Interaction of Radiation with Biological Matter: (what is biological dose? ) Bill Mc. Bride Division of Cellular and Molecular Oncology Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. wmcbride@mednet. ucla. edu Room B 3 -109, x 47051 WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Objectives: – Know the characteristics of ionizing radiation that make it useful for RT – Define LET and RBE and what is meant by quality of radiation – Know the difference between direct and indirect action of radiation and the role of free radicals – Recognize the impact of oxygen on initial radiation damage and of hypoxia in tumor RT – Understand how biological radiation dose and physical radiation dose differ WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Radiation Therapy • Approximately 50% of cancer patients receive RT with curative intent • Approximately half of these are cured Radiation Therapy has a long history! WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Roentgen with his wife’s hand, 1895 X-rays were rapidly adapted for use as a clinical treatment, initially for noncancerous conditions, but soon for cancer, as well. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
FIRST CURE OF CANCER BY X-RAYS 1899 - BASAL CELL CARCINOMA X-rays were used to cure cancer very soon after their discovery WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
And rapidly became a standard treatment Hammersmith Hospital, London, 1905 WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Although side-effects were encountered! This is a picture of a 70 year old person who was irradiated by Freund at the of age 5 in Austria 1896 for nevus pigmentosus piliferus. L. Freund, Ein mit Rontgenstrahlen behandelter fall von nevus pigmentosus piliferus. Wein. Med. Wochschr. 47, 428 -434 (1987). WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Initially more non-cancerous diseases were treated that cancer (still popular in Europe) Lupus Epilepsy WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
The Nobel Prize in Physiology or Medicine 1946 "for the discovery of the production of mutations by means of X-ray irradiation However, its use for benign conditions has been limited in most countries for fear of radiation-induced cancer. The carcinogenic effects of X-rays was discovered using fruit flies by Muller in 1946. Hermann J. Muller http: //dmco. ucla. edu/Mc. Bride_Lab WMc. B 2008
Natural radioactivity was discovered by Becquerel, who was awarded the Nobel Prize in Physics in 1903 along with Marie and Pierre Curie "in recognition of the extraordinary services they have rendered by their joint researches on the radiation phenomena" Henri Becquerel Maltese cross Marie Curie “One wraps a Lumiere photographic plate with a bromide emulsion in two sheets of very thick black paper, such that the plate does not become clouded upon being exposed to the sun for a day. One places on the sheet of paper, on the outside, a slab of the phosphorescent substance, and one exposes the whole to the sun for several hours. When one then develops the photographic plate, one recognizes that the silhouette of the phosphorescent substance appears in black on the negative. If one places between the phosphorescent substance and the paper a piece of money or a metal screen pierced with a cut-out design, one sees the image of these objects appear on the negative. One must conclude from these experiments that the phosphorescent substance in question emits rays which pass through the opaque paper and reduces silver salts. Paris ” 1896 WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Natural Radioactivity • particles – Positively charged, helium nucleus • particles – Negatively charged, electrons • -rays – No charge, EMR WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Radioisotopes also were soon being used to treat and cure cancer. First cure of cancer by radium plaque 1922 Radioactive plaques and implants are still in common use, for example in prostate implant seeds. Radium applicators were used for many other conditions! http: //dmco. ucla. edu/Mc. Bride_Lab WMc. B 2008
Therapeutic Benefit and R. T. There is always a need to derive a therapeutic benefit from RT. There are 2 main ways by which this is achieved: 1. Physical means – distributing dose by treatment planning 2. Biological means – dose fractionation WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
1 -25 Me. V 500 Ke. V 150 Ke. V 20 Ke. V Megavoltage Orthovoltage Superficial Therapy Contact Therapy Grenz Rays Major improvements in RT during the mid-1900 s came from improved penumbra and decreased skin dose associated with higher energy x-rays, cobalt, and high energy photons. More recently conformal RT, IMRT, IGRT, Gammaknife, Cyberknife, tomotherapy, SRS, SRT, protons, heavy ions, etc. have added considerable variety to the choices for physical radiation delivery and present radiobiological challenges. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
