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Illinois Institute of Technology

Illinois Institute of Technology. Physics 561 Radiation Biophysics Lecture 7: Radiation sensitivities of tumors and normal tissues Andrew Howard 24 June 2014. Plans For This Class. In vivo assays of normal tissue Acute lethal response Teratogenesis Nonstochastic effects (chapter 10)

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Illinois Institute of Technology

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  1. Illinois Institute of Technology Physics 561 Radiation Biophysics Lecture 7:Radiation sensitivities of tumors and normal tissues Andrew Howard24 June 2014 tumor and normal-tissue responses

  2. Plans For This Class • In vivo assays of normal tissue • Acute lethal response • Teratogenesis • Nonstochastic effects (chapter 10) • Late effects on normal tissue (chapter 11) ch 10 tumor and normal-tissue responses

  3. Skin Exposure of epidermis can be modeled with MTSH kinetics. We find Do ~ 4.35 Gy, n = 12.Note Dq = D0ln n = 10.81 Gy. tumor and normal-tissue responses

  4. Acute Lethal Effects (< 1 Month) • Fig. 10.1  Populations of cells • D & E categories are responsible for most acute effects: • D: mitotic, translatable in & out • E: mitotic, translatable out (stem cells…) tumor and normal-tissue responses

  5. How do humans die of acute radiation exposure? • Acute lethal dose typically above 5 Gy • Organ systems affected: • Blood-forming organs:sensitivity mostly dependent on cycle time Cell type cycle time sensitivity • Granulocyte (PMN) 4 days very high • Platelet 12 days moderate • Erythrocyte 40 days low • Gastrointestinal organs • Central Nervous System • Lymphocytes tumor and normal-tissue responses

  6. Acute Lethal Effects (< 1 Month) 1 - 2 - 5 Gy Lethality • Blood-forming effects • 3 weeks • Not very repairable • GI - If not fatal within 10 days, recovery likely • Central Nervous Systems: resuts are dose-dependent • 1 Gy • Vomiting • Results from direct stimulation of neurons? • 100 Gy • Massive disorientation • Death tumor and normal-tissue responses

  7. Lymphocytes: a special case • Mature lymphocytes are fairly radiosensitive • This is unusual for a nondividing, terminal cell type • Some kind of “interphase death” tumor and normal-tissue responses

  8. A possible explanation • There’s a lot of p53 gene product produced in lymphocytes: maybe they’re being stimulated into dying with moderate radiation exposure • http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb31_1.html p53 core domainPDB structure 2BIN tumor and normal-tissue responses

  9. A detour into molecular biology • The “central dogma” of molecular biology involves: • Replication (cellular DNA can be duplicated before mitosis) • Transcription (DNA codes for messenger RNA and other types of RNA) • Translation (mRNA codes for protein synthesis in the ribosomes) • So in prokaryotic (anuclear) organisms, it’s simple: gene DNA transcription mRNA message (To ribosome) translation Gene product protein tumor and normal-tissue responses

  10. How this works at the base-pair level • DNA Duplex:DNA strand: 5’-A-T-T-C-C-G-3’DNA strand: 3’T-A-A-G-G-C-5’ • DNA-RNA hybrid, produced by transcription of DNA:DNA strand: 5’-A-T-T-C-C-G-3’RNA strand: 3’-U-A-A-G-G-C-5’ • Resulting RNA strand that can code for protein:RNA strand: 3’-U-A-A-G-G-C-5’ • Note that DNA nucleotides are dA, dC, dG, dT;RNA bases are A,C,G,U (thymine is 5-methyluracil) tumor and normal-tissue responses

  11. In eukaryotes, it’s more complex gene DNA transcription Full-length message mRNA mRNA processing (splicing) Processed message nucleus (To ribosome) translation Gene product protein cytoplasm tumor and normal-tissue responses

  12. Numbers matter, too! • Suppose the original gene was 2000 base-pairs long. • The full-length message will therefore be 2000 bases. • The truncated (processed) mRNA might be 720 bases. • The resulting protein would be 720/3 = 240 amino acids long. • Note that only 36% of the DNA is actually coding for protein in this case. tumor and normal-tissue responses

