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Introduction to Radiation Biology

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Introduction to Radiation Biology Outline Introduction to • Terminology Radiation Biology • Development of radiobiological damage • Cell cycle • Cell survival curves Survey of Clinical Radiation Oncology • Radiobiological damage: oxygenation, fractionation, and 4 R’s of radiobiology Lecture 2 • Cell and tissue radiosensitivity Radiation biology Types of ionizing radiations • Radiation biology is the study of the action of • Electromagnetic radiations ionizing radiation on living organisms – X-rays and Gamma-rays • The action is very complex, involving physics, chemistry, and biology • Particulate radiations – Different types of ionizing radiation – Electrons, protons, a-particles, heavy charged – Energy absorption at the atomic and molecular level particles leads to biological damage – Neutrons – Repair of damage in living organisms • All charged particles: directly ionizing radiation • Basic principles are used in radiation therapy with the objective to treat cancer with minimal damage • X and g-rays, as well as neutrons – indirectly to the normal tissues ionizing radiation Types of ionizing radiations Linear Energy Transfer • If radiation is absorbed in biologic material, ionizations and excitations occur in a pattern that depends on the • Linear energy transfer (LET) is the energy type of radiation involved transferred per unit length of the track • Depending on how far the primary ionization events • The special unit usually used for this quantity is are separated in space, radiation is characterized as sparsely ionizing (x-rays) or densely ionizing (a- keV/mm of unit density material particles) • It is an average quantity, typically track averaged • Heavier particles with larger charge produce higher ionization density • For a given particle type, the density of ionization LET dE/ dl decreases as the energy (and velocity) goes up 1 Linear Energy Transfer Relative Biological Effectiveness • Equal doses of different types of radiation do not produce equal biologic effects – 1 Gy of neutrons produces a greater biologic effect than 1 Gy of x-rays due to the difference in the pattern of energy deposition at the microscopic level • The relative biologic effectiveness (RBE) of some test radiation (r) compared with 250 kV x-rays is defined D RBE 250kV • The method of averaging makes little difference for x- Dr rays or for mono-energetic charged particles, but the track • D250kV and Dr are the doses of x-rays and the test average and energy average are different for neutrons radiation required for equal biological effect Relative Biological Effectiveness Development of radiobiological damage • Because the x-ray and neutron survival curves have different shapes the resultant RBE depends on the level of biologic damage chosen • The RBE for a fractionated regimen with neutrons is greater than for a single exposure (because the RBE is larger for smaller doses) Development of radiobiological Characteristic time scales damage • The physical event of absorption occurs over Incident radiation about 10-15 seconds • The biologic lifetime of the free radical is on Radiation absorption the order of 10-10 - 10-9 seconds (10-5 seconds in the presence of air) Excitation and ionization • The expression of cell death may take up to Free radical formation days to months • The expression of carcinogenesis may take Brakeage of chemical bonds years or generations Biological effects 2 Absorption of radiation Biological effect • Biological systems are very sensitive to radiation • The biological effect is expressed in cell • Absorption of 4 Gy in water produces the rise in killing, or cell transformation (carcinogenesis temperature ~10-3 oC (~67 cal in 70-kg person) and mutations) • Whole body dose of 4 Gy given to human is • The primary target of radiation is DNA lethal in 50% of cases (LD50) molecule, suffering breaks in chemical bonds • The potency of radiation is in its concentration • Depending on the extent of the damage, it can be repaired through several repair mechanisms and the damage done to the genetic material of in place in a living organism each cell The structure of DNA DNA as a target • DNA molecule has many deoxyribo-nucleotides (bases) • Single-strand breaks are of little linked in a chain-like arrangement biologic consequence because they • Bases are held by hydrogen bonds are repaired readily using the and are paired complimentary opposite strand as a template (adenine with thymine; cytosine • Double-strand breaks are believed with guanine) to be the most important lesions • Each half is a template for produced in chromosomes by reconstruction of the other half radiation; the interaction of two • During cell division each strand is self-replicated double-strand breaks may result in