History of Fractionation 1896 Freund - treated hairy nevus with fractionated doses 1900 Stenbeck - cured skin cancer with single doses 1906 Bergonie and Trubandeau introduced the “Law” that radiosensitivity is related to cell proliferation (NOT TRUE!) to explain why fractionated doses sterilized rams without skin reactions Regaud - treated uterine cancer with fractionated doses 1914 Schwartz - Fractionation is superior because of cell cycle redistribution 1919 Coutard cures deep-seated H&N tumors 1932 Coutard shows fractionation superior to single dose 1944 Strandquist - empirical laws for changing dose per fraction 1967 Ellis - Nominal Standard Dose (NSD) formula 1980 s Linear Quadratic formula gains favor WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
The First Radiation Dosimeter! Early x-ray machines took a long time to deliver effective dose and gave skin reactions that could be circumvented by dose fractionation. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
From Amaldi and Kraft, “Radiotherapy with beams of carbon ions, Reports on Progress in Physics, 68, (2005) WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
History has repeatedly shown that dose fractionation results in a therapeutic advantage “In order to save machine time, a 3 -day-a-week schedule was initiated in 1962. This schedule was quickly abandoned in preoperative irradiation because of increased wound healing problems. Although acute reactions in the 3 -day-a-week schedule for protracted radical irradiation were not excessive, late radiation sequelae are probably more pronounced as observed 2 or more years later. ” Fletcher, 1966. 3 x 3. 3 Gy 5 x 2 Gy http: //dmco. ucla. edu/Mc. Bride_Lab WMc. B 2008
Clinical RT is Changing, which Presents Challenges and Opportunities for Radiobiology Conventional treatment: Tumors are irradiated to a specified dose with 2 Gy fractions delivered, more or less homogeneously, in a 6 week time period • Varying this schedule impacts outcome • Radiobiological modeling attempts to provide guidelines for customization of RT using – Radiobiological principles derived from preclinical data – Radiobiological parameters derived from clinical altered fractionation protocols Modern treatment: IMRT etc allows optimized non-homogeneous dose distributions, concomitant boosts, dose painting - dose heterogeneity SRS, SRT, HDR, Protons, Heavy Ions - high dose/fx issues Molecular and chemical targeting - dose adjustment Molecular prognosis and diagnosis promise individualized treatment plans and biological treatment planning WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
• Radiobiology has derived means of understanding why dose fractionation gives a therapeutic benefit. • New physical delivery methods need to incorporate and/or modify these concepts. • In order to understand either conventional or newer treatment effects, one needs to know the differences between physical and biological radiation dose WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
What is Radiation? • Radiation is classified into two main categories: - Non-ionizing radiation - Ionizing radiation WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
ELECTROMAGNETIC RADIATIONS (cms) 10 -9 10 -8 10 -7 E (e. V) 1. 24 x 107 10 -6 10 -5 10 -4 10 -3 10 -2 1 10 102 103 1. 24 x 102 Radar Microwaves rays U. V. IONIZING RADIATION 104 1. 24 x 10 -13 v i s i b l e X-rays 10 -1 Infra Red T. V. Radio Short Waves Radio Waves NON-IONIZING RADIATION Photon E = h (energy = Planck’s const x frequency) = hc/ (c = speed of light, = wave length) WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
• Non-ionizing radiation – Is a particle or wave that has enough kinetic energy to raise thermal energy of an outer shell electron and cause excitation with emission of low energy EMR (infrared) • Ionizing radiation excitation and ionization particle excitation ionization -ray ’ray – Ionizing radiation has enough kinetic energy to detach at least one electron from an atom or molecule, creating ions – Charged particles such as electrons, protons, heavy ions, alpha and beta particles are directly ionizing because they can interact directly with atomic electrons through coulombic forces and transfer a major part of their kinetic energy directly – In contrast, photons (x rays, rays) and neutrons are chargeless and therefore more penetrating. They are indirectly ionizing. They have sufficient kinetic energy to free an orbital electron producing a ‘fast’ recoil or Compton electron that is, in turn, directly ionizing • Energy is deposited in “packets”, which is why, when it is deposited in DNA, ionizing radiation is an efficient cytotoxic agent • Ionizing radiation has an energy in excess of 124 e. V, which corresponds to a < about 10 -6 cm. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Ionization produces ions, ion radicals, and free radicals concentrated along tracks and especially at Bragg peak of primary and secondary electrons. They are highly reactive and cause damage to biological matter SECS 10 -18 10 -16 10 -14 10 -12 Ion formation – H 2 O+ and e- Absorption of energy Excitation and H and OH radical formation Physical effects ION RADICAL LIFETIME Chemical lesions 10 -6 Mins-Hrs FREE RADICAL LIFETIME 100 BREAKAGE OF BONDS CHEMICAL REPAIR / MISREPAIR ENZYMIC REPAIR / MISREPAIR EARLY BIOLOGICAL EFFECTS Hrs-Days-Years 106 LATE BIOLOGICAL EFFECTS Chemical repair Enzyme repair/lesion Cellular effects Tissue effects Systemic effects • Ion - atom or molecule that has lost an electron and is charged. • Free radical - atom or group of atoms that contains an unpaired electron and is highly reactive • Aqueous electron - has lost kinetic energy and has been captured by water - a powerful reducing agent. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
The Gray is the Physical Unit of Radiation • • 1 GRAY, the unit of absorbed dose (1 joule / Kg), – Causes 1 -2 x 105 ionization events / cell – 1% in DNA – A single cobalt 60 ray will deposit about 1 m. Gy in a cell Rad (Radiation Absorbed Dose) is the old unit = c. Gy WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Direct and Indirect Action of Radiation • Indirectly ionizing radiation can act directly or indirectly on biological targets • If the ion pairs and free radicals are produced in a biologic target (DNA) then this is direct action • If water or other atoms or molecules are ionized, diffusible free radicals can act as intermediaries to cause damage - this is indirect action WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Direct and Indirect Action of Ionizing Radiation on DNA 4 nm photon H 2 O OH . ep+ INDIRECT ACTION photon R. 2 nm http: //dmco. ucla. edu/Mc. Bride_Lab ep+ DIRECT ACTION WMc. B 2008
Reactive Oxygen Species (ROS) • Since H 2 O is the major component in cells, the most common ionization event is radiolysis of water, producing reactive oxygen species (ROS) • The most relevant water is within 2 nm of the DNA and tightly bound • ROS produced include: H. - reducing; OH. - oxidizing; HO 2. - oxidizing (O 2 + H. ); H 2 O 2 - oxidizing • The net effect is oxidation of cellular constituents • About 60% of DNA damage caused by x-rays is due to ROS • About 75% of the indirect action of radiation is due to hydroxyl radicals (OH. ) WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Free OH. radicals generate organic radicals by: – Addition – Hydrogen abstraction – Electron transfer R + OH. RH + OH. R + OH. . ROH R. + H 2 O R. + OH - Where R is the organic moiety WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Free Radicals and their Scavengers Matter • • • Biological effects of ionizing radiation are determined in large part by free radicals Free radicals are involved in many biological processes, including cellular respiration We have defenses against free radicals – Endogenous free radical scavengers - most relevant within 2 nm of the DNA – Anti-oxidants • eg superoxide dismutase, especially in mitochondria, and catalase • Free radical scavengers can protect normal tissue from radiation – eg Amifostine • • Depleting free radical scavengers will radiosensitize What interacts with free radicals, in particular radicals in biological materials will be important in determining outcome at this level • Oxygen interacts with free radicals WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Oxygen Matters • Binds H radicals forming hydrogen peroxide H. + O 2 HO 2. (+HO 2. ) H 2 O 2 (+O 2) • Binds electrons to give superoxide e- + O 2 - + (H 2 O) • HO 2. + OH- Binds organic radicals to form peroxides R. + O 2 RO 2. (radical peroxide) RO 2. + R’ H ROOH + R’ (hydroperoxide) RO 2. + R’. ROOR’ (peroxide) Oxygen “fixes” the radical lesions in DNA in a form that can not be easily chemically repaired and therefore is a very powerful radiosensitizer. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Oxygen Enhancement Ratio (OER) = Dose required to produce a specific biological effect in the absence of oxygen Dose required for the same effect in its presence OER varies with level of effect but can be 2. 5 - 3 fold 1) Culture Cells 4) irradiate under oxic or hypoxic conditions 5) Plate cells and grow for about 12 days 0 Gy 2) Suspend Cells ( trysinization) 3) Count cells in hemocytometer Physical Dose = Biological Dose http: //dmco. ucla. edu/Mc. Bride_Lab 2 Gy 4 Gy . . . . 6 Gy 6) Count colonies 1. 0 S. F. hypoxic 0. 1 0. 01 0 2 4 6 Dose (Gy) 8 10 WMc. B 2008
Clinical Relevance of Hypoxia The effects of hypoxia were first discovered in 1909 by Schwarz who showed that strapping a radium source on the arm gave less of a skin reaction than just placing it there. This was used to give higher doses to deep seated tumors. Giacca and Brown Pimonizadole (oxygen mimetic) staining colorectal carcinoma • Hypoxic areas occur almost solely in tumors and are more radioresistant than oxic areas. • Hypoxia contributes to treatment failure • Reoxygenation occurs between radiation dose fractions giving a rationale for dose fractionation • The oxygen effect is greater for low LET than high LET radiation WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