  13. Can it get messier? Yes. • One full-length message can be spliceosomally processed in multiple ways to produce several viable protein products gene DNA transcription mRNA mRNA splicevariant #1 mRNA splicevariant #2 mRNA splicevariant #3 Protein product #1 Protein product #2 Protein product #3 tumor and normal-tissue responses

  14. Bcl3: an example • Bcl3 is an important gene in regulation of apoptosis and therefore in carcinogenesis and other developmentally-related pathologies. • Exists in multiple splice variants, all derived from a single gene. • Some variants stimulate apoptosis, others inhibit it! • See Gil Ast, “The Alternative Genome,”Scientific American, April 2005, pp. 58-65. tumor and normal-tissue responses

  15. Why do we talk about this here? • Alternative splicing may look like a topic that only a true molecular biologist would care about, but it isn’t. • If a certain gene is being stimulated into producing more of its starting mRNA, the protein-dependent outcome of that stimulation may be complex or even counter-intuitive, depending on this phenomenon • If ionizing radiation were to turn on the BCL3 gene, would that increase or decrease apoptosis? Unclear • Even if we knew that, would we know whether that would be radioprotective? Not necessarily. tumor and normal-tissue responses

  16. Gestational Radiosensitivity • Fig. 10.10 provides a long list of radiosensitivity data for various organs and organ systems • In some cases the maximum sensitivities are early, in others much later tumor and normal-tissue responses

  17. Teratogenesis & Fetal Development • Teratogenesis - Embryological abnormalitymonster • It’s traditional to argue that the fetus is highly radiosensitive, but it actually isn’t, compared to other rapidly dividing cell systems. • We need to distinguish among: • Damage to gametes before fertilization • Somatic damage to growing organism • Damage to mother that influences development tumor and normal-tissue responses

  18. Measurement Problems associated with Teratogenesis • Confounding effects(how can one tell these phenomena apart?) • Genetic damage before fertilization • Damage to embryo/fetus • Damage to placental system • High background • High incidence of birth defects in unexposed subjects • 5% of all births involve some significant abnormality tumor and normal-tissue responses

  19. Why does a high background matter? • With low background, a small dose-response effect can be discerned even in the presence of some experimental error • With high and nonuniform background, it’s hard to pick the signal out of the noise. Response(fetal abnormalities) Response (Background) Dose Results with low background Results with high background tumor and normal-tissue responses

  20. Stages of Development • Single cell  rather sensitive • Conceptus • 2 cell: Rather resistant:both cells are totipotent, i.e. capable of differentiation into all necessary tissue types • All cells remain totipotent in the first few cell divisions; differentiation begins just before implantation • Severe damage to embryo can prevent implantation • Early differentiation: Onset of abnormalities tumor and normal-tissue responses

  21. Types of fetal damage • Severe mental retardation • Occurs in 1-5 Gy range? • Is this really teratogenic or does it involve damage to mother at higher doses? • Microcephaly • Might occur even in 1 Gy range • Data supporting that are disputable • Other types of damage described in mouse studies Microcephalic woman:in utero in Hiroshima when the bomb fell tumor and normal-tissue responses

  22. Possible explanation for radiation-induced microcephaly • Fujimori et al. (2008) Biochem.Biophys.Res.Comm. 369:953 • Authors argue that a gene product called ASPM is downregulated by in utero exposure to ionizing radiation • Related to problems withmitotic spindle regulation tumor and normal-tissue responses

  23. Developmental Toxicity • This is an attempt to get you to think about the collected information in fig. 10.10. • Fig. 10.10 provides a long list of radiosensitivity data for various organs and organ systems • In some cases the maximum sensitivities are early, in others much later • Most effects on the eye (other than cataracts) occur relatively late • Most functional disorders are very late • Cephalic disorders occur all through gestation tumor and normal-tissue responses

  24. Stochastic Effects of Radiation • One of two overarching categories of damage, particularly as it produces long-term effects: • Percent of population affected by the exposuremay be dose-dependent -BUT- • Severity of condition in an affected individual is independent of dose • Cancer is traditionally regarded as stochastic,but that may be an oversimplification • Nonstochastic damage is damage that does display dose-response relationships in an individual tumor and normal-tissue responses

