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Radiation and Cell Cycle High Yield Summary Reviews in Radiation Oncology Radiation and Cancer Biology Gayle E. Woloschak, PhD Tuesday, June 18, 2019 11:00 a.m. – 1:00 p.m. Eastern Daylight Time June 25, 2019 Gayle E. Woloschak PhD Professor of Radiation Oncology, Radiology, and Cell & Molecular Biology Associate Dean for Graduate Student and Postdoctoral Affairs Northwestern University Feinberg School of Medicine June 25, 2019 Definitions • Bq-2.7x10-11 Ci—equal to one disintegration per sec • Ci—3.7x1010 disintegrations per sec • Gy—absorbed radiation dose, the quantity which deposits 1 Joule of energy per kg—1Gy=100rad • Sievert—dose equivalence—multiply absorbed dose in Gy by the Quality Factor (Q)— 1Sv=100rem • LET—measure of the rate of energy transfer from an ionizing radiation to the target material—keV of energy lost/micron track length Unit Conversion Factors: SI and Conventional Units • 1 Bq = 2.7 × 10–11 Ci = 27 pCi • 1 Ci = 3.7 × 1010 Bq = 37 GBq • 1 Sv = 100 rem • 1 rem = 0.01 Sv • 1 Gy = 100 rad • 1 rad = 0.01 Gy • 1 Sv Bq–1 = 3.7 × 106 rem μCi–1 • 1 rem μCi–1 = 2.7 × 10–7 Sv Bq–1 • 1 Gy Bq–1 = 3,7 × 106 rad μCi–1 • 1 rad μCi–1 = 2,7 × 10–7 Gy Bq–1 Biomolecular Action of Ionizing Radiation; Editor:Shirley Lehnert, 2007 Units Used in Radiation Protection • Equivalent dose—average dose x radiation weighting factor—Sv • Effective dose—sum of equivalent doses to organs and tissues exposed, each multiplied by the appropriate tissue weighting factor—Sv • Committed equivalent dose—equivalent dose integrated over 50 years (relevant to incroporated radionuclides)—Sv • Committed effective dose—effective dose integrated over 50 years (relevant to incorporated radionuclides)--Sv • Collective effective dose—product of the average effective dose and the number of individuals exposed—person-Sv • Collective effective dose committed—integration of the collective dose over 50y (relevant to incorporated radionuclides)—person-Sv uR/hr US Geological Survey, 1993 2-6 Annual Report 2008 NCRP, July 2006 Indirect Action For Low LET radiation, 67% damage is indirect action For High LET radiation, most (all?) damage is direct action Critical distance of indirect action is within 2nm radius from DNA. Hall and Giaccia, 2018 Stochastic vs Deterministic • Heritable effects and cancer • Non-cancer somatic effects • Single cell effect • Organ effect • 2 severity states • Different severity states (present/absent) (graded) • No threshold dose • Threshold • Low dose or high dose • Intermediate or high dose • Dose-response: Linear • Dose-response: threshold Quadratic sigmoid • Relevant to radiation • Relevant to normal tissue early protection, diagnostic radiology and late effects in radiotherapy • Example: cancer • Example: cataracts, normal tissue damage Summary of Aberrations • Chromosomal Aberrations • cell is irradiated in G1 (before duplication of chromosomes) • break occurs in single strand of chromatin replicated in S, seen in M phase • translocations dicentrics and rings – both lethal • dicentrics used for dose estimates, 25cGy is sensitivity • Chromatid Aberrations • cell is irradiated after S (after duplication) • radiation causes break in both chromatids • observe it in M phase • anaphase bridge--lethal • Correlation of chromosome aberrations and disease: • physical abnormalities • mental retardation • cancer • lethality Issues of Radiation Genetics • No unique mutations • Most mutations are not detected; those that are detected are most often dominant (single gene) • Mutations are rare events • Within the same species, genes vary both in their spontaneous mutation rate and in their vulnerability to radiation. • Number of mutations is proportional to dose. Summary of Radiation Genetics • Doubling dose for mutations in male mice (low LET): acute 20-30cGy; protracted 90-100cGy • Estimated mutagenic hazard in humans:2-3x10-7 mutations/gene/cGy • Period at risk for expression of a radiation mutation: 10 genetic generations of 30y each=300 y • Genetic maximum permissible dose limits: occupational 50mSv/y; general population 1mSv per year Radiation and Cell Cycle 1.Cells are most sensitive to radiation at or close to M 2.Cells are most resistant to radiation in late S 3.For prolonged G1 → a resistant period is evident early G1 followed be a sensitive period in late G1 4.Cells are usually sensitive to radiation in G2 (almost as sensitive as in M) There are exceptions to these rules in some cell lines. Frequency of chromosomal aberrations is a linear quadratic function of dose. Low Dose: both aberrations caused by the same e- High Dose: caused by different electrons FIGURE 2.20 The frequency of chromosomal aberrations (dicentrics and rings) is a Iinearquadratic function of dose because the aberrations are the consequence of the interaction of two separate breaks. At low doses, both breaks may be caused by the same electron; the probability of an exchange aberration is proportional to dose (D). At higher doses, the two breaks are more likely to be caused by separate electrons. The Q probability of an exchange aberration is