RADIATION QUALITY AND BIOLOGICAL EFFECTIVENESS WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
LINEAR ENERGY TRANSFER Separation of ion clusters in relation to size of biological target LOW LET Radiation gamma rays deep therapy X-rays soft X-rays alpha-particle LET is average energy (d. E) imparted by excitation and Ionization events caused by a charged particle traveling a set distance (dl) - LET = d. E/dl (ke. V/ m) http: //dmco. ucla. edu/Mc. Bride_Lab HIGH LET Radiation WMc. B 2008
• A dose of 1 Gy will give 2 x 103 ionization events in 10 -10 g (the size of a cell nucleus). This can be achieved by: excitation and ionization – 1 Me. V electrons • 700 electrons which give 6 ionization events per m. – 30 ke. V electrons particle • 140 electrons which give 30 ionization events per m. – 4 Me. V protons excitation • 14 protons which give 300 ionization events per m. ionization -ray ’-ray • The biological effectiveness of these different radiations vary! WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Relative Biological Effectiveness (RBE) of the Radiation Matters = Dose of 250 k. Vp x-rays required to produce an effect Dose of test radiation required for the same effect 1. 0 0. 1 S. F. 0. 01 Low LET, HDR High LET 0. 001 DOSE Gy Physical Dose = Biological Dose WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
RBE and OER as a function of LET 8 4 Fast Neutrons 6 Alpha Particles RBE (for cell kill) overkill 4 2 0 3 RBE Co-60 Diagnostic gamma rays X-rays 0. 1 1 10 OER 100 OER 2 1 1000 0 Linear Energy Transfer (LET ke. V/ m) OER is the inverse of RBE because OER depends considerably on the indirect action of ionizing radiation RBE is maximal when the average distance between ionization events = distance between DNA strands = 2 nm WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
DNA is the Primary, but not the only, Cellular Target for Radiation • Microbeam irradiation of cell cytoplasm does not generally cause cell death, but irradiation of the nucleus does • Tritiated thymidine incorporated into cells can kill them • Radiation-induced chromosomal abnormalities correlate with cell death and carcinogenesis • However, irradiation of the cytoplasm is not without biological consequences WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
The lesions in DNA that are associated with cell death and carcinogenesis after radiation exposure are large Lesion size about 15 -20 nucleotides OH. eaquv OH. eaqu OH. eaqu Spur 4 nm diam 3 ion pairs 100 e. V energy 95% of energy deposition events Blob 7 nm diam. 12 ion pairs The high cytotoxic efficiency of ionizing radiation can be ascribed to the deposition of low levels of energy in small packets within the DNA that cause lesions large enough to be fatal WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
DOUBLE STRAND BREAK 30/ CELL / GRAY SINGLE STRAND BREAK 1000 / CELL / GRAY INTRASTRAND CROSSLINK 0. 5 / CELL / GRAY BASE CHANGE (eg C - U) BASE LOSS INTERSTRAND CROSSLINK 1000 / CELL / GRAY * DNA-PROTEIN CROSSLINK 1 / CELL / GRAY BASE MODIFICATION (eg thymine/cytosine glycol) SUGAR DAMAGE (abstraction of hydrogen atom) WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
• Not all ionization events are lethal!! • As a rough guide the fraction of cells surviving 2 Gy (SF 2 Gy) is about 0. 5 • If the S. F. 2 Gy is 0. 5, what is the S. F. after 60 Gy? = 0. 530 = 0. 9 x 10 -9 • If the S. F. 2 Gy is 0. 7, what is the S. F. after 60 Gy? = 0. 730 = 2. 2 x 10 -5 WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
What is the Lethal Lesion? WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
X- or -radiation is sparsely ionizing; most damage can be repaired 4 nm Repairable Sublethal Damage 2 nm WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
It is hypothesized that the lethal lesions are large double strand breaks with Multiply Damaged Sites (MDS) that can not be repaired. They are more likely to occur at the end of a track 4 nm Unrepairable Multiply Damaged Site 2 nm Single lethal hit Also known as - type killing. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
At high dose, intertrack repairable Sublethal Damage may Accumulate forming unrepairable, lethal MDS Also known as - type killing WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Dose Rate Matters 1. 0 Low Dose Rate 0. 1 allows continuous SLDR S. F. 0. 01 Low LET, HDR 0. 001 DOSE Gy Physical Dose = Biological Dose WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Chromatin Structure Matters • Each cell contains about 2 m of DNA • The basic structure is the nucleosome, which is 146 base pairs of DNA wrapped around 2 copies of histones H 2 A, H 2 B, H 3, and H 4 • Nucleosomes are in turn wrapped around other proteins to form compacted chromatin • Chromatin is maximally compacted during mitosis • Transcription requires decompaction to facilitate initiation (binding of transcription factors and RNAP II) and elongation miniband - 30 nm 840 nm http: //dmco. ucla. edu/Mc. Bride_Lab WMc. B 2008
