biological effects of ionizing radiation at molecular and cellular levels l.
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BIOLOGICAL EFFECTS OF IONIZING RADIATION AT MOLECULAR AND CELLULAR LEVELS. Module VIII-a. Historical b ackground. Discovery of X r ays (1895). Wilhelm Conrad Roentgen. Discovery of u ranium ’s n atural r adioactivity. Antoine Henri Becquerel. Marie Curie.

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historical b ackground
Historical background

Module Medical VIII.

discovery of x r ays 1895
Discovery of X rays (1895)

Wilhelm Conrad Roentgen

Module Medical VIII.

discovery of u ranium s n atural r adioactivity
Discovery of uranium’snatural radioactivity

Antoine Henri Becquerel

Marie Curie

Module Medical VIII.

first r eports on h armful e ffects of r adiation
First reports on harmful effects of radiation
  • First radiation-induced skin cancer reported
  • in 1902
  • First radiation-induced leukemia described
  • in 1911
  • 1920s:bone cancer among radium dial painters
  • 1930s:liver cancer and leukemia due to Throtrast administration
  • 1940s: excess leukemiaamong first radiologists

Module Medical VIII.

effects of r adiation on c ell s at a tomic l evel
Effects of radiation on cells at atomic level

Ionization

Excitation

Module Medical VIII.

direct a ction
Direct action

Ionizing radiation + RH R- + H+

Bond breaks

OH

I

R – C = NH

imidol (enol)

O

II

R – C = NH2

amide (ketol)

Tautomeric Shifts

Module Medical VIII.

indirect a ction
Indirect action

OH-

H

O

H+

Xray

 ray

e-

H

Ho

P+

OHo

Module Medical VIII.

radiolysis of h 2 o m olecule
Radiolysis of H2O molecule

Shared electron

Shared electron

H-O-H  H+ + OH- (ionization)

H-O-H  H0+OH0 (free radicals)

Module Medical VIII.

reactions with f ree r adicals
Reactions with free radicals

H0 + OH0 HOH (recombination)

H0 + H0  H2 (dimer)

OH0 +OH0  H2O2 (hydrogen peroxide)

OH0+RH R0+HOH (radical transfer)

Module Medical VIII.

effects of o xygen on f ree r adical f ormation
Effects of oxygen on free radical formation

Oxygencan modify the reaction by enabling creation of other free radical species with greater stability and longer lifetimes

H0+O2  HO20 (hydroperoxy free radical)

R0+O2 RO20 (organic peroxy free radical)

Module Medical VIII.

lifetimes of f ree r adicals
Lifetimes of free radicals

RO2o

HO2o

Ho

OHo

3nm

OHo

Ho

Because short life of simple free radicals (10-10sec), only those formed in water column of 2-3 nm around DNA are able to participate in indirect effect

Module Medical VIII.

relation b etween let and a ction t ype
Relation between LET and action type

Direct action is predominant with high LET radiation, e.g. alpha particles and neutrons

Indirect action is predominant with low LET radiation,e.g. X and gamma rays

Module Medical VIII.

biochemical r eactions with ionizing radiation
Biochemical reactions with ionizing radiation

DNA is primary target for cell damage from ionizing radiation

Module Medical VIII.

types of radiation induced lesions in dna
Types of radiation induced lesions in DNA

Base damage

Single-strand breaks

Double strand breaks

Module Medical VIII.

mechanisms of dna r epair
Mechanisms of DNA repair

Module Medical VIII.

dna r estoration f ailure
DNA restoration failure

Incorrect repair of

DNA damage

Unrejoined DNA

double strand breaks

Cytotoxic effect

Mutations

Module Medical VIII.

chromosomes
Chromosomes

Module Medical VIII.

dna l esions and c hromosome a berrations
DNA lesions and chromosome aberrations

DNA SİNGLE

STRAND BREAK

DNA DOUBLE

STRAND BREAK

Module Medical VIII.

radiosensitivity of c ell in c ell c ycle
Radiosensitivity of cell in cell cycle

Relative

Survivability

G1 S G2 G1

M

Relative survivability of cells irradiated in different phases of the cell cycle. Synchronised cells in late G2 and in mitosis (M) showed greatest sensitivity to cell killing.

Module Medical VIII.

mitotic d eath
Mitotic death

NORMAL

IRRADIATED

Module Medical VIII.

bergoni and tribondeaus law 1906
Bergonié and Tribondeaus’ ‘law’ (1906)
  • The most ‘radiosensitive’ cells are
    • actively proliferating/dividing at the time of exposure
    • undifferentiated (non-specialized in structure and function)

Module Medical VIII.

interphase death
Interphase death

Why are peripheral blood lymphocytes highly sensitive to radiation, although well differentiated?

Module Medical VIII.

modification of radiation injury
Modification of radiation injury
  • Dose rate and fractionation
  • Radiation quality
  • Temperature
  • Chemical modification
    • Oxygen
    • Radiosensitizing agents
    • Radioprotective agents

Module Medical VIII.

dose r ate and f r actionation
Dose rate and fractionation

Time

Acute

dose

Acute exposure with high dose rate

Time

Prolonged exposure

with lower dose rate

Fractionated dose

Module Medical VIII.

radiation q uality
Radiation quality

Module Medical VIII.

survival curve for mammalian cells exposed to high a and low let b r adiation
Survival curve for mammalian cells exposed to high- (A) and low-LET (B)radiation

n

Dq

1-1/e

1-1/e

,037

D0

D0

B

A

Module Medical VIII.

temp e rature
Temperature
  • For cell kiling effects, tissues are more radiosensitive at higher temperatures
  • Chromosome aberrations increase at lower temperatures (suppression of repair process)

Module Medical VIII.

chemical modification o xygen
Chemical modification: oxygen
  • Dissolved oxygen in tissues increases stability and toxicity of free radicals
  • Oxygen enhancement ratio (OER) is determined by:

The OER has a maximum value of 3.0

Dose required to cause effect without oxygen

OER =

Dose required to cause effect with oxygen

Module Medical VIII.

radiosensitizing a gents
Radiosensitizing agents
  • Halogenated and substituted analoges of DNA bases:5-bromo-uracil and 6-thio-guanine
  • Electroaffinic compounds:

Nitroimidazoles(misonidazole, nitroimidazole, and nitrofuran)sensitization enhancement ratio (SER) of 1.2 to 1.4

Module Medical VIII.

radioprotective a gents
Radioprotective agents
  • Thiols(cysteine, 2-mercaptoethylamine, cystamine and thiourea). Thiols have dose reduction factor (DRF) ratio of 1.4 to 2.0

They are thought to protect cells by

    • scavenging free radicals
    • producing hypoxia
    • temporarily inhibiting DNA synthesis, allowing time for the repair enzymes to complete repair of sublethal damage
    • forming disulphide bonds in proteins,thereby strengthening them

Module Medical VIII.