Metronidazole (Flagyl): characterization as a cytotoxic drug specific for hypoxic tumour cells

Abstract

Summary.-The cytocidal properties of metronidazole against hypoxic mammalian cells are described. This chemotherapeutic action has been shown to be dependent on drug concentration and duration of exposure. The x-ray TCD50 for a murine anaplastic carcinoma was reduced from 6081 rad to 4643 rad when animals were given metronidazole orally for 36 h before radiation treatment. The effect is attributed to the direct killing of hypoxic tumour cells by a mechanism analogous to that proposed for the action of the drug on anaerobic micro-organisms. It is concluded that further work with metronidazole as a cytotoxin specific for hypoxic cells is warranted, particularly in view of the reported lack of toxicity associated with the preliminary clinical use of the drug as a radiosensitizer in man.

Interaction of hyperthermia and the hypoxic cell sensitizer Ro-07-0582 on the EMT6 mouse tumour

“…Fewer experiments have been performed with these intra-tumour measurements than the total number of experiments in this series. The data demonstrate that the toxic effect of Ro-07-0582 is marked at intra-tumour temperatures of more than 42*5°C, whereas at intra-tumour tempera- In vitro cytotoxicity to metronidazole (2-methyl-5-nitroimidazole-1-ethanol) has been reported by Sutherland (1974) and Mohindra and Rauth (1976) and, in vivo, by Inch and McCredie (1975) and Foster et al (1976). In vitro hypoxic cell cytotoxicity of Ro-07-0582 has been reported by Sutherland et al (1976) and Hall and Roizin-Towle (1975).…”

“…Small changes in temperature over the range 42-45°C may produce large changes in cell killing. It has also been reported that hypoxic cells are more sensitive to killing by heat than in oxic cells (Gerweck et at., 1974;Kim et at., 1975a). The surviving fractions assayed in this paper will therefore be a product of the temperature and hypoxic cell gradients.…”

“…The nitroimidazoles appear to be a particularly promising group of agents, and of these the 2-nitroimidazole (1-(2-nitroimidazol-l-yl)-3-methoxy-2-propanol), designated Ro-07-0582, has been most extensively investigated, as reviewed by Adams and Fowler (1976). Evidence is also now accumulating that these imidazole compounds may be selectively cytotoxic for hypoxic cells (Sutherland, 1974;Hall and RoizinTowle, 1975;Mohindra and Rauth, 1976;Foster et al, 1976;Brown, 1975;Sutherland et al, 1976).…”

“…Synergistic effects have been described when hyperthermia is combined with chemotherapy (Hahn, Braun and Har-Kedar, 1975) and reviewed by Har-Kedar and Bleehen (1976), and Dickson and Suzangar (1976). Evidence has also been presented that cell killing by hyperthermia may be enhanced by hypoxia (Gerweck, Gillette and Dewey, 1974;Kim, Kim and Hahn, 1975a) and that a significant reduction in oxygen enhancement ratio (OER) may be obtained when irradiated cells are subsequently treated for 2 h at 42°C (Kim,Kim and Hahn,1]…”

In vivo interaction of anti-cancer drugs with misonidazole or metronidazole: methotrexate, 5-fluorouracil and adriamycin

“…Also, poorly nourished tumour cells tend to be slowly proliferating (Tannock, 1968(Tannock, , 1970Hirst & Denekamp, 1979) whereas most anti-cancer drugs are more active against rapidly proliferating cells (Tannock, 1978 Taylor & Rauth, 1978) and to induce necrosis of hypoxic cells in the centre of multicellular spheroids (Sridhar et al, 1976). At high concentration, the same drugs have good penetration into hypoxic regions of tumours, and have been shown to kill hypoxic cells in some, but not all, mouse tumours (Foster et al, 1976;Brown, 1977;Denenkamp, 1978;Pederson et al, 1979). Also MISO may be metabolized in hypoxic tumour regions, with release of metabolites that can kill neighbouring better-oxygenated cells (Brown, 1977;Brown & Yu, 1979).…”