Chromatin Structure and Radiation Responses • Compact chromatin is more radiosensitive than non-compacted –Mitotic cells • are 2. 8 times more sensitive to DNA breaks than interphase cells • have a lower OER (eg 2. 0 compared with 2. 8) • do not have much of a “shoulder” on their survival curve –Actively transcribing genes are less sensitive to damage • Decompaction and compaction require acetylation and deacetylation of histones by acetyltransferases (HAT) and deacetylases (HDAC) • HDAC inhibitors are entering the clinic as anti-cancer agents and can radiosensitize • Radiation Damage to DNA is not randomly distributed. • It varies with cell cycle phase and level of gene expression 1 S. F. LATE S . 1 EARLY S Physical Dose = Biological Dose . 01 0 G 1 PHASE G 2/M PHASE 4 8 12 Dose (Gy) 16 20 WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
700 R 1500 R Withers, H. R. and Elkind, M. M. Radiology 91: 998, 1968 Used the macrocolony assay in mouse jejunum to assessed the effects of 2 radiation doses given varying times apart to measure the time to and extent of repair, redistribution, and repopulation (regeneration) between dose fractions. Repopulation Redistribution 12. 5 Gy 14. 0 Gy 15. 5 Gy Repair 17. 0 Gy Colony derived from a single surviving clonogen WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Tissue Type Matters ACUTE RESPONDING TISSUES (responses seen during standard therapy) Gut Skin Bone Marrow Mucosa LATE RESPONDING TISSUES 1 Surviving Fraction Acute Responding Tissues and Many Tumors . 1 Late Responding Tissues (responses seen after end of therapy) Brain Spinal Cord Kidney Lung Bladder . 01 0 4 8 12 16 20 Dose (Gy) Physical Dose = Biological Dose http: //dmco. ucla. edu/Mc. Bride_Lab WMc. B 2008
Dose Fractionation 1 Surviving Fractionated dose Late responding tissues. 1 Fractionated dose Acute responding tissues Single dose Late responding tissues Single dose Acute responding tissues . 01 0 4 8 12 16 20 24 Dose (Gy) Dose fractionation spares late responding tissues more than acute responding tissues and many tumors WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
The Aim is to Increase Therapeutic Benefit! 1. 0 Probability of tumor control/ of normal tissue damage therapeutic benefit 0 A B Dose (Gy) C Normal tissue complication dose-response curves are steep! WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Biological effectiveness of RT varies with • • • Size of Dose (D) - (alpha and beta) Size of Dose Per Fraction (d) - (alpha and beta) Time over which it is delivered (T)- (alpha and beta) Time between fractions (t) Volume irradiated (V) Quality of Radiation (Q) - RBE Presence/Absence of Oxygen - OER DNA Repair efficiency and completeness Cell cycle phase and level of gene activation Tissue/Tumor Type Physical Dose = Biological Dose WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
4 Rs OF RADIOBIOLOGY RELEVANT TO CLINICAL DOSE FRACTIONATION • Repair of sublethal damage - spares late responding normal tissue preferentially • Reassortment/Redistribution of cells in the cell cycle – increases acute effects – no influence on late effects – increases damage to tumor • Repopulation/Regeneration – – – spares acute responding normal tissue preferentially no influence on late effects, danger of tumor repopulation • Reoxygenation – no influence on normal tissue responses – increases tumor damage WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
Questions on Interaction of Radiation with Biological Matter: what is biological dose? Bill Mc. Bride Dept. Radiation Oncology David Geffen School Medicine UCLA, Los Angeles, Ca. wmcbride@mednet. ucla. edu WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
1. The lifetime of radicals in target molecules is about – 10 -3 secs – 10 -6 secs – 10 -9 secs – 10 -12 secs #2 – free radicals are highly unstable and reactive WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
2. Electromagnetic radiation is considered ionizing if it has a photon energy greater than – 1. 24 e. V – 124 e. V – 1. 24 ke. V #3 – this is sufficient to break bonds in biological molecules WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
3. The S. I. unit of absorbed dose is – Becquerel – Sievert – Gray – Roentgen #3 The International System (IS) unit is the Gray, named after the radiobiologist Louis “Hal” Gray who was based in London WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
4. Which of the following are not charged particles? – Electrons – Neutrons – Protons – Heavy ions – Alpha particles #2 – which is why they are called NEUTRons WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
