Nicotinamide and Other Benzamide Analogs as Agents for Overcoming Hypoxic Cell Radiation Resistance in Tumours

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Abstract
Oxygen deficient hypoxic cells, which are resistant to sparsely ionising radiation, have now been identified in most animal and some human solid tumours and will influence the response of those tumours to radiation treatment. This hypoxia can be either chronic, arising from an oxygen diffusion limitation, or acute, resulting from transient stoppages in microregional blood flow. Although clinical attempts to overcome hypoxia have met with some success, the results have been far from satisfactory, and efforts are still being made to find better methods. Extensive experimental studies, especially in the last decade, have shown that nicotinamide and structurally related analogs can effectively sensitise murine tumours to both single and fractionated radiation treatments and that they do so in preference to the effects seen in mouse normal tissues. The earliest studies suggested that this enhancement of radiation damage was the result of an inhibition of the repair mechanisms, as was well documented in vitro. However, recent studies in mouse tumours have shown that the primary mode of action actually involves a reduction in tumour hypoxia. More specifically, these drugs prevent transient cessations in blood flow, thus inhibiting the development of acute hypoxia. This novel discovery led to the suggestion that the potential role of these agents as radiosensitizers would be when combined with treatments that overcame chronic hypoxia. The first attempt to demonstrate this combined nicotinamide with hyperthermia and found that the enhancement of radiation damage by both agents together was greater than that seen with each agent alone. Similar results were later seen for nicotinamide combined with a perfluorochemical emulsion, carbogen breathing, and pentoxifylline, and in all these studies the effects in tumours were always greater than those seen in appropriate normal tissues. Of all the analogs, it is nicotinamide itself which has been the most extensively studied as a radiosensitizer in vivo and the one that shows the greatest effect in animal tumours. It is also an agent that has been well established clinically for the treatment of a variety of disorders, with daily doses of up to 6 g being considered reasonably safe and associated with a low incidence of side effects. This human dose is equivalent to 100–200 mg/kg in mice and such doses will maximally sensitize murine tumours to radiation. These findings have now resulted in phase I/II clinical trials of nicotinamide, in combination with carbogen breathing, as a potential radiosensitizing treatment.