4 r's of radiobiology radiotherapy 5 r's
TRANSCRIPT
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4R's of Radiobiology
-Dr Abish AdhikariMD Resident,
NAMS/BPKMCH
2012.11.26
H. R. Withers, The four r's of radiotherapy, Adv. Radiat. Biol. 5 (1975) 241–247.
abishadh @ gmail . com
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Definition
The most important biological factors influencing the responses of tumours and normal tissues to fractionated treatment are often called the “four Rs”:
● Repair (few hours)
● Reassortment (few hours)
● Repopulation (5 – 7 weeks)
● Reoxygenation (hours to few days)
Radiation Biology: A Handbook for Teachers and Students
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Introduction
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1. Repair of Radiation Induced DNA Damage
● Radiation generates Highly reactive oxygen species (hROS), from water molecules. They are short-lived and rapidly interact with biomolecules in cells.
● Those that are generated within 2 nm of the DNA are more important in causing DNA damage.
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Types of Damage
● Lethal—irreversible, irreparable, leads to cell death
● 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.
● Potentially Lethal Damage (PLD)—can be modified by the post-irradiation environment.
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There is a point at which an increase in the number of fractions will no longer increase survival—plateau in the response
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Repair
● Base Excision Repair● Nucleotide Excision Repair● Homologous Recombination● Non Homologous End Joining
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● Base Excision Repair
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Homologous Recombination
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DNA-dependent protein kinase Cernunnos-XLF/XRCC4/DNA ligase IV
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2. Redistribution / Reassortment
● Cells exhibit differential radiation sensitivity while in the different phases of the cell cycle.
● Cells in mitosis are most sensitive to DNA damaging agents and cells in late S-phase being most resistant.
● With multiple doses, cells progress through to a new phase of the cell cycle (sensitive)
● “Sensitization due to re-assortment” causes therapeutic gain.
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Mammalian cellsmitotic shake-offgive 6.6Gy at various timesdo survival
Resistance in S : Conformation of DNA. Sensitivity at G2: little time to repair.
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Experiments of Warren Sinclair: Survival curves during cell cycle
----- calculated for -hypoxic conditions of-Mitotic cells
M>G2>G1>early S>late S for sensitivity
Shoulder vs no shoulder
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3. Repopulation
● Damage and cell death occur during the course of the treatment may induce an increased rate of cell proliferation.
● Most important in early-responding normal tissues (e.g., skin, GIT)
● True for tumours as well. Accelerated repopulation can occur in the later part of a course of fractionated therapy. (HNSCC: 3 - 4 wks)
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Repopulation
● Influences local tumor control in HNSCC or cervical cancer.
● Local control is reduced by ~0.5% for each day that overall treatment time is prolonged.
● Rationale for accelerating fractionated radiation therapy.
● Overall treatment time would be expected to be less important for slower-growing tumors such as prostate or breast cancer.
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Accelerated Repopulation
● Clonogenic cells which survive radiation treatment may repopulate the tumor quickly.
Hermens & Barendsen (1969)
● Following a single radiation dose of 15 – 35 Gy there was cleare evidence of acclerated repopulation. Speed increased with bigger doses.
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4. Reoxygenation
● Sensitivity to radiation increases with oxygen.
● Tumors under 1 mm in size are fully oxic, but tumors over this size develop regions of hypoxia.
●
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Reoxygenation Mechanisms
● Reopening of temporarily occluded blood vessels (minutes).
● Reduced respiration of lethally damaged cells (minutes to hours).
● Resorption of dead cells leads to decreased distance from capillaries to tumor cells, improving their oxygen supply (days).
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OER
● Oxygen Enhancement Ratio● Ratio of radiation doses in hypoxic and
aerated conditions to get the same biological effect.
● X-Rays/γ-Rays : maximum ~ 2.5-3.0● OER is less than 2 in G1 phase.● ~1 for High LET radiations (alpha particles)
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Summary
● Reassortment, Repair, Reoxygenation are all benefits of fractionation.
● Repopulation is the negative associated with fractionation of radiation.
● Repair occurs in normal cells and tumor cells.● Reassortment occurs in cycling cells—mostly
tumor but some normal cells● Reoxygenation occurs only in tumor cells.● Repopulation occurs in the tumor cells.
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But
● Repair and Repopulation tend to make the tissue more resistant to second dose of radiation.
● Reassortment and Reoxygenation tend to make it more sensitive.
● The overall sensitivity of the tissue depends on:
The Fifth 'R' : Radiosensitivity
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Radiosensitivity
Seibert, 1996.
● In 1906 Bergonie and Tribondeau realized that cells were most sensitive to radiation when they are:
● Rapidly dividing
● Undifferentiated
● Have a long mitotic future
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The relative susceptibility of cells, tissues, organs, organisms, or other substances to the injurious
action of radiation.NRC
Radiosensitivity
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Thank you
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Cause of Radiosensitivity
● High metabolism of the tumor cells was early recognized as a prominent factor in radiosensitivity.
● Radiosensitivity can be judged by rate of growth.
● Increased or unstable vascularity also goes with rapid growth,
● So that three factors are generally combined to render rapidly growing tumors sensitive to radiation. Annual Meeting, at Chicago, Dec. 3–7, 1928.
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Radiosensitivity
● 17 tumor types were placed in 5 categories.● Categories A to E with decreasing sensitivity.● A: Lymphoma, Myeloma, Neuroblastoma.● B: Medulloblastoma, SCLC● C: Breast, Bladder, Cervix● D: Pancreas, Colo-Rectal, Squamous Lung.● E: Melanoma, Osteosarcoma, Glioblastoma, RCC
The radioresponsiveness of human tumours and the initial slope of the cell survival curve. Deacon J, Peckham MJ, Steel GG. Radiother Oncol. 1984 Dec;2(4):317-23.