The clinical effectiveness of nitroimidazole hypoxic cell radiation sensitizers such as misonidazole (MISO) is reduced by the dose limitation imposed by neurotoxic side effects. Considerable recent effort has been made to develop more efficient or less toxic sensitizers to replace MISO for clinical use. Our studies have concentrated on the development of an animal model which integrates drug distribution, quantitative functional tests and histopathology in order to screen for nitroimidazole neurotoxicity in terms of predictive significance. Our data indicate that the mouse model is useful in giving a quantitative rank order for the neurotoxicity of the sensitizers tested which differ in relative toxicity by a factor of 1.5-2.0. Although differences in mouse strain sensitivity to sensitizers do occur and the route of administration may be important in determining relative neurotoxicity of similar sensitizers, a general finding has been that for sensitizers of equal electron affinity, less lipophilic compounds are less neurotoxic. We have also shown that inhibition of glycolysis is a potential mechanism for sensitizer neurotoxicity. The major general objectives of this renewal proposal are (1) to determine the relative neurotoxicity of several newly synthesized sensitizers (eg. Ro-03-8799, SR 2508, RSU-1087) which are candidates for the replacement of MISO in the clinic and (2) to better define the biochemical mechanism(s) of radiation sensitizer toxicity to normal tissue, with an emphasis on inhibition of glycolysis and the pentose phosphate shunt. We propose to use the techniques developed