resulting in identical molecules cell killing, carcinogenesis, or mutation Direct and indirect actions • In direct action, a secondary Free radicals electron resulting from absorption • A free radical is an atom or molecule carrying an unpaired of an x-ray photon interacts with orbital electron in the outer shell. This state is associated the DNA to produce an effect with a high degree of chemical reactivity • In indirect action, the secondary • Since 80% of a cell is composed of water, as a result of the electron interacts with, for interaction with a photon or a charged particle, the water example, a water molecule to molecule may become ionized: produce a hydroxyl radical (OH-), which in turn produces the H2O H2O e damage to the DNA + -10 • H2O is an ion radical with a lifetime of ~10 s; it decays • The DNA helix has a diameter of to form highly reactive hydroxyl free radical OH ~ 2 nm; free radicals produced in H O H O H O OH a cylinder with a diameter ~ 4 nm 2 2 3 can affect the DNA • About 2/3 of the x-ray damage to DNA in mammalian -3 • Indirect action is dominant for cells is caused by the hydroxyl radical (lifetime of ~10 s) sparsely ionizing radiation (x-rays) 3 Chromosomes Chromosome aberrations • DNA molecules carry the • Damage to DNA may result in lethal damage genetic information or repair efforts modulated by specific • Chromosome is an enzymes may result in mutations which can be organized structure of DNA perpetuated in subsequent cellular divisions and DNA-bound proteins (serve to package the DNA • Mutations are mostly characterized by and control its functions) deletions (where part of the genetic message is lost) or translocations where a segment of a • Chromosomes are located chromosome is lost from its proper location mostly in cell nucleus (some and recombines with another chromosome amount is in mitochondria) Radiation-induced aberrations Radiation-induced aberrations A: Symmetric translocation: radiation produces breaks in two different pre-replication chromosomes. The broken pieces are exchanged between the two chromosomes, and the “sticky” ends rejoin. B: Deletion: radiation produces two breaks in the same arm of the same chromosome Lethal aberrations include dicentrics (A), rings (B), and Symmetric translocations and small anaphase bridges (C) deletions are nonlethal The cell cycle Mutations • M - mitosis, identifiable by • If occur in the germ cells (sperm and ova) they light microscopy and the can be passed on as genetic abnormalities in most constant time (~ 1 hr) offspring • S - DNA synthesis phase • If they occur in the somatic cells (the cells that • G1 - the first gap in activity, make up an organism) they can lead to the between mitosis and the S development of diseases including cancer - this is phase (most variable length) called carcinogenesis • G2 - the second gap in • There are genes called oncogenes that affect activity, between S phase cancer incidence and the next mitosis • If an inhibitory oncogene is lost due to a deletion • If the cells stop progressing the patient is at higher risk for cancer formation through the cycle (if they are arrested) they are in G0 4 Variation of radiosensitivity Molecular checkpoint genes with cell age in the mitotic cycle • Cell-cycle progression is • Cells are most sensitive at or close to M (mitosis) controlled by a family of molecular checkpoint genes • G2 phase is usually as sensitive as M phase • Their function is to ensure the • Resistance is usually greatest in the latter part correct order of cell-cycle events of S phase due to repairs that are more likely to • The genes involved in radiation occur after the DNA has replicated effects halt cells in G2, so that an inventory of chromosome • If G1 phase has an appreciable length, a resistant damage can be taken, and repair period is evident early in G1, followed by a initiated and completed, before the mitosis is attempted sensitive period toward the end of G1 • Cells that lack checkpoint genes are sensitive to radiation-induced cell killing, and carcinogenesis Mechanisms of cell death after Cell survival curves irradiation • The main target of radiation is cell’s DNA: single breaks are often reparable, double breaks lethal • Mitotic death – cells die attempting to divide, primarily due to asymmetric chromosome aberrations; most common mechanism • Apoptosis – programmed cell death; characterized by a predefined sequence of events resulting in cell separation in apoptotic bodies • A cell survival curve describes the relationship between the • Bystander effect – cells directly affected by radiation dose and the proportion of cells that survive radiation release cytotoxic molecules inducing • Usually presented in the form with dose plotted on a linear scale death in neighboring cells and surviving fraction on a log scale Cell survival curve
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