CELL DAMAGE Flashcards
what is differentiated and undifferentiated cells?
undifferentiated - stem cells, does not have any specific physiological function except to develop into mature cells. cell death = loss of proliferative capability
differentiated - aka mature cells, perform specific functions in the living body. cell death = loss of cellular function
organelles of cell
cell membrane, ER, golgi apparatus, mitochondria, lysosomes, ribosomes, centrosomes, nucleus, nucleolus
function of cell membrane
functions as a barricade to protect cellular contents from their environment and controls the passage of water and other materials into and out of the cell
function of ER
enables cell to communicate with the extracellular environment and transfers food from one part of the cell to another
function of golgi apparatus
unites large carbohydrate molecules and combines them with proteins to form large glycoproteins; transports enzymes and hormones through the cell membrane so that they can exit the cell
function of mitochondria
produce energy for cellular activity by breaking down nutrients through a process of oxidation
function of lysosomes
dispose of large particle such as bacteria and food, as well as smaller particles; contain hydrolytic enzymes that can break down and digest proteins, certain carbohydrates and the cell itself
function of ribosomes
manufacture the various proteins that cell require
function of centrosomes
believed to play some part in the formation of mitotic spindle during cell division
contains centrioles
function of DNA
contains the genetic material; controls cell division and multiplication and biochemical reactions that occur within the living cell
function of nucleolus
holds large amount of RNA
base pair of DNA and RNA
DNA: G-C C-G T-A A-T
RNA: G-C C-G A-U T-A
describe the protein synthesis process
in the nucleolus, mRNA is synthesised from DNA (transcription).
mRNA carries information from the DNA in the nucleus to a ribosome in the cytoplasm, where protein is synthesised.
mRNA (template strand), complementary tRNA transports specific amino acid to the ribosome to form long chain of AA ie protein (translation)
1 amino acid = 3 bases in the RNA
type of proteins and their functions
hemoglobin (transport protein) - makes RBC, picks up O2 from air in lungs and release to cells elsewhere in body
insulin (hormone) - tells cells when to remove sugar from blood after a meal
antibody (defence protein) - fights infections from bacteria and viruses
lactase (enzyme in digestive tract) - digests lactose in milk and dairy products
collagen (structural protein) - provides tough structural framework of skin, bones, tendons and cartilage
keratin (structural protein) - provides resistant outer layer of skin and tough structural material of hair and nails
myosin (structural protein + enzyme) - uses energy derived from food and works together with actin to cause muscle to contract
phases in the cell cycle
-> M -> G1 -> S -> G2 ->
how many check points and at where
3 - G1/S, G2/M, M
describe the G1 phase
During this phase, the cell is producing many proteins and enzymes, increasing the number of organelles present and growing in size. The variation in cell cycle time occurs in the G1 phase. This phase can vary from hours to hundreds of hours.
describe the S phase
DNA replication occurs, in which all chromosomes are duplicated by producing two sister chromatids. At the end of this phase, the DNA present within the cell has doubled
describe the G2 phase
This is the final stage before mitosis. Here again, the cell grows in size
briefly describe the mitosis phase
This is the point where the cell divides into two new cells identical to one another and to the original cell. The key event here is the separation of the two chromatids to opposing ends of the cell
describe the stages of mitosis
prophase - chromosomes become visible, centrioles migrate to the poles, nuclear membrane disappears, nucleolus disappears, spindle forms
metaphase - chromosomes line up on the equator, spindle attaches
anaphase - chromatids separate at the centromere and move to opposite poles
telophase - chromosome disappears, nuclear membrane reforms, nucleoli reappears, spindle disappears, centrioles duplicate
describe cytokinesis
division of the cytoplasm to form 2 new daughter cells, organelles are divided, daughter cells are genetically identical
briefly describe meiosis
Meiosis I splits the homologous chromosomes of the original diploid cell into two, creating daughter cells that are haploid.
Meiosis-II is like normal somatic cell division where at the end the two daughter cells of meiosis I become four daughter cells which are all haploid in nature.
examples of cells that undergo meiosis
sperm cells
ovum cells
which stage in meiosis does crossing over take place
prophase I
what’s the difference between SSB and DSB
SSB - only hydrogen bonds between base pair broken
DSB - sugar phosphate backbone bond is broken, therefore making repair more difficult
what are the chances of DSB than SSB?