5. Which of the following is NOT a characteristic of the indirect action of ionizing radiation – Production of diffusible free radicals – Production of reactive oxygen species – Involvement of anti-oxidant defenses – Causes a change in redox within a cell favoring reduction of constituents #4 the free radicals produced makes ionizing radiation an oxidative stress overall WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
6. Which of the following is true about the oxygen enhancement ratio – Is the same at all levels of cell survival – Can be measured by the dog-leg in a cell survival curve after single high dose irradiation of tumors – Is the ratio of doses needed for an isoeffect in the absence to the presence of oxygen – Is low for cells in S cell cycle phase compared to cells in G 2/M phase #3 responses should be compared by the doses needed for a particular isoeffect. The OER varies with the level of effect eg survival WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
7. Which of the following is true about Linear Energy Transfer – It is a measure of the biological effectiveness of ionizing radiation – Shows an inverse correlation with the oxygen enhancement ratio – Is maximal at a relative biological effectiveness of 150 ke. V/micrometer – Is measured in ke. V/micrometer #4 LET is an average value imparted per unit path length. Because the radiations vary in energy, the LET is not biologically very useful WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
8. The Relative Biological Effectiveness of a radiation is – Assessed by the dose required for to produce the same effect as 250 k. Vp X-rays – Is the ratio of the dose required of 250 k. Vp X -rays to that of the test radiation for a given isoeffect – Is directly related to Linear Energy Transfer – Is about 3 for alpha particle radiation #2 - again, measured by isoeffective doses – classically relative to 250 k. Vp x-rays, but often more recently 60 Co has been used WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
9. The lethal lesion caused in DNA by low LET ionizing radiation is – 15 -20 nucleotides in size – Caused by alpha-type events – Does not correlate with chromosomal aberrations – Due to oxygen fixation #1 The lesions are large i. e they are not point mutations. WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
10. Approximately how many DNA double strand breaks are caused per cell per Gray? – 1 -10 – 15 -25 – 30 -40 – 45 -60 – 60 -75 #3 This probably varies considerably depending on numerous factors, but this is a reasonable approximation WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
11. If the fraction of cells surviving 2 Gy irradiation is 0. 5, what is a reasonable estimate of the percent of DNA double strand breaks that are effectively repaired? – 99% – 95% – 75% – 50% #1 If 60 -80 DSB/2 Gy kills half the cells, then >99% must be repaired WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
12. If the fraction of cells surviving 2 Gy is 0. 4, what is the surviving fraction after 50 Gy given in 2 Gy fractions? – 10 -8 – 10 -9 – 10 -10 – 10 -11 #3 - 0. 425 = 1. 12 x 10 -10 WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
13. Sublethal DNA damage is most likely to accumulate – At high total doses given at high dose rate – At high total doses under hypoxia – After high LET radiation – After low fractionated doses of radiation #1 Intertrack interactions between ionization events are more likely at high dose and high dose rate WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
15. Sublethal DNA damage is most likely to be repaired – After high total doses given at high dose rate – If cells are held in a non-proliferative state – After high LET radiation – Between low fractionated doses of radiation #4 The lower the number of ionization events in time and space, the more likely they are to be repaired WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
15. Which of the following is true about chromatin structure in cells – Compacted chromatin is more radiosensitive than non-compacted chromation – During mitosis cells decompact their chromatin and become radiosensitive – Compact chromatin in S phase mediates radioresistancy – Compaction facilitates gene transcription #1 –compaction occurs in mitosis, which is why chromosomes can be seen under the microscope during this phase WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
16. Which of the following is correct about alpha-type cell killing following radiation exposure – It represents single lethal hits – It is due to accumulated damage – It requires intertrack interactions – It is not oxygen dependent #1 – Intratrack lesions dominate and accumulated damage plays only a small role WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
17. Which of the following radiobiological phenomena occurring between dose fractions has little or no effect on normal tissue radiation responses? – Repair – Redistribution of cells in the cell cycle – Repopulation – Reoxygenation #4 – Normal tissues are generally considered to be well oxygenated WMc. B 2008 http: //dmco. ucla. edu/Mc. Bride_Lab
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