Oncology 2
HC 1-2
2.1
DNA is a double-helical model made up of two chains of nucleotides. A nucleotide, in turn, is
composed of a sugar, phosphate and a nitrogenous base. There are two groups of bases, the
pyrimidines (cytosine and thymine) and the purines (adenine and guanine). This portion of
our genome that encodes a protein, which are the coding genes, is transcribed into RNA and
then translated into a protein. There are two distinct parts of a gene: the 5’ end of a gene
contains nucleotide sequences that make up the promoter region – this regulates the
expression of the gene. It associates with RNA polymerase and contains the TATA box which
is needed to initiate transcription. There are also enhancer elements that can increase the
expression. Downstream of the promoter region, towards the 3’ end, there is the actual
coding sequence. It contains introns and exons; the primary RNA transcript contains both
but is spliced to only contain the exons. Because only the exons are translated into the
protein. There are some slight posttranslational modifications that constitute into the final
protein.
2.2
Most carcinogens are mutagens that may modify the DNA or cause chromosomal damage.
They induce mutations which range from transitions (purinepurine), transversions
(purinepyrimidine), deletions, insertions, etc. Base substitutions also randomly occur due
to a faulty DNA polymerase mechanism. Oxidation and alterations of chromatin structure
can cause misreading of the DNA template and hence mutations. Insertions and deletions
can cause frameshift mutations (truncated proteins). Translocations often lead to
expressional changes and gene amplification. In essence, a mutation can occur anywhere in
the genome, but depending on the location, the consequences vary. If in the wobble base,
the third nucleotide of an amino acid, the degeneracy does not lead to major consequences.
Others, causing missense or nonsense mutations, do have different or shortened proteins,
as a consequence. Driver mutations are those located in cancer genes and those in the
promoter region alter the expression.
All in all, it must still be realized the carcinogenesis is a multi-step process that takes time
and has several requirements. There is an initiation event (DNA damage), promotion event
(cell proliferation) and progression (invasion, migration, metastases).
2.3
Radiation is energy, of which there are two forms: as a wave or as a stream of particles. The
first is electromagnetic radiation like gamma radiation and X-rays. They either or of high- or
low energy, meaning short or long wavelengths. The second consists of particles like alpha,
beta, protons or neutrons. Both can cause DNA damage and carcinogens. Radiation can be
quantified:
- Gy = energy released by a certain radiation source and absorbed by the body tissues,
so joule/kg tissue.
- Sv = the amount of biological damage caused by a particular source of radiation,
used in radiation risk estimates. It can be calculated with the absorbed dose in Gy
, multiplied by the radiation quality factor, which differs per entity. For a photon, it is
1 and for neutrons it is 20.
The linear energy transfer (LET) is used to describe the rate at which energy is released. So,
the average energy per unit distance deposited by a charged particle. Low-LET radiation has
a diffuse ionization track, so one Gy gives rise to 1000 tracks; examples are X-rays and
gamma rays. High-LET radiation emits more energy than low-LET over the same distance, as
it has a dense ionization track that confers more irreparable DNA damage. In general, the
higher the LET, the higher the cell kill per Gy. An alpha particle, low-LET, is stopped by a
piece of paper already. Beta particles are stopped by clothing and gamma rays are only
stopped by several feet of concrete.
If the radiation injury is excessive or irreparable, this leads to apoptosis, senescence,
necrosis or autophagy – cell death. However, if this programming is erroneous, there are
mutations and chromosomal aberrations that turn into a malignant transformation. If
however the injury and damage can be overseen, activation of the survival response is
kickstarted and the DNA is repaired – the cell survives. Important to note is the time frame;
a reaction or ionization occurs in 10 -12th of a second, whereas actual biological changes
including carcinogenesis may take up to 1000 days. So, one physical change can lead to a
cancer, three years later. It is thus best to control radiation exposure and prevent
carcinogenesis, rather than cure it.
There are two major types of biologically damaging radiation:
- Ionizing radiation is radiation that ionizes an atom, resulting in the emission of an
electron which is then free to damage the DNA directly, or can damage it indirectly
by fueling the formation of ROS, which then damage the DNA. One such formed ROS
is the hydroxide radical. The hydroxide radical interacts with the DNA, fixating
oxygen to a rest-group and thereby forming ROOH. This unfortunately fixates the
damage. The most frequent cancer from ionizing radiation is leukemia, with age as
the most important risk factor and children running the highest risk. Moreover, the
risk of solid cancer increases with dose in a linear fashion. Ionizing radiation induces
single- and double strand breaks, in the G2/M-phase.
Nowadays, proton radiation is used more extensively in cancer treatment, as its
ionizing capability is less thorough so the chance of affecting surrounding healhty
tissue is lower – so it has a lower carcinogenic risk.
Radiation induced cancers are not a likely event. Information is obtained from
epidemiological studies and past events, which has shown that (despite having no
quantitative dosimetric information and long-term follow-up) secondary tumors due
to radiation are uncommon. The latency of a tumor is the time period between
exposure to radiation and manifestation of a tumor. The risk period is the time
during which the risk to die from cancer is increased. Both have shown that tumors
like leukemia are more likely to develop from radiation, than solid tumors.
- Ultraviolet radiation (specifically UV-B) from the sun is also carcinogenic, especially
of the skin. The double bonds absorb the UV and forms pyrimidine dimers, thereby
causing a bend in the DNA helix. Polymerase cannot read the DNA template and
inserts adenine, a point-mutation of CG into AT, sensitive in the S-phase.
