Human studies with "high dose" metronidazole: a non-toxic radiosensitizer of hypoxic cells

Abstract

Summary.-The serum concentrations of the radiosensitizer metronidazole have been determined in mice for both oral and intraperitoneal doses of the drug and these have been related to radiosensitization studies in murine tumour systems.In preliminary work before a possible clinical trial the serum metronidazole concentration/time curves have been determined in 7 patients using single doses of metronidazole of up to 15 g. The data suggest that a linear relationship exists between the metronidazole dose expressed in mg/kg and the peak serum concentration.The possibility of achieving radiosensitization of tumours in patients after tolerable doses of metronidazole is discussed in relation to enhancement ratios determined for in vitro and in vivto systems. It is concluded that predictions from in vitro systems give values that are probably too optimistic.

Hypoxic cell radiosensitizers and local control by X-ray of a transplanted tumour in mice

“…These results agree well with those from other studies (Table IV). The doses administered here should correspond to 100 and 850 p.g/ml serum concentrations (Deutsch et al, 1975), which in vitro would yield ERs of 193 and 197 respectivelv, close to those observed in vivo.…”

“…The maximum tolerated dose is about 180 mg/kg, which produces a serum level of 200,ug/ml (Deutsch et al, 1975). Thus an ER of 1-2 obtained for the lowest dose tested in the anaplastic MT tumour is probably a slight underestimate of what could be achieved clinically, but nevertheless still corresponds to an increase in the local control rate of from 20 to 80% (see Fig.…”

Radiation and nitroimidazoles in supratentorial high grade gliomas: a second clinical trial

“…Metronidazole was chosen in 1973 for clinical studies as a radiosensitizer, and its toxicity and pharmacological properties at oral high doses has been previously reported (Urtasun et al, 1974(Urtasun et al, , 1975Deutsch et al, 1975). Misonidazole, a 2-nitroimidazole derivative (1-(2-nitroimidazol -1 -yl) -3 -methoxypropan-2-ol; Ro-070582; NSC-261037, MISO) has been shown to be a more efficient radiosensitizer of hypoxic mammalian tumour cells, both in vitro and in vivo (Adams et al, 1978;Brown, 1975;Denekamp et al, 1.…”

Serum concentration measurements in man of the radiosensitizer Ro-07-0582: some preliminary results

“…The concentration of Ro-07-0582 in the serum was determined directly as described previously for metronidazole (Deutsch et al, 1975) using a polarographic technique (Kane, 1961).…”

“…The nitro-heterocyclic drug metronidazole (Flagyl, May and Baker) has been shown to increase the radiosensitivity of solid murine tumours (Begg, Sheldon and Foster, 1974;Rauth and Kaufman, 1975;Stone and Withers, 1974) and possesses favourable pharmacological and toxicological properties (see Asquith et al, 1974a for references) which have enabled the high drug doses required (about 200 mg/kg body weight) to be used in conjunction with radiotherapy in man (Urtasun et al, 1974;Deutsch et al, 1975).…”