Effects Of Oxygen On Radiation Therapy

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Effects Of Oxygen On Radiation Therapy

  1. 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
  2. 2. Outline 1. A mechanism of hypoxia signal transduction <ul><li>Oxygen effects on Radiotherapy </li></ul><ul><li>---OER and factors affecting OER </li></ul><ul><li>---Reoxygenation </li></ul><ul><li>---Overcoming tumor hypoxia </li></ul><ul><li>---Oxygenation enhancement </li></ul><ul><li>---Hypoxia sensitizers </li></ul><ul><li>---Hypoxia toxins </li></ul><ul><li>---Hypoxia-activated gene therapy </li></ul>
  3. 3. The Hypoxia-Inducible Factor Family
  4. 4. Denko, N.C., Nature Reviews Cancer 8, 705-713 (September 2008) Mechanisms of hypoxia-inducible factor 1  (HIF1  ) stabilization
  5. 5. pO 2 Anaerobic Metabolism degradation Angiogenesis VEGF  Glut-1  ROS mt Metastasis LOX  ; E-cadherin  Muscle tissue survival Cul2 Elong. HIF1,2 Notch  Embryo gastrulation Oct-4  Lung Morphogenesis EGFR  Tenascin-C  Erythropoesis EPO  VHL DNA Repair Stem Cell Differentiation Tumorigenesis Differentiation-Development Mitoch. O 2 consumption Proteasome HIF O 2 Maxwell & Coumenis, 2006 PHD 1,2,3   FIH msh2/msh6  PDK1   OH  OH 
  6. 6. Semenza GL, Drug Discovery Today, 12:853-9, 2007
  7. 7. Semenza GL, Drug Discovery Today, 12:853-9, 2007
  8. 8. Biology of Tumor Hypoxia Hypoxic Region Blood Vessel O 2 / Drug Concentration Gene/Protein Regulation Increased Glycolysis Increased Angiogenesis Increased Genomic Instability Selection of Apoptosis Resistance Chemo/Radio-therapy Resistance
  9. 9. Evans and Koch, 01 Hypoxia (EF5, Red) and Proliferation (Ki67, Green)
  10. 10. Fei P. et al. Cancer Cell, 6:597, 2004 Proapoptotic BNIP3L is Induced by p53 under Hypoxia
  11. 11. C.V. Dang, et al. Nature Reviews Cancer 8, 51-56, 2008 The HIF1, HIF2 and MYC protein–protein interaction transcriptional network.
  12. 12. Kinzler KW and Vogelstein B Nature, 379, 1996 Graeber TG et al. Nature 379, 1996 Hypoxia Selects for Apoptosis Resistant Clones
  13. 13. Graeber TG, et al. Nature, 379:88, 1996 Hypoxia Selects for Apoptosis Resistant Clones
  14. 14. <ul><li>Point mutations </li></ul><ul><li>Oxidative base damage </li></ul><ul><li>DSBs/SSBs </li></ul><ul><li>Gene amplification </li></ul><ul><li>DNA over-replication </li></ul>Hypoxia Increases Genome Instability <ul><li>Genetic instability induced by the tumor microenvironment. </li></ul><ul><li>Reynolds, T.Y., S. Rockwell, and P.M. Glazer. Cancer Res , 1996. 56(24): p. 5754-7. </li></ul><ul><li>Diminished DNA repair and elevated mutagenesis in mammalian cells </li></ul><ul><li>exposed to hypoxia and low pH . </li></ul><ul><li>Yuan, J., Narayanan, L., Rockwell, S. and P.M Glazer. Cancer Res , 2000. 60(16): p. 4372-6. </li></ul><ul><li>Decreased expression of the DNA mismatch repair gene Mlh1 under </li></ul><ul><li>hypoxic stress in mammalian cells. </li></ul><ul><li>Mihaylova, V.T., Bindra, R.S., Yuan, J., Campisi, D, Narayanan, L., Jensen, R., </li></ul><ul><li>Giordano, F., Johnson, R.S., Rockwell S, and P.M. Glazer. Mol Cell Biol , 2003. 23(9): p. 3265-73. </li></ul>
  15. 15. Mihaylova VT, et al. Mol. Cell. Biol. 24:8504, 2004 Hypoxia Suppresses Mismatch Repair (MMR)
  16. 16. Bindra RS, et al. Mol. Cell. Biol. 24:8504, 2004 Hypoxia/Reoxygenation Represses Homologous Recombination (HR)
  17. 17. Hypoxia/Reoxygenation Represses Homologous Recombination (HR) Bindra RS, et al. Mol. Cell. Biol. 24:8504, 2004
