Thiol compounds have long been known to protect living cells against the harmful effects of ionizing radiation. Maetallothionein is a naturally occurring low molecular weight polypeptide rich in cysteine residues and may be useful in protection against low-level radiation effects. Radiation damage to DNA and its nucleotide components and the radioprotective effect of metallothionein have been studied in model chemical systems and compared to its effect on cells. Metallothionein acts both as a free radical scavenger and a reductant, and its radioprotective effectiveness has been studied as a function of dose, drug concentration, and in the presence and absence of oxygen. It is more effective in protecting against sugar-phosphate damage under hypoxic conditions. The chemical modification is greater than that of cell killing as measured by the loss of colony-forming ability. Dose reduction factors greater than two are observed for DNA radioprotection, but the values in cells are much lower. These findings will be discussed in terms of the molecular mechanisms and their implications.

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This study was undertaken to investigate the mechanism of chemical radiosensitization by halogenated bases incorporated into DNA. Radiation-induced base and sugar-phosphate backbone damage to 5-bromouridine-5'-monophosphate (5-BrUMP) was monitored using a flow system connected in series with a recording spectrophotometer, a bromide (Br-)-specific ion analyzer and a Technicon auto-sampler. The system was used to assay loss of UV-absorbing 5,6 double-bond, release of Br- and inorganic phosphate (Pi) release using an automated colorimetric method, as a function of gamma-ray dose. Results obtained with radical scavengers indicate that, unlike non-halogenated nucleotides where the hydroxyl radical (.OH) is the principal damaging species, 5-BrUMP is damaged by the hydrated electron (e-aq), hydrogen atom (H.) and .OH, producing a high yield of base damage and Br- and Pi release in anoxia. Another novel feature of 5-BrUMP radiolysis is that oxygen, by converting e-aq and H. to the unreactive superoxide radical anion (O2-), has a protective effect on both base and phosphate ester damage. Under .OH-scavenging conditions, where the radiation yield of reductive debromination is 3.8, there is some Pi release, suggesting the possibility of intramolecular hydrogen atom transfer from the sugar ring to the 5-uracilyl radical and subsequent sugar-phosphate bond cleavage. This hypothesis is supported by the action of oxygen and thiols in modifying the e-aq-mediated sugar-phosphate damage.

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