Radiobiology 5 PDF

Oxygen Enhancement Ratio (OER) 1 Two identical doses may not produce identical responses due to other modifying factors Factors Affecting Radiation Response are, Physical Factors Biological Factors Linear energy Oxygen E...

Oxygen Enhancement Ratio (OER) 1 Two identical doses may not produce identical responses due to other modifying factors Factors Affecting Radiation Response are, Physical Factors Biological Factors Linear energy Oxygen Effect transfer Phase of cell Relative cycle biological Ability to Repair effectiveness Chemical Agents Fractionation Hormesis & protraction  OER The oxygen enhancement ratio (OER) is the ratio of doses under hypoxic to aerated conditions that produce the same biologic effect. The presence or absence of molecular oxygen dramatically influences the biologic effect of x-rays. Oxygen presence (aerated cells) increases radiation effectiveness for cell killing. Lack of oxygen (hypoxic cells) results in more radio resistant cells. 3  Ionizing radiation at low LET is more effective in the presence of oxygen than in its absence in producing most biological effects. The reciprocal of OER is Relative Radio-sensitivity, defined as 1.0 at 0% O2. When this is plotted against oxygen concentration the graph typically looks like that shown in Figure 1.  Radio-sensitivity and O2 Concentration  Most of the change of sensitivity occurs as the oxygen tension increases from 0 to 30 mm Hg.  A further increase of oxygen content has little further effect.  A relative radio- sensitivity halfway between anoxia and full oxygenation occurs for a pO2 of about 3 mm Hg, which corresponds to a concentration of about Fig: The dependence of radio-sensitivity on 0.5% oxygen. oxygen concentration 7 7 X-ray photons  Nature of the Oxygen Effect Surviving Fraction Cells are much more sensitive to x-rays in the presence of molecular oxygen than in its absence (i.e., under hypoxia). The ratio of doses under hypoxic to aerated conditions necessary to produce the same level of cell killing is called the oxygen enhancement ratio (OER). 7  Oxygen Effect  To produce its effect, molecular oxygen must be present during the radiation exposure or at least during the lifetime of the free radicals generated by the radiation.  Oxygen “fixes” (i.e., makes permanent) the damage produced by free radicals.  In the absence of oxygen, damage produced by the indirect action may be repaired. 8  Oxygen Fixation ion pairs CH3 CH2 free radicals functional free Methylene radical, group unpaired electron Generally, the free-radical reactions go like this: CH2 + O2 CH2O 2 an organic peroxide “fixes” the indirect damage (oxygen has no impact on direct damage) 9 OER Effect  OER varies from 2-3, increasing with dose  Low-LET radiations  oxygen effect is more pronounced  High-LET radiations  oxygen effect is non- existent (OER = 1) Low-LET radiation  Other Radiations and the OER 15 MeV Neutrons particles 1.0 1.0 OER = 1.6 OER = 1.0 0.1 0.1 0.01 Hypoxic 0.01 0.001 Aerated 0.001 0 2 4 6 0 1.0 2.0 3.0 Dose, Gy Dose, Gy High-LET radiation 11  OER and LET Fig. :Oxygen enhancement ratio as a function of linear energy transfer.  At low LET, corresponding to x- or γ-rays, the OER is between 2.5 and 3; As the LET increases, the OER falls slowly at first, until the LET exceeds about 60 keV/µm, after which the OER falls rapidly and reaches unity by the time the LET has reached about 200 keV/µm 12  OER & RBE as a function of LET Fig: Variation of OER and RBE as a function of LET of the radiation involved. Variation of the OER and the RBE as a function of LET. The two curves are virtually mirror image of each other. The optimal RBE and the rapid fall of OER occur at about the same LET value, 100 keV/µm The distance to which oxygen can diffuse is limited largely by the rapid rate at which it is metabolized by respiring tumor cells. For some distance from a capillary, tumor cells are well oxygenated (white). At greater distances, oxygen is depleted, and tumor cells become necrotic (black). Hypoxic tumor cells form a layer, perhaps one or two cells thick, in between (gray). The distance to which oxygen can diffuse is about 70 ᴜm at the arterial end of a capillary and less at the venous end.  Acute hypoxia is the result of the temporary closing of a tumor blood vessel owing to the malformed vasculature of the tumor, which lacks smooth muscle and often has an incomplete endothelial lining and basement membrane. Tumor blood vessels open and close in a random fashion, so that different regions of the tumor become hypoxic intermittently. There is clinical evidence that in addition to causing radioresistance, hypoxia may play an important role in malignant progression and in metastasis  On the one hand, hypoxic tissues are more resistant to radiation effects. On the other hand, it is known that tumoral cells are in general in hypoxic conditions. In the process of radiotherapy, after a tissue irradiation, tumoral cells that were in hypoxic conditions are better oxygenated due to an easier access to oxygen sources because of the death of surrounded cells. As a consequence, tumoral cells that were resistant to radiation become more and more radiation sensitive due to this process of Re-oxygenation.  Immediately after irradiation, essentially 100% of the viable cells are hypoxic because such a dose kills a large proportion of the aerated cells. By 6 hours after irradiation, the percentage of hypoxic cells has fallen to a value close to the preirradiation level. Percentage of hypoxic cells in a transplantable mouse sarcoma as a function of time after a dose of 10 Gy of x-rays  A dose of x-rays kills a greater proportion of aerated cells than hypoxic cells because aerated cells are more radiosensitive. Therefore, immediately after irradiation, most cells in the tumor are hypoxic. the preirradiation pattern tends to return because of reoxygenation. If the radiation is given in a series of fractions separated in time sufficient for reoxygenation to occur, the presence of hypoxic cells does not greatly influence the response of the tumor.  Conclusion OER is the ratio of hypoxic-to-aerated doses OER decreases as LET increases Oxygen must be present during irradiation, or very soon after (microseconds) Only a small of amount O2 is required (< 5%) 21