DNA as the target
Although there is only circumstantial evidence, DNA is believed to be the target for radiation and the reason cells die after radiation is administered. The evidence for this is:
- Radioactive tritiated thymidine causes cell death after integration into the DNA
- Thymidine analogous introduced into cell cultures lead to increased radiosensitivity dependent on the levels of the analog.
- Factors that alter cell radiosensitivity (oxygen, altered LET / RBE) lead to a quantitative similar increase in the level of chromosomal damage following radiation
- In plants, the larger the chromosome volume the more radiosensitive the plant.
DNA as the target of ionising radiation leads to several important therapeutic implications:
- Radiation damage that occurs in clusters that match the size of the DNA strand may be more effective in causing damage.
- Electrons generated through Compton interactions may cause further ionisations. These newly liberated electrons have a small range, typically about the size of a DNA strand, and may cause a cluster of lesions within the DNA strand. This lesion may be more difficult to repair and lead to cell death
- The ideal linear energy transfer is 100 keV/um, corresponding to an ionisations occuring within each side of the DNA strand. This may explain the variation in relative biological effectiveness seen with different qualities of radiation.
- Drugs that target DNA may have synergistic effects with radiation
- Cisplatin causes DNA crosslinks. These crosslinks may make it more difficult for cells to repair DNA damage. Cisplatin is known to cause increased sensitivity to radiation
- 5-fluorouracil and gemcitabine affect the production of DNA nucleotides. If they are present in the cell, its capacity to repair DNA damage is reduced. These drugs may greatly increase the radiation sensitivity of cells.
- People with genetic defects in the radiation damage response may exhibit increased levels of DNA mutation or cell death following radiation exposure
- People with ataxia-telangiectasia have a defect in the ATM gene, which is important in sensing double strand breaks induced by radiation. They have a greatly increased radiation sensitivity as well as predisposition to develop unusual cancers with high frequency.
- Points in the cell cycle where DNA is more susceptible to damage are also more sensitive to radiation
- In M phase, the chromosomes are lined up on the spindle and repair is difficult. DNA damage in this part of the cell cycle is frequently fatal to the cell and cells are most sensitive to ionising radiation in this phase.
- In S phase, when DNA is being replicated, cells seem more able to repair DNA damage. This may be due to the cellular environment in this phase, as well as the presence of duplicated DNA strands which may provide a useful template for repair.
- The cycling of cells has an impact on the radiation sensitivity of the cell type
- Cells which cycle rapidly require intact DNA to function, and a more commonly in mitosis. They tend to be more sensitive.
- Cells which are terminally differentiated are typically highly resistant to radiation as they do not enter the cell cycle.
Intrinsic radiosensitivity / radioresistance
There are two classical radioresistant populations:
- Cells that spend a long period of time in G0 phase (resting) will be able to repair a significant portion of DNA damage before they enter mitosis, increasing their survival. Late responding tissues and slow growing tumours fall into this category.
- Cells that are dividing very rapidly will have a long S phase relative to G1, G2, and M phases. This includes rapidly growing tumours and early responding tissues. This can be overcome by fractionating a dose and allowing cells to be redistributed into other parts of the cell cycle.
As described above, some cell types are more sensitive to radiation damage than others. Rapidly dividing cells (which may also be resistant due to a comparatively longer amount of time in S phase) are unable to repair DNA damage before entering into M phase, leading to mitotic catastrophe.
Lymphocytes are an unusual radiosensitive population. They are terminally differentiated cells and therefore never enter M phase, a feature typical of radioresistant cells. They respond to radiation by initiation of apoptosis, an uncommon method of death from radiation. It seems that lymphocytes have a unique sensitivity to ionising radiation which causes them to activate apoptosis pathways.