Metronidazole (flagyl) and misonidazole (Ro-07-0582): reduction by facultative anaerobes and cytotoxic action on hypoxic bacteria and mammalian cells in vivo.

The toxic actions of the "nitro" radiosensitizers, metronidazole and misonidazole on the bacteria E. coli B/r and Serratia marcescens have been investigated under anareobic and aerobic conditions. The rates of reduction of the drugs by suspensions of these bacteria as well as by suspensions microorganisms from the rat caecum have been measured. Both drugs were reduced or were toxic only under anaerobic conditions. In all instances misonidazole was reduced more rapidly than metronidazole but metronidazole was more toxic. It is suggested that these phenomena may model those occurring with hypoxic mammalian cells in vivo and that care should be taken before automatically extrapolating in vitro data to the in vivo situation.

Metronidazole (Flagyl), misonidazole (Ro 07-0582), iron, zinc and sulphur compounds in cancer therapy.

The nitro radiosensitizers, metronidazole and misonidazole, have been shown to react rapidly with the sulphydryl compounds cysteine and cysteamine in the presence of ferrous ions. Similar reactions occur in the presence of copper ions but these are much slower. The initial interactions of the drugs and of oxygen with an iron-cysteine complex are extremely rapid: in the case of oxygen reaction half-lives of 27 ms have been measured. Misonidazole also reacts rapidly with glutathione in the presence of ferrous ions and is subsequently reduced: metronidazole is reduced only slowly if at all. These reactions, which have been found to be inhibited by high concentrations of zince ions, are discussed in the light of the known radiosensitizing and chemotherapeutic efficiencies of the nitro drugs and the side effect of peripheral neuropathy sometimes observed during their clinical use.