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Hypoxia is a deficiency of oxygen at the tissue level, and is a common condition of tumors. As a tumor grows, it needs oxygen in order to survive. Although the tumor develops new blood vessels by a process of angiogenesis, these vessels are typically of poor quality and are less extensive than in normal tissues. As a result, the tumor cells do not receive adequate oxygen from the blood, leading to hypoxia.
Treatment of patients by X-irradiation is designed to kill the tumor cell by ionizing radiation. The radiation causes the formation of a reactive chemical species called a free radical in the DNA molecule of the cell. If the cell has adequate oxygen, the oxygen quickly reacts with the free radical, making the detrimental changes in the DNA molecule permanent. In the case of the hypoxic cell, another chemical species called a sulfhydril group can donate hydrogen to the free radical, restoring the DNA to its original state. Chemotherapy is compromised in tumors as they grow due to the distance the drugs have to travel in order to reach all cells of the tumor. There is an inverse relationship between drug concentrations in the cells and distance from a capillary. Since tumors are already poorly vascularized, the drug concentrations may be inadequate to kill the more distant cells. The cells in the interior of the cells are more hypoxic, which makes them less responsive to the drugs. Improving treatment success by prior oxygenation of tumors Recognizing that hypoxic cells are more difficult to treat, researchers tried measures to oxygenate the tumors to overcome the hypoxia. The first procedure attempted was to have the patients inhale hyperbaric oxygen before radiation therapy. Hyperbaric oxygen is the administration of pure oxygen at higher than atmospheric pressure. However, this procedure resulted in only inconsistent responses and posed safety issues. The next attempt was the use of carbogen, a mixture of 95% oxygen and 5% carbon dioxide. Again, carbogen administration only inconsistently improved the effectiveness of radiation therapy. Radiosensitizing agents Since attempts to change the hypoxic state by the administration of oxygen were largely unsatisfactory, researchers then turned to the use of electron-affinic drugs. The idea behind this approach was that these drugs mimicked the action of oxygen in radiation treatment, that is, they fixed the free radical damage to DNA. The most studied radiosensitizing drugs are the nitromidazoles. The first drug in this class, misonidazole, seemed very promising in the lab for sensitizing tumors to irradiation therapy, but produced severe neurological disease in clinical studies. The next drug that was developed, etanidazole, was less toxic than misonidazole, and appeared to have the same antitumor effect. However, a large-scale clinical trial failed to show a significant benefit to the use of the drug. A third drug of the class, nimorazole, has given promising results in clinical trials. It appears that radiosensitizers may be most effective in situations where oncologists administer large, single doses of radiation to fully hypoxic tumor cells. (Brown) Go To Page: 1 2 |
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