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Effects Of Oxygen On Radiation Therapy
1. Effects of Oxygen on Radiation Therapy February 19, 2009 Zhong Yun, PhD Department of Therapeutic Radiology, HRT-313 Yale University School of Medicine Tel: 737-2183; zhong.yun@yale.edu
18. Oxygen Influences Biological Effects of Radiation 1. Less damage to tightly pressed skin, Swartz 1912, 2. Radiation inhibited germination of vegetable seeds only in the presence of O 2 , Petry 1923 3. Oxygen effect on tumor radiosensitivity championed by Mottram 1930s 4. 1 st quantitative study on O 2 effects on radiation-induced growth inhibition of broad bean, Gray 1953 5. O 2 levels decrease in respiring tumor cells located away from blood vessels, Tomlinson and Gray 1955
19. Brown JM & Wilson WR, 2004 Ability of ionizing radiation to kill cells is highly dependent on pO 2 ---Tomlinson and Gray , 1950s
20. Oxygen Enhancement Ratio (OER) The ratio of HYPOXIC to AEROBIC IR doses needed to achieve the SAME biological effects. OER = D 0 (hypoxic) D 0 (aerobic)
21. Radiosensitivity and pO 2 1.0 2.0 3.0 0 20 40 60 80 155 760 2280 Air 100% O 2 HBO (3 ATA) Venous Blood Relative Radiosensitivity Oxygen tension (mmHg) (Rockwell et al .) Half maximum sensitivity = 3 mmHg or 0.5% O 2 Kirkpatrick JP, et al. Intl. J. Rad. Oncol. Biol. Phys. 59:822, 2004 CHO Cells Relative Radiosensitivity
22. The Oxygen Fixation Hypothesis X-rays + H 2 O H + H 3 O + + OH HO 2 H 2 O 2 O 2 - H 2 O + + e - H 2 O OH R RH RO 2 O 2 H + O 2 O 2 t 1/2 : 10 -10 sec for ion pairs; 10 -5 sec for free radicals Non-repairable
23. Parameters Affecting OER 1. Nature of cellular sensitivity 2. Nature of radiation (x-ray, neutron, alpha particle, or LET) 3. pO 2 5. Cell Cycle ( cells in S-phase are more resistant.) 4. Time of oxygen presence
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25. 2. Nature of Radiation X-rays neutrons -particles LET = 2.0
27. 4. Oxygen effect is time-dependent 1. O 2 needs not to be present DURING radiation 2. O 2 has to be present WITHIN milliseconds after radiation Radiation Ion pairs Free Radicals T = 10 -10 sec T = 10 -5 sec (0.01 msec) Time delay is determined by lifetime of free radicals
28. Sinclair W and Morton R, Radiat. Res. 29:450, 1966 Sinclair W, Radiat. Res. 33:620, 1968 5. Cell Cycle and Radiation Sensitivity Most Sensitive Phase: G2/M Most Resistant Phase: Late S Early G1
29. OER varies slightly during cell cycle S phase (OER = 2.8-2.9) G2/M phase (OER = 2.3-2.4) G1 phase > > OER remains unchanged for ALL dose levels in a given phase of cell cycle.
31. Factors Affecting Reoxygenation 2. Clearance of dead cells by macrophages, etc. 1. Rate of angiogenesis. 3. Inflammatory response 4. Tissue remodeling.
32. Mouse mammary Carcinoma Rat sarcoma Mouse fibrosarcoma Mouse osteosarcoma Mouse fibrosarcoma Variable Rates of Reoxygenation
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34. MGd Improves Tumor Oxygenation E. Donnelly & S. Rockwell, 2005 * * * p < 0.01 * * * *
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36. Brown JM & Wilson WR, 2004 Activation of Hypoxia-Selective Prodrugs