proportional to the square of the dose (D2). Hall and Giaccia 2018 Contribution to Killing • M phase/G2—alpha-large beta-nil • G1 phase—alpha-large beta-small • Early S—alpha and beta are medium • Late S—alpha-small beta-large Cell-survival curves Survival curve describes the relationship between the proportion of cell survival and radiation dose linear-quadratic model: 2 S = e−D−D S = fraction of surviving D = dose , = constants D = D2 → D = / (dose at which the linear and quadratic contributions to cell killing are equal) densely ionizing radiation: / sparsely ionizing radiation: / Hall and Giaccia 2018 Single hit. multitarget Single target 2-component L-Q model Biomolecular Action of Ionizing Radiation; Editor:Shirley Lehnert, 2007 Cells are more sensitive to Radiation in the presence of Oxygen than in its absence High dose region of survival curve Low dose region of survival curve Hall and Giaccia 2018 Oxygen Concentration and Sensitivity to Radiation Approx. partial pressure of O2 Cells reach full at which gamma-irradiated cells radiosensitization at exhibit radiosensitivity halfway 20-40mmHg, near the between their fully aerobie O2 concentration in and fully hypoxic response venous blood. is near 3mmHg 1mmHg=1Torr Radiosensitivity increases until about 30mmHg is achieved, and then it remains the Same for all oxygen concentrations. The most dramatic increase is seen at low O2 Concentrations near 0.5% (3mmHg). From Hall and Giaccia, 2018 Sizes of Tumors and presence of necrotic core regions All tumors with a radius of 200um or greater have necrotic centers. Tumors with a radius of less than 160um usually do not have necrotic centers. From Hall and Giaccia, 2018 Diffusion of Oxygen through Tumor Tissue Regions of hypoxia also have low pH, glucose, GFs Oxygen can generally diffuse 150um at the arterial end of the capillary and less at the venous end. From Hall and Giaccia, 2018 HPH or PHD From Hall and Giaccia, 2018 Relationship of OER/RBE with LET The point at which the RBE increases is where the OER drops most dramatically. Hall and Giaccia 2018 Biomolecular Action of Ionizing Radiation; Editor:Shirley Lehnert, 2007 Oxygen Effect During Cell Cycle OER – • Oxygen enhancement ratio • Varies throughout the cell cycle G2 phase OER = 2.3 - 2.4 S phase OER = 2.8 – 2.9 • For any given phase of the cell cycle, OER was the same for all doses • For asynchronous cells, OER does vary with doses: OER is smaller at higher levels of survival OER is higher at lower levels of survival • Little therapeutic significance High vs. Low LET Effect High LET Low LET DNA damage Mostly direct 2/3 is indirect Ionizations Dense (blobs) Sparse (spurs) survival curve Steeper slope; reduce Smaller slope, larger shoulder shoulder Alpha/beta Alpha is high, beta is Alpha is less important constant Cell cycle effects +/- ++++ SLDR none ++ PLDR none ++ OER O2 has little or no effect on O2 enhances low LET high LET effects Radioprotectors Little effect (?) effective Categories of Cellular Radiation Damage 1. Lethal—irreversible, irreparable, leads to cell death 2. Sublethal (SLD)—repaired in hours; if a second dose is given, can interact with more damage to create lethal damage; represents shoulder on cell survival curve Sublethal Damage Repair—increase survival when a dose is fractionated over time 3. Potentially Lethal Damage (PLD)—can be modified by the post-irradiation environment Dose-Rate Effect for HeLa Cells -Decrease dose-rate, survival curve is More shallow, shoulder disappears, Survival is an exponential function of dose Shallow shoulder to survival curve -For HeLa Cells: dose-rate effect is most for low dose rate Evident at .01-1 Gy/min. Above or below That there is little effect. -Dose rate effect varies from one cell type To another similar Hall and Giaccia 2018 Amifostine •WR2721 → WR1065 (in vivo) •Active transport of drug to normal tissues vs. tumor (?) Give drug minutes before radiation, ↓ normal tissue toxicity •Alkaline phosphatase (liver) converts inactive prodrug amifostine into the active drug in the body. •Tissue variability: good protection: hematopoietic system, gut lining, salivary glands no protection: CNS (doesn’t cross blood-brain barrier) •Hydrophilic nature gives ↑ uptake in normal tissues •Dose-limiting toxicity: hypotension •Also call ethyol •Is FDA approved for use as a radioprotector Law of Bergonie and Tribondeau The radiosensitivity of a cell varies: • DIRECTLY with its rate of mitosis. • DIRECTLY with its mitotic future. • INDIRECTLY with its degree of morphologic and functional differentiation. • EXCEPTION: Lymphocytes which are very radiosensitive but are fixed post- mitotic cells. Cassarett’s formulation: The more differentiated, the more radioresistant the cell type. Cells with increased capability for division are more radiosensitive than non-dividing cells. Exception: Lymphocytes (D0 of 80cGy) Hall and Giaccia 2010 10-49h Doses given in Gy, but they represent Gy of gamma-rays or x-rays Narrow window of dose over which BM transplants are useful following TBI LD50 increases with antibiotics and nursing.
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