Radiosensitisers are agents that increase the lethal effects of radiation when given during (or shortly prior) to its delivery. There are three clinically used radiosensitisers - hypoxic cell sensitisers, hypoxic cell cytotoxics and the halogenated pyrimidines - that increase the sensitivity of tumour cells with minimal effect on normal tissues.
Chemotherapy agents can be radiosensitisers but also exert significant effects on normal tissues - Hall classifies them elsewhere so I'll do the same.
Hypoxic Cell Sensitisers
Hypoxic cells are relatively radioresistant to commonly used radiation types (photons, electrons). There are several methods of targeting these cells:
- Use of high linear energy transfer radiations (such as protons or ions) that act directly on the DNA without the need for oxygen
- Increasing oxygenation of tumour cells through hyperbaric O2 or by transfusing anaemic patients prior to therapy.
- Using drugs that mimic the effect of oxygen to increase the sensitivity of hypoxic cells.
- Using cytotoxic agents that are only active in hypoxic cells
The hypoxic cell sensitisers fall into this last group. They ideally:
- Sensitise hypoxic tumour cells selectively
- Are chemically stable
- Can diffuse into hypoxic cells (often some distance from capillaries by virtue of the hypoxia)
- Are relatively inexpensive
- Are non-toxic
Nitroimidazoles are a class of compounds containing a pentagonal ring with two nitrogen atoms present. The nitroimidazole ring is broken down in hypoxic conditions, releasing the compound attached to the ring.
Nitroimidazoles were first used in treating anaerobic bacteria with metronidazole. When the nitroimidazole ring is broken down in anaerobic bacteria, it releases toxic products that can kill the cell. Because metronidazole is only activated in hypoxic bacteria, it prevents toxicity in other bacteria and in normal human cells.
Misonidazole was the first nitroimidazole developed to increase the radiosensitivity of hypoxic cells. When activated in hypoxic cells, it mimics the presence of oxygen by 'fixing' radiation damage to DNA. It has been shown in laboratory studies to increase the sensitivity of hypoxic cells.
Human trials were less successful, although there is evidence of good effect in patients with pharyngeal cancers and high haemoglobin levels.
Etanidazole is a less toxic compound that misonidazole and can be given in larger concentrations. Studies show no benefit from its clinical use.
Nimorazole is less active than misonidazole but much less toxic and can be given in large concentrations. It has been shown to increase local control and overall survival in a Danish study, but is not used elsewhere.
Hypoxic Cell Cytotoxics
These are a class of drugs that cause cell death in hypoxic cells (rather than increasing the effect of radiation in those cells). The best example of this class is tirapazamine. This is a prodrug that is activated selectively in the nuclei of hypoxic cells to a free radical which causes DNA damage and cell death.
Interestingly, the addition of tirapazamine to radiotherapy has shown a sensitising effect over and above the expected additive effect in in vitro and in vivo studies. The reasons for this are unclear. A TROG trial has shown no evidence of a benefit in head and neck cancer; although there was no selection of patients according to the hypoxic status of their tumour.
Halogenated pyrimidines are compounds structurally similar to the DNA precursor thymidine. A member of the halogen group of elements (iodine, chlorine, bromine) is substituted for a CH3 group. The compounds may be integrated into DNA. When sufficient quantities of the altered DNA molecules are present, the effectiveness of radiation is increased.
Unfortunately, despite the theorised difference in uptake between cancer cells and normal cells due to different cycle times, these compounds produced unacceptable normal tissue effects and are only used rarely. There is some evidence for use in glioma and sarcomas.
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