08 radiation protector


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08 radiation protector

  1. 1. RADIATION PROTECTORS AND SENSITIZERS JING-MIN HWANG, MD, PHDDepartment of Radiation Oncology, Buddhist Tzu Chi General Hospital,Taipei Branch, and Tri-Service General Hospital; Division of Radiology, Tzu Chi University, National Defense Medical Center
  2. 2. Radiation absorption
  3. 3. Radiation absorptionIndirect action is dominant for sparsely ionizing radiation
  4. 4. Radiation absorptionDirect action dominates for more densely ionizing radiations such as neutrons.
  5. 5. Radiobiology• About 2/3 of the biological damage by x- rays is due to indirect action.• Indirect action can be modified by chemical sensitizers or protectors.• High-LET radiations produce most biological damage by the direct action, which can’t be modified by chemical sensitizers and protectors.
  6. 6. Survival curve for mammalian cells exposed to radiation
  8. 8. Radioprotectors containing SH group serve as free radicalscavengers and is most effective for low LET because the dominant indirect DNA effects
  9. 9. The discovery of radioprotectors• Vasoconstriction• Upset metabolism to reduce the oxygen concentration in critical organs: sodium cyanide, carbon monoxide, epinephrine, histamine, serotonin.
  10. 10. The discovery of radioprotectors• Dose reduction factor (DRF), Cysteamine (150mg/kg in animal study, DRF = 1.8) Dose of radiation in the presence of drugs DRF = Dose of radiation in the absence of drugs (to produce a given level of lethality)
  11. 11. The mechanisms of SH-mediated cytoprotection• Free radical scavenging – protect against oxygen-based free radical generation by ionizing radiation or chemotherapy agents (e.g. alkylating agents).• Hydrogen-atom donation to facilitate direct chemical repair at DNA damage sites.
  12. 12. The protective effect of sulfhydryl compounds• Is parallel to the oxygen effect• Being maximal for sparsely ionizing radiations (e.g., x- or r- rays).• Being minimal for densely ionizing radiation (e.g., low energy α-particle).• The largest DRF would equal to OER, with a value of 2.5 ~ 3.
  13. 13. Development of more effective radioprotectors
  14. 14. Amifostine as a radioprotector in radiotherapyAmifostine dephosphorylation WR-1065 (active metabolite readily enter normal cells and scavenges free radicals Alkaline phosphatase generate by irradiation or C/T (high conc. in normal cells agents) and capillary)
  15. 15. Mechanisms of amifostine as a radioprotector• Protection of normal tissues versus tumor is through a differential uptake and conversion of amifostine to WR-1065 in tumors.• The drug is active transport into normal tissues and passive diffusion into tumors.• Better vasculature in normal tissues.• The differential sparing of normal tissue compared with tumors achieved within minutes after the administration of the drugs.• Hydrophilic membrane structure of normal cells.
  17. 17. The oxygen fixation hypothesis
  18. 18. Chemotherapeutic agents (cisplatinum and paclitaxel) and radiobiology
  19. 19. The basic strategy of hypoxic cells radiosensitizers
  20. 20. Survival curves for BUdR and IUdR substituted cells exposed to x-rays
  21. 21. Properties of hypoxic cells radiosensitizers• Selectively sensitize hypoxic cells → acceptable toxicity• Chemically stable → metabolic breakdown↓.• High solubility in water and lipids and must be capable of diffusing a considerable distance (as far as 200um from the nearest capillary) through a nonvascularized mass to reach the hypoxic cells.• Be effective at the relatively low daily dose (a few Gy).
  22. 22. The basic ring structure of the nitroimidazoles
  23. 23. The basic ring structure of the nitroimidazoles
  24. 24. misonidazole
  25. 25. Randomized prospective controlled trials by the RTOG: no statisticallysignificant advantage for misonidazole.The only promising trial: Denmark head-and-neck group.Limitation of misonidazole – dose-limiting toxicity (from peripheralneuropathy to CNS.
  26. 26. The development of misonidazole• Metronidazole• ↓• Misonidazole: more active and toxic; benefit in subgroups.• ↓• Etanidazole: less toxic, no benefit.• ↓• Nimorazole: less active, much less toxic; benefit in head-neck cancer.
  27. 27. Hypoxic cytotoxinsThree classes of agents• The quinone antibiotics (e.g. mitomycin-C, active against hypoxic cells).• Nitroaromatic compounds• The benzotriazine di-N-oxide
  28. 28. Tirapazamine (SR 4233, TPZ)
  29. 29. Response of mouse carcinoma to TPZ, RT, or both
  30. 30. Clnical trial with Tirapazamine (TPZ)• Little clinical trials with TPZ (activated by the enzyme cytochrome p450): vomiting and muscle cramping.• A phase III study of cisplatin vs. cisplatin + TPZ for non-small cell lung cancer (stage IIB and IV): doubling of response rate and increased survival rate.
  31. 31. Markers of hypoxic cells: tritiated thymidine (by autoradiography), orpositron-emitting radionuclide (iodine-123) using a sugar molecule (by PET) labeled nitroimidazole;
  32. 32. Thanks