  18. 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. 19. Brown JM & Wilson WR, 2004 Ability of ionizing radiation to kill cells is highly dependent on pO 2 ---Tomlinson and Gray , 1950s
  20. 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. 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. 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. 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
  24. 24. <ul><li>Cellular </li></ul><ul><li>Sensitivity </li></ul>Resistant Cells High OER Sensitive Cells Low OER
  25. 25. 2. Nature of Radiation X-rays neutrons  -particles LET = 2.0
  26. 26. LET and OER 60
  27. 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. 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. 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.
  30. 30. Reoxygenation Normoxic Hypoxic Necrotic X-ray Recovery X-ray X-ray X-ray Hypoxic Fraction No change Decreased Increased
  31. 31. Factors Affecting Reoxygenation 2. Clearance of dead cells by macrophages, etc. 1. Rate of angiogenesis. 3. Inflammatory response 4. Tissue remodeling.
  32. 32. Mouse mammary Carcinoma Rat sarcoma Mouse fibrosarcoma Mouse osteosarcoma Mouse fibrosarcoma Variable Rates of Reoxygenation
  33. 33. Strategies to Overcome Tumor Hypoxia <ul><li>1. Radiation Dose Fractionation </li></ul><ul><li>- Limiting damage to normal tissue </li></ul><ul><li>- Reoxygenation of hypoxic tumor cells </li></ul><ul><li>2. Improve Tumor Oxygenation </li></ul><ul><li>- Hyperbaric oxygen breathing </li></ul><ul><li>- Compounds to improve oxygenation (Motexafin Gadolinium or MGd) </li></ul><ul><li>- Allosteric modifiers of hemoglobin-oxygen binding such as RSR13 </li></ul><ul><li>(to reduce O 2 affinity for efficient O 2 discharge) </li></ul><ul><li>3. Hypoxic Cell Sensitizers (Nitroimidazoles with high electron affinity) </li></ul><ul><li>- Misonidazole: more active, but toxic (peripheral neuropathy) </li></ul><ul><li>- Etanidazole: less toxic, but no benefit </li></ul><ul><li>- Nimorazole: less active, much less toxic (benefit in H&N cancer--Danish study) </li></ul><ul><li>4. Hypoxia Cytotoxins (Bioreductive agents that selectively kill hypoxic cells) </li></ul><ul><li>- Tirapazamine: high Hypoxic toxicity ratio </li></ul><ul><li>- Mitomycin C: low Hypoxic toxicity ratio </li></ul>
  34. 34. MGd Improves Tumor Oxygenation E. Donnelly & S. Rockwell, 2005 * * * p < 0.01 * * * *
  35. 35. MGd: Clinical Tumor Oxygenation Observations <ul><li>Effects of MGd on tumor oxygenation were measured during Phase I head and neck cancer clinical trials </li></ul><ul><ul><li>Median Tumor pO 2 </li></ul></ul><ul><ul><ul><li>Before treatment: 6.8 mmHg </li></ul></ul></ul><ul><ul><ul><li>1 mg/kg MGd, one week: 27.0 mmHg </li></ul></ul></ul><ul><ul><li>Improved Tumor Response </li></ul></ul><ul><ul><ul><li>8 of 9 patients experienced complete tumor response </li></ul></ul></ul><ul><ul><ul><li>7 patients still in remission after 9 months </li></ul></ul></ul>D.M. Brizel, Duke University
  36. 36. Brown JM & Wilson WR, 2004 Activation of Hypoxia-Selective Prodrugs
  37. 37. JM Brown, Stanford Univ. Topo II TPZ Preferentially Kills Hypoxic Cells
  38. 38. Brown JM & Wilson WR, 2004 A Strategy for Hypoxia-Activated Gene Therapy
  39. 39. Semenza GL, Drug Discovery Today, 12:853-9, 2007

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