Effect of acute and chronic misonidazole administration on peripheral-nerve electrophysiology in mice

Abstract

Summary.-I.p. administration at several dose levels over periods of up to 12 weeks, or continuous i.v. infusion of high doses of misonidazole (MISO) for 15 h, produced no significant change in peripheral nerve conduction velocity (NCV) and did not prevent the normal increase in NCV as the animals matured from 12 to 24 weeks of age. Peripheral NCV (sural nerve) was reduced in both MISO-treated and control mice with hind-limb tumour implants, presumably owing to physical pressure due to tumour growth. In addition, neither the medial nerves nor the tibial nerve in the normal limbs of the tumour-implanted, drug-treated animals showed any change. Consequently our earlier and present studies do not confirm the recent reports of changes in NCV following either acute or chronic MISO administration to mice.

Evoked potentials in rats with misonidazole neurotoxicity

“…dose or after chronic administration of MISO (18 days). However, Conroy and co-workers (7,31) were unable to confirm these findings. Dose-dependent changes in the nerve action potential (NAP) of predominantly lower extremity sensory nerves has been reported in patients who had symptoms of polyneuropathy subsequent to MISO treatment (21).…”

In vivo response of KHT sarcomas to combination chemotherapy with radiosensitizers and BCNU

“…MISO, an electronaffinic nitroimidazole currently being clinically evaluated as a radiation sensitizer, is preferentially cytotoxic to hypoxic cells Brown, 1977;Conroy et al, 1979;Stratford & Adams, 1977;Sutherland et al, 1980) and is capable of enhancing the cytotoxicity of certain anti-tumour agents to cells in EMT-6 spheroids and Lewis lung tumours in vivo (Rose et al, 1980). In order to exploit this type of enhanced cytotoxicity therapeutically most efficiently, it is essential to evaluate various drug administration schedules.…”

“…Depression of the peripheral white-cell count, a major toxicity associated with BCNU treatment (Katz & Glick, 1979) was not significantly different between groups of animals treated with BCNU alone or in combination with MISO. Likewise, rotorod performance, a measure of peripheral neuropathy (Conroy et al, 1979) one of the major dose-limiting toxicities experienced in clinical trials with MISO (Dische et al, 1978) was not significantly different between groups of animals which received MISO alone or in conjunction with BCNU. Experiments designed to quantitate and compare tumour and normal tissue enhancement ratios are in progress.…”

A biochemical method for assessing the neurotoxic effects of misonidazole in the rat

“…As a first step, the effect of single and multiple doses of MISO on various functional, behavioural and pathological end-points in rodents have been examined. These systems, which include measurement of nerve conduction velocity (Conroy et al, 1979;Hirst et al, 1978, 1 979) electron and light microscopy of peripheral nerves and CNS (Adams et al, 1980;Conroy et al, 1979) and behavioural tests such as rota-rod and foot-splay droptest (Conroy et al, 1979) (Dewar & Moffett, 1979). The j ustification for measuring the activities of these two enzymes is that they have been shown to increase dramatically during the second phase of Wallerian degeneration (Hollinger & Rossiter, 1952;McCaman & Robins, 1959) (Cavanagh, 1973).…”