Chemical carcinogens work by being electrophilic and thus reacting with nucleophilic sites in
the purine and pyrimidine rings of nucleic acids. Other carcinogens become active by the
body’s metabolism. There are two major types of chemical carcinogens:
HC 1-2
2.1
DNA is a double-helical model made up of two chains of nucleotides. A nucleotide, in turn, is
composed of a sugar, phosphate and a nitrogenous base. There are two groups of bases, the
pyrimidines (cytosine and thymine) and the purines (adenine and guanine). This portion of
our genome that encodes a protein, which are the coding genes, is transcribed into RNA and
then translated into a protein. There are two distinct parts of a gene: the 5’ end of a gene
contains nucleotide sequences that make up the promoter region – this regulates the
expression of the gene. It associates with RNA polymerase and contains the TATA box which
is needed to initiate transcription. There are also enhancer elements that can increase the
expression. Downstream of the promoter region, towards the 3’ end, there is the actual
coding sequence. It contains introns and exons; the primary RNA transcript contains both
but is spliced to only contain the exons. Because only the exons are translated into the
protein. There are some slight posttranslational modifications that constitute into the final
protein.
2.2
Most carcinogens are mutagens that may modify the DNA or cause chromosomal damage.
They induce mutations which range from transitions (purinepurine), transversions
(purinepyrimidine), deletions, insertions, etc. Base substitutions also randomly occur due
to a faulty DNA polymerase mechanism. Oxidation and alterations of chromatin structure
can cause misreading of the DNA template and hence mutations. Insertions and deletions
can cause frameshift mutations (truncated proteins). Translocations often lead to
expressional changes and gene amplification. In essence, a mutation can occur anywhere in
the genome, but depending on the location, the consequences vary. If in the wobble base,
the third nucleotide of an amino acid, the degeneracy does not lead to major consequences.
Others, causing missense or nonsense mutations, do have different or shortened proteins,
as a consequence. Driver mutations are those located in cancer genes and those in the
promoter region alter the expression.
All in all, it must still be realized the carcinogenesis is a multi-step process that takes time
and has several requirements. There is an initiation event (DNA damage), promotion event
(cell proliferation) and progression (invasion, migration, metastases).
2.3
Radiation is energy, of which there are two forms: as a wave or as a stream of particles. The
first is electromagnetic radiation like gamma radiation and X-rays. They either or of high- or
low energy, meaning short or long wavelengths. The second consists of particles like alpha,
beta, protons or neutrons. Both can cause DNA damage and carcinogens. Radiation can be
quantified:
- Gy = energy released by a certain radiation source and absorbed by the body tissues,
so joule/kg tissue.
- Sv = the amount of biological damage caused by a particular source of radiation,
used in radiation risk estimates. It can be calculated with the absorbed dose in Gy
, multiplied by the radiation quality factor, which differs per entity. For a photon, it is
1 and for neutrons it is 20.
The linear energy transfer (LET) is used to describe the rate at which energy is released. So,
the average energy per unit distance deposited by a charged particle. Low-LET radiation has
a diffuse ionization track, so one Gy gives rise to 1000 tracks; examples are X-rays and
gamma rays. High-LET radiation emits more energy than low-LET over the same distance, as
it has a dense ionization track that confers more irreparable DNA damage. In general, the
higher the LET, the higher the cell kill per Gy. An alpha particle, low-LET, is stopped by a
piece of paper already. Beta particles are stopped by clothing and gamma rays are only
stopped by several feet of concrete.
If the radiation injury is excessive or irreparable, this leads to apoptosis, senescence,
necrosis or autophagy – cell death. However, if this programming is erroneous, there are
mutations and chromosomal aberrations that turn into a malignant transformation. If
however the injury and damage can be overseen, activation of the survival response is
kickstarted and the DNA is repaired – the cell survives. Important to note is the time frame;
a reaction or ionization occurs in 10 -12th of a second, whereas actual biological changes
including carcinogenesis may take up to 1000 days. So, one physical change can lead to a
cancer, three years later. It is thus best to control radiation exposure and prevent
carcinogenesis, rather than cure it.
There are two major types of biologically damaging radiation:
- Ionizing radiation is radiation that ionizes an atom, resulting in the emission of an
electron which is then free to damage the DNA directly, or can damage it indirectly
by fueling the formation of ROS, which then damage the DNA. One such formed ROS
is the hydroxide radical. The hydroxide radical interacts with the DNA, fixating
oxygen to a rest-group and thereby forming ROOH. This unfortunately fixates the
damage. The most frequent cancer from ionizing radiation is leukemia, with age as
the most important risk factor and children running the highest risk. Moreover, the
risk of solid cancer increases with dose in a linear fashion. Ionizing radiation induces
single- and double strand breaks, in the G2/M-phase.
Nowadays, proton radiation is used more extensively in cancer treatment, as its
ionizing capability is less thorough so the chance of affecting surrounding healhty
tissue is lower – so it has a lower carcinogenic risk.
Radiation induced cancers are not a likely event. Information is obtained from
epidemiological studies and past events, which has shown that (despite having no
quantitative dosimetric information and long-term follow-up) secondary tumors due
to radiation are uncommon. The latency of a tumor is the time period between
exposure to radiation and manifestation of a tumor. The risk period is the time
during which the risk to die from cancer is increased. Both have shown that tumors
like leukemia are more likely to develop from radiation, than solid tumors.
- Ultraviolet radiation (specifically UV-B) from the sun is also carcinogenic, especially
of the skin. The double bonds absorb the UV and forms pyrimidine dimers, thereby
causing a bend in the DNA helix. Polymerase cannot read the DNA template and
inserts adenine, a point-mutation of CG into AT, sensitive in the S-phase.
Chemical carcinogens work by being electrophilic and thus reacting with nucleophilic sites in
the purine and pyrimidine rings of nucleic acids. Other carcinogens become active by the
body’s metabolism. There are two major types of chemical carcinogens:
