In principle, radiation sensitizers with therapeutic ratios greater than that of misonidazole can be obtained either by increasing sensitizing efficiency, decreasing toxicity or preferably both. This paper illustrates, firstly that a 5-nitroimidazole (S73-0662) with an electron affinity close to that of metronidazole shows sensitizing efficiency similar to misonidazole both in vitro and in vivo. The suggestion is made that this compound should receive a detailed toxicological study to ascertain if its toxicity is lower than misonidazole. Secondly, Imuran, a 5-substituted 4-nitroimidazole and one of a series of compounds which show sensitizing efficiencies in vitro much greater than would be predicted from electron affinity considerations, also shows good sensitization in vivo. Compounds in this series are generally metabolically unstable and the positive results with Imuran in vivo provide a direction for future synthesis of novel sensitizers.

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PubMedDate not supplied

Potentiation in vivo of melphalan activity by nitroimidazole compounds.

Many nitroimidazole compounds have been shown to potentiate the activity of melphalan against the murine anaplastic MT tumor. The degree of potentiation achieved by these compounds probably depends on their octanol-water partition coefficient and electron affinity: for the greater the partition coefficient of electron affinity, the greater the potentiation. The mechanism of this potentiation remains uncertain. However, it is not due to either nitroimidazole-induced hypothermia, or to the elimination of the recovery from melphalan-induced potentially lethal damage (PLD).

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PubMedDate not supplied

Neurotoxicity of radiation sensitizers in the mouse.

The neurotoxicity of a homologous series of 1-substituted, 2-nitroimidazole compounds, synthesized in this laboratory, has been studied in mice. This involves measurement of the enzyme beta-glucuronidase in the distal sciatic, tibial and common peroneal nerves. The amount of compound required to give a known neurotoxic response, in terms of elevated beta-glucuronidase (arbitrarily set at 60% increase) has been determined. A correlation between increased number of methylene groups (N) in the side chain and neurotoxicity has been shown. A correlation between increased neurotoxicity and effective octanol; water coefficient, at pH 7.4, was also established. A more soluble version of the n = 4 member of the homologous series, that is the compound RSU 1047 (NSC 328897), and misonidazole also fit this correlation of partition coefficient and dose.

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