Abstract
Amifostine is added to chemoradiation regimens in the treatment of many cancers on the basis that, by reducing the metabolic rate, it protects normal cells from toxic effects of therapy. We tested this hypothesis by measuring the metabolic rate (by gas exchange) over 255 min in 6 healthy subjects, at two doses (500 mg and 1000 mg) of amifostine infused over 15 min at the start of the protocol. We also assessed the ventilatory response to six 1 min exposures to isocapnic hypoxia mid-protocol. There was no change in metabolic rate with amifostine as measured by oxygen uptake (p = 0.113). However in carbon dioxide output and respiratory quotient, we detected a small decline over time in control and drug protocols, consistent with a gradual change from carbohydrate to fat metabolism over the course of the relatively long study protocol. A novel result was that amifostine (1000 mg) increased the mean ± SD acute hypoxic ventilatory response from 12.4 ± 5.1 L/min to 20.3 ± 11.9 L/min (p = 0.045). In conclusion, any cellular protective effects of amifostine are unlikely due to metabolic effects. The stimulatory effect on hypoxic ventilatory responses may be due to increased levels of hypoxia inducible factor, either peripherally in the carotid body, or centrally in the brain.
Highlights
The drug amifostine (whose active metabolite is 2-((aminopropyl)amino)ethanethiol) is added to the chemoradiation regimens in the treatment of several cancers to protect normal healthy cells from the toxic effects of treatment and to reduce side effects such as xerostomia
There appears to be a decline over time in CO2, but less so in O2, such that Respiratory quotient (RQ) declines over time
We report the novel finding that high doses of amifostine markedly increased hypoxic ventilatory response
Summary
The drug amifostine (whose active metabolite is 2-((aminopropyl)amino)ethanethiol) is added to the chemoradiation regimens in the treatment of several cancers to protect normal healthy cells from the toxic effects of treatment and to reduce side effects such as xerostomia. If some of the cancer therapeutic literature is correct and amifostine reduces whole-body metabolic rate, we might expect it to reduce the magnitude of hypoxic ventilatory response. If the line of enquiry relating to HIF-1α and the carotid body is correct, we would expect the hypoxic ventilatory response to be increased It is important in the field of cancer therapeutics that the actions of drugs like amifostine is known. We wished to establish if (as suggested by the cancer therapeutic literature) metabolic rate is reduced by amifostine This would be an important and novel finding as we are not aware of any drug or therapy that reduces basal metabolic rate in humans. We wished to assess by direct measurement whether hypoxic ventilatory response is increased or reduced by amifostine
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