0.04x at a dose of 2Gy
define lethal damage and sublethal damage
lethal damage - cellular damage which is irreversible, irreparable and leads to cell death
sublethal - cellular damage which can be repaired in hours unless additional sublethal damage is added that eventually leads to lethal damage
name some examples of chromosome structures that lethal aberrations may cause
ring formations, dicentrics fragments, anaphase bridges, acentric fragments
describe the non-lethal chromosomal abberations
deletion - loss of a portion of chromosome
duplication - presence of an extra chromosomal segment
inversion - fragmentation of a chromosome by 2 breaks, followed by a reconstitution of the segment between the breaks with inversion
insertion - rare event involving 3 chromosomal breaks and which a segment is removed from one chromosome and then inserted into a broken region of a non homologous chromosome
translocation - exchange of segment of chromosome
what are the cellular effects of radiation
interphase death -
Death of irradiated cells before the cells reach mitosis
Irradiating non-dividing or rarely dividing cells with very high doses, of about 100 Gy
Apoptosis is the most known example of interphase death
Apoptosis - Most common form of programmed cell death
Usually begins 6 to 24 hours after irradiation
Characterized by nuclear fragmentation, cell lysis and
phagocytosis by neighboring cells
Mitotic cell death -
In-vivo predominant mechanism of cell death, requires a dose of about 2 Gy
Occurs during or after mitosis where cells die attempting to divide because of damaged chromosomes
Caused by lethal chromosomal aberrations which include rings, dicentrics and anaphase bridges
Usually happens within 1 to 2 cell cycles (15 hours to 2 weeks in actively cycling cells)
Mitotic (division) delay -
Cells in interphase at the time of irradiation are delayed in the G2 phase where the cells attempt to repair previous radiation damage
Senescence -
a state of permanent loss of cell proliferative capacity
Metabolically active but non-dividing
Cells appear enlarged and flattened with increased granularity
Necrosis or cell injury -
Passive cell death as a result of exhaustion of oxygen, ATP
Cells swell visibly with breakdown of cell membrane.
Cells have an atypical nuclear shape with vacuolization, non-condensed chromatin
and disintegrated cellular organelles
Mitochondria swells and cell membrane ruptures - loss of intracellular contents
differentiate between direct and indirect action of radiation
direct:
radiation -> dna damage -> cell death
predominates for high LET radiations and at high radiation doses
radiation interact directly with DNA
indirect:
radiation -> free radicals -> DNA damage -> cell death
predominates for low LET radiations and at low radiation doses
radiation interacts with water, produce harmful by-products (such as free radicals and hydrogen peroxide), and the free radicals then diffuse and damage the DNA in the cell
free radicals may also combine with other nearby free radicals, forming new molecules such as H2O2 that are toxic to the cell
Since the majority of the cell consists of water, the probability (chance) of damage occurring through indirect action is greater than the probability (chance) of damage occurring through direct action
define LET
average energy deposited by radiation per unit path length in soft tissue
list some examples of low LET and high LET radiation
low LET:
gamma ray
x-ray
beta
high LET:
alpha particles
neutrons
define RBE
provides a relative comparison of the cell killing effectiveness of a test radiation to the dose of a 250kV x-ray
describe the factors affecting LET
- the more massive the particle, the larger the LET
- the slower the particle, the larger the LET
describe the overkill effect
refers to the reduced biological effect when LET values are above 100keV/um in tissue. beyond this, ionisation density within a single cell is greater than the two hits needed to inactive the cell. in other words, any dose beyond what is needed to produce the 2 hit per cell is wasted
how does presence of oxygen enhance radiological damage
free radical damage is made permanent and irreparable when oxygen is available. the oxygen effect is most significant for low-LET radiations with low RBE
law of bergonie and tribondeau
immature (stem) cell - more radiosensitive than mature cells
younger tissue and organs - more radiosensitive than older tissue and organs
the higher the metabolic cell activity, the more radiosensitive
the greater the proliferation and growth rate for tissues, the greater the radiosensitivity
what is surviving fraction
refers to the proportion or fraction of cells that still retain the ability to proliferate after irradiation, relative to an unirradiated control population
what is fractionation