  25. Nonstochastic Effects on Normal Tissue • Severity of condition does show dose dependence • Possible threshold dose (no effect below DT) • Most important mechanism: disruption of vascularization (Casarett model, Fig. 11.1) Response Dose DT tumor and normal-tissue responses

  26. Casarett model for microvasculature • Sequence of events beginning with irradiation and ending with loss of function, susceptibility to disease, and death • Shown in Fig. 11.1 • Note cyclic effect of fibrosis and secondary vascular regression tumor and normal-tissue responses

  27. Casarett model, graphically Endothelial changesin fine vasculature Irradiation ofSensitiveTissue Volume Direct Cell Killing “Indirect” effect Mononuclear infiltrationand active fibroblast proliferation(inflammation & fibrosis) Aging Changes Increased endothelialpermeability Reduced microcirculatorycapacity & inhibited diffusion Progressive fibrosis;increased diffusional barriers Reduced parenchymal functionsecondary to microvasculatureand diffusion changes Replacement fibrosis &secondary vascularregression Loss of function,susceptibility to disease, and death tumor and normal-tissue responses

  28. Vascular endothelium as target • Endothelial cells lining capillaries are a cell-renewal system, so damage there will hurt the organ that those capillaries supply with blood. • Types of damage: • Direct: interphase death of cells in wall(DNA damage leading to apoptosis) • Indirect: interference with cell renewal tumor and normal-tissue responses

  29. Mechanism I • Yazlovitskaya et al. (2008) Cell Death & Differentiation 1-13 • cytosolic PLA2 activated by radiation • increases LysoPC • activation of Flk1 • phosphorylation of AkT • Activates ERK1 & 2 • Modifies cell viability tumor and normal-tissue responses

  30. Mechanism II • Seeds of its own destruction: • Inhibition of the survival pathway leads to cell death and radiosensitization tumor and normal-tissue responses

  31. Gastrointestinal systems where this mechanism predominates • Esophagus • Stomach • Small & large intestine • Rectum (not the only mechanism) tumor and normal-tissue responses

  32. Other systems where this mechanism predominates • Skin (dermal layer) &other epidermal mucosal organs • Liver (except for hepatitis) • Kidneys (many other mechanisms) • Lung (other mechanisms) • Brain • Spinal cord (low-dose effects are of this type) tumor and normal-tissue responses

  33. Functional Subunits • Concept: The fate of an organ depends on individual functional subunits (FSUs). • When all the stem cells that give rise to the functioning cells in a functional subunit die, then the functional subunit can’t continue to operate • Examples: • In the kidney: the nephron • In the lung: the alveolus • In the pancreas: a single islet of Langerhans • In the small intestine: a gastrointestinal crypt • Can we generalize this to all tissues? Maybe not. tumor and normal-tissue responses

  34. Other types of late damage • The assertion: If vascular damage were the whole story for the late effects of radiation, then the time of onset of late damage should be more or less the same for all organs. That’s false! • Stromal and parenchymal damage • parenchymal cells are those involved in the actual function of an organ, e.g. the cells in the liver that actually filter out damaging chemicals • Stromal cells are the support cells that undergird and provide morphological support for the parenchymal cells tumor and normal-tissue responses

  35. Non-endothelial late effects • Rectum: thinning & perforation of rectum • Epidermal layer of skin: desquamation • Kidneys: complicated, multi-causal;tubular disfunction in glomerulus unrelated to vascular disorders • Lung: killing of type 2 alveolar cells • Spinal cord: fast paralysis involves damage to myelin sheath around cord • Eye: improper differentiation of lens fiber cells leads to cataracts tumor and normal-tissue responses

  36. Summary of organ-specific effects See table in the html documents on Blackboard for full summary on nonstochastic effects tumor and normal-tissue responses

  37. And now for something mostly different • We’ll move away from nonstochastic late effects to a discussion of treatment modalities for tumors. • Here we’re focusing on the fact that tumors are somewhat DNA repair-deficient and therefore respond differently to ionizing radiation than healthy tissues do • We’ll look, in particular, at dose fractionation as a component of treatment planning for cancer tumor and normal-tissue responses

  38. Fractionation • Radiotherapy can’t wait for research:people need answers now • Even in the 1930’s and 40’s it was recognized that there was an advantage in treating tumors to fractionate the dose, i.e. if the total dose you wanted to deliver was 5 Gy, you got a better therapeutic ratio if you delivered it in several small doses rather than all at once. • We’ll now explore some quantitative models of the relationship between damage and fractionation tumor and normal-tissue responses

  39. Power Law and Timing • Witte:measured dose D required to reach the threshold for skin erythema as a function of dose rate or number of fractions n: • Power law:lnD = a + blnn, i.e.D = ea+blnn = ea eblnn = ea elnnbD = Qnb, where Q = ea. tumor and normal-tissue responses

  40. Power-law treatments, continued • Strandqvist: total time of treatment T:D = UT1-p; 1-p for skin was about 0.2. • Cohen: 1-p is tissue specific (0.30 normal, 0.22 for carcinomas); this enables radiotherapy! Strandqvist modelU=2 Gy1-p = 0.2 tumor and normal-tissue responses

  41. Normalized Standard Dose • Ellis: tolerance dose D for normal tissue is related to the number of fractions Nand the overall treatment time in days, T: • D = rT0.11N0.24 • The value of r is called the Normalized Standard Dose or NSD; it can be determined separately for each tissue and each treatment modality. # of treatments tumor and normal-tissue responses

  42. What are we really doing here? • This is curve-fitting in its most unapologetic form. • As far as I know there is no attempt to attach physical meanings to the exponent (1-p) in the Strandqvist model. • Nor is there a reason to think there’s anything physically significant about the 0.11 and 0.24 exponents in the Ellis formulation tumor and normal-tissue responses

  43. Time of treatment and number of fractions • Clearly time and number of fractions are (anti-)correlated variables • BUT this approach can be helpful in treatment planning, at least within the range of conditions for which the formulas are valid. tumor and normal-tissue responses

  44. Can we do better than this? • Explicit accounting for damage in terms of repairability: • Sublethal • Potentially lethal • Nonrepairable • Model suggests that the limiting slope of lnS vs D as you fractionate a lot is determined by the single-hit (nonrepairable) mechanism tumor and normal-tissue responses

  45. Effect of Fractionation Fig. 11.3: Repair capability;limiting slope determined by fraction sizes < W Radiation Dose Y W X Limiting slope forfraction sizes < W orlow dose rates 0.1 Surviving fraction Effective slope,fraction size X 0.01 Limiting slopefor largedose fraction Effective slope,fraction size Y 0.001 tumor and normal-tissue responses

  46. Douglas & Fowler • Used mouse-foot skin reaction to fractionated doses: ≤ 64 fractions , constant overall time • For an isoeffect, the following equation held: n(aD+bD2) = gwhere n = # of fractions, D = dose per fractionnote: I’m using D where Alpen uses D, to reduce potential confusion with the overall dose. tumor and normal-tissue responses

  47. Douglas-Fowler Assumptions • Repair occurs after single doses • Biological outcome depends on surviving fraction of critical clonogenic cells • Every equal fraction will have same biological effect tumor and normal-tissue responses

  48. Survival fraction,Douglas&Fowler formulation • lnS = n(Fe/a)D • Note that a is not a. • For an appropriate choice of a, Fe = 1/(nD) • Single-dose cell survival is S = exp[(Fe/a)D] • So we do an isoeffect plot of Fe vs. D:Fe = b + cD tumor and normal-tissue responses

  49. Douglas & Fowler Survival Fraction, Continued • Thus lnS = n(bD/a + cD2/a) • cf. Standard LQ model, assuming constant effect per fraction: lnS = -n(aD + bD2) • Defining E = -lnS, E/(nD) = a + bD1/(nD) = a/E + bD/E • plotDvs Fe = 1/(nD)to geta/E, b/E. • In practical situations we may not be able to measure E directly tumor and normal-tissue responses

  50. Fig. 11.4: finding a/E, b/E • a/E = intercept = 1.75 Gy-1 • b/E = slope = 27 Gy-2 • a/b = ratio = 0.0648 Gy 6 4 1/total Dose, Gy-1 2 0.05 0.10 0 0.15 Dose per fraction, Gy tumor and normal-tissue responses

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