. Development of a Novel Enzyme/Prodrug Combination for gene Therapy of Cancer: Horseradish Peroxidase/Indole-3-Acetic Acid. Cancer Gene Therapy, 7, pp.1414-1420. Fieser, F., Fieser M., 1966. Advanced organic chemistry. New York: Reinhold Publishing corporation. Jongmans, W., Hal, J., 1999. Cellular responses to radiation and risk of breast cancer. European Journal of Cancer, 35, pp. 540-548. Harrison, L.B., Chadha, M., Hill, R.J., Hu, K. and Shasha, D., 2002. Impact of tumour hypoxia and anaemia on radiation therapy outcomes. Oncologist, 7, pp. 492-508. Hayakawa, K., Mitsuhashi, N., Katano, S., Saito, Y., Nakayama, Y., Sakurai, H., Akimoto, T., Hasegawa, M., Yamakawa, M. and Niibe, H., 2001. High-dose radiationtherapy for elderly patients with inoperable or unresectable non-small cell lung cancer. Lung Cancer, 32, pp. 81-88. Huang, P., 2000. Superoxide Dismutase as a Target for the Selective Killing of Cancer Cells. Nature, 407, pp. 390-395. Ikeda, H., Isobe, K., Hirota, S., Hasewaga, M., Nakamura., Sasai, K. and Hayabuchi, N., 2000. Tumour bulk as a prognostic factor for the management of localized aggressive non-Hodgkin’s lymphoma: a survey of the Japan lymphoma radiation therapy group. International Journal of radiation Oncology/Biology/Physics, 56, pp. 161-168. Karlsson, J., 1997. Introduction to Nutraology and Radical Formation. In: Antioxidants and Exercise. Illinois: Human Kinetics Press. McMurry, J., 2007. Organic chemistry. Hampshire: Cengage Learning Inc. Nesmeianov, A., Nesmeianov H., 1970. The beginning of organic chemistry. Moscow, Chemistry. Uno, T., Sumi, M., Ikeda, H., Teshima, T., Yamashita, M. and Inoue, T., 2002. Radiationtherapy for small-cell lung cancer: results of the 1995–1997 patterns of care process survey in Japan. Lung Cancer, 35, pp. 279-285. Wang, H., 2001. Phospholipid hydroperoxide glutathione peroxidase protects against singlet oxygen-induced cell damage of photodynamic therapy. Free radical biology and medicine, 8, pp. 825-835. Weiss, M., Sutton, L., Marcial, V., Fowble, B., Packer, R., Zimmerman, R., Schut, L., Bruce, D. and D’angio, G., 2009. The role of radiation therapy in the management of childhood craniopharyngioma. International Journal of radiation Oncology/Biology/Physics, 17, pp. 1313-1321. Wardman, P., 2002. Indol-3-Acetic Acids and Horseradish Peroxidase: A new Prodrug/Enzyme Combined for Targeted cancer Therapy. Current Pharmacological Design, 8, pp. 1363-1374. Guren, M., Dueland, S., Skovlung, E., Fossa, S., Poulsen, J. and Tveit, K., 2003. Quality of life during radiotherapy for rectal cancer. European Journal of Cancer. 5, pp. 587-594 Read More