conventional fractionation is the splitting of doses into multiple fractions
to spare normal tissue through a repair of sublethal damage between dose fractions and allow for repopulation of the cells
to allow for repopulation of the cells (more so for early responding normal tissue)
to increase tumour damage through reoxygenation and redistribution of tumour cells
what is protraction
dose that is delivered continuously but at a lower dose rate
what does low a/b ratio mean
late responding late side effects wider shoulder region more radioresistant require large dose to kill the cell
describe the 5Rs in radiobiology
repair - repair damage
repopulation - cells repopulate while receiving fractionated dose of radiation
redistribution - radiosensitization of cells due to the cells reassorting or progressing to a new phase within cell cycle
reoxygenation - of hypoxic cells occur during fractionated course of treatment, making them more radiosensitive to subsequent doses of radiation
radiosensitivity - mammalian cells have different radio-sensitivities
sort the radiosensitivity from highest to lowest in the cell cycle
M -> G2 -> G1 -> early S -> late S
define Dq, n and D0
Dq - quasithreshold dose
extrapolation of D0 to the 100% line
n - extrapolation number of target number
found by extrapolating D0 backwards to meet the vertical axis
thought to represent the number of targets in the cell
D0 - dose obtained from the slope of the linear portion of the curve, at which 37% of the cells survive
formula for RBE
(dose in Gy from 250kVp x-rays) / (dose in Gy of test radiation)
formula of OER
(dose necessary under anoxic conditions to produce a given effect) / (dose necessary under aerobic conditions to produce the same effect)
formula of plating efficiency
[(no. of colonies counted) / (number of cells seeded)] x100%
what is plating efficiency
percentage of seeded cells that survive to form colonies under controlled conditions
formula of surviving fraction in a controlled condition
(colonies counted post-irradiation) / (cells seeded x plating efficiency in %)
describe the relationship between radiation dose and radiation-induced death in human
radiation-induced death follows a nonlinear, threshold dose-response relationship
lower than approx 1Gy of whole body exposure, no one is expected to die
above approx 6Gy, all irradiated persons die unless vigorous medical support is available
above 10Gy, even vigorous medical support does not prevent death
without medical intervention, LD50/60 for humans is 3.5Gy.
LD50/60 = does that kills 50% of the population in 60 days
what are the 3 classic syndromes of ARS and explain them
bone marrow (aka hematopoietic syndrome) - full syndrome will usually occur with a dose between 0.7 and 10Gy. mild symptoms may occur as low as 0.3Gy.
gastrointestinal (GI) syndrome - full syndrome usually occue with a dose greater than approx 10Gy although some symptoms may occur as low as 6Gy.
cerebrovascular (CV)/CNS syndrome - full syndrome usually occur with dose greater than approx 50Gy although some symptoms may occur as low as 20Gy. Death occurs within 3 days and is likely due to collapse of the circulatory system and increased pressure in confining cranial vault as a result of increased fluid content
4 stages of ARS
prodromal - nausea, vomiting, diarrhea
latent - biological damage builds up without manifestation of any syndrome
manifest illness - radiation syndrome appear, as a result of the organ damage sustained, subject becomes ill
recovery or death
describe the GI syndrome
in the crypts, there are a number of highly dividing cells that are radiosensitive, but as they mature and move up to the villus and become highly differentiated, they become less responsive to radiation
if radiation dose is high enough, there is rapid cell loss in the crypts, the vili becomes short and blunted -> poor absorption of nutrients lead to high bacterial content -> cause diarrhea -> loss of fluid and electrolytes
what are the 2 biological effects of radiation exposure classified into
deterministic effect - those effect for which the severity of the effect in the exposed individual increases as the radiation dose increases, and which there is a threshold dose
stochastic effect - random in nature, and are those in which the probability of the effect occurring depends on the amount of radiation dose. this effect increases as the dose increases. there is no threshold dose
how does therapeutic radiation affect fetus growth
< 3 weeks - unlikely to produce malformations, more likely to cause abortion
4-11 weeks - most likely to produce severe malformations
11-16 weeks - severe mental retardation and growth retardation, and mild malformation
> 16 weeks - mild mental retardation and growth retardation
> 30 weeks - no gross abnormalities
