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Bioinformatics Database on
"Radiosensitisers and Radioprotectors"

        Radiotherapy is regarded as one of the most important therapeutic modality for the treatment of malignant lesions. This field is undergoing rapid advancements in the recent times. With the use of radiosensitizers and radioprotective agents, the course of radiotherapy has improved the sensitization of tumor cells and protection of normal cells, respectively.
        The aim of this paper was to critically review and analyze the available compounds used as radiosensitizers, radioprotectors, and radiation mitigators. For reviewing, the author used the electronic search for the keywords 'Radiosensitizers', 'Radioprotectors', 'Radiation mitigators' on PubMed for inclusion of previously published articles and further search of reference papers on individual radiosensitizing and radioprotecting agents was done. Radiosensitizers are agents that sensitize the tumor cells to radiation. These compounds apparently promote fixation of the free radicals produced by radiation damage at the molecular level. The mechanism of action is similar to the oxygen effect, in which biochemical reactions in the damaged molecules prevent repair of the cellular radiation damage. Free radicals such as OH + are captured by the electron affinity of the radiosensitizers, rendering the molecules incapable of repair. Radioprotectors are compounds that are designed to reduce the damage in normal tissues caused by radiation. These compounds are often antioxidants and must be present before or at the time of radiation for effectiveness. Other agents, termed mitigators, may be used to minimize toxicity even after radiation has been delivered. This article tries to discuss the various aspects of radiosensitizers, radioprotectors, and radiation mitigators including the newer agents.
        Radiosensitizers are intended to enhance tumour cell killing while having much less effect on normal tissues. Some drugs target different physiological characteristics of the tumour, particularly hypoxia associated with radioresistance. Oxygen is the definitive hypoxic cell radiosensitizer, the large differential radiosensitivity of oxic vs hypoxic cells being an attractive factor. The combination of nicotinamide to reduce acute hypoxia with normobaric carbogen breathing is showing clinical promise. 'Electron-affinic' chemicals that react with DNA free radicals have the potential for universal activity to combat hypoxia-associated radioresistance; a nitroimidazole, nimorazole, is clinically effective at tolerable doses. Hypoxia-specific cytotoxins, such as tirapazamine, are valuable adjuncts to radiotherapy. Nitric oxide is a potent hypoxic cell radiosensitizer; variations in endogenous levels might have prognostic significance, and routes to deliver nitric oxide specifically to tumours are being developed. In principle, many drugs can be delivered selectively to hypoxic tumours using either reductase enzymes or radiation-produced free radicals to activate drug release from electron-affinic prodrugs.
        A redox-active agent based on a gadolinium chelate is being evaluated clinically. Pyrimidines substituted with bromine or iodine are incorporated into DNA and enhance free radical damage; fluoropyrimidines act by different mechanisms. A wide variety of drugs that influence the nature or repair of DNA damage are being evaluated in conjunction with radiation; it is often difficult to define the mechanisms underlying chemoradiation regimens.
        Drugs being evaluated include topoisomerase inhibitors (e.g. camptothecin, topotecan), and the hypoxia-activated anthraquinone AQ4N; alkylating agents include temozolomide.
        Drugs involved in DNA repair pathways being investigated include the potent poly(ADP ribose) polymerase inhibitor, AG14,361.
        Proteins involved in cell signalling, such as the Ras family, are attractive targets linked to radioresistance, as are epidermal growth factor receptors and linked kinases (drugs including vandetanib [ZD6,474], cetuximab and gefitinib), and cyclooxygenase-2 (celecoxib). The suppression of radioprotective thiols seems to offer more potential with alkylating agents than with radiotherapy, although it remains a strategy worthy of exploration.