ABSTRACT
In the fluctuation test the mutation frequency of Klebsiella pneumoniae by the 5-nitroimidazoles panidazole and dimetridazole was increased by adding the non-mutagenic substances 4-nitrotoluene or toluene-4-sulfonamide. This effect was not found with 1-methyl-5-nitroimidazole, metronidazole, ronidazole, nimorazole and 1-methyl-2-hydroxymethyl-5-nitroimidazole. It is suggested that the molecules of panidazole or dimetridazole form some association, which is destroyed by 4-nitrotoluene or toluene-4-sulfonamide, thus increasing the concentration of mutagenic particles.
Subject(s)
Klebsiella pneumoniae/drug effects , Mutagenesis , Nitroimidazoles/toxicity , Toluene/analogs & derivatives , Dimetridazole/toxicity , Drug Synergism , Metronidazole/toxicity , Nimorazole/toxicity , Structure-Activity Relationship , Toluene/toxicityABSTRACT
Nimorazole, a 5-Nitromidazole compound has been shown in animal studies to have similar radiosensitizing properties to misonidazole at clinically acceptable dose levels. The drug is well absorbed in humans after oral administration with peak plasma levels occurring around 90 min after ingestion (range 35-135 min) and a plasma half life between 2 and 4.8 hours. Total doses of Nimorazole up to 60 grams given in daily doses with conventional radiation therapy have demonstrated a significant lack of side effects, in particular no demonstrable neurotoxicity.
Subject(s)
Neoplasms/metabolism , Nimorazole/metabolism , Nitroimidazoles/metabolism , Radiation-Sensitizing Agents/metabolism , Adult , Aged , Dose-Response Relationship, Drug , Drug Evaluation , Female , Humans , Male , Middle Aged , Nimorazole/blood , Nimorazole/toxicity , Radiation-Sensitizing Agents/blood , Radiation-Sensitizing Agents/toxicity , Time FactorsABSTRACT
The hypoxic cell radiosensitizing properties of nimorazole have been investigated in a C3H mammary carcinoma transplanted to the feet of C3D2F1. The results have been compared with those obtained with misonidazole (MISO) in the same animal tumour system. For single-dose irradiation in air, nimorazole gives an enhancement ratio (ER) of approximately 1.4, independent of the dose of drug administered over the range 0.1-1.0 mg/g. MISO yields a similar ER at the 0.1 mg/g level but, unlike nimorazole, shows a steep dose-response curve with an ER of 2.2 when given in a concentration of 1.0 mg/g. No such dose-response relationship is seen with nimorazole despite the fact that tumour and plasma concentrations of the 2 drugs have an identical dose relationship. With irradiation given in 5 daily fractions, nimorazole and MISO at a dose of 0.3 mg/g per fraction both show an ER of approximately 1.3. The high drug doses used in single-fraction radiation experiments in animals bear little relation to those applicable to clinical practice since these would result in unacceptable toxicity. The results of the present studies are therefore of interest as nimorazole is potentially less toxic than MISO in humans but demonstrates similar radiosensitizing properties at clinically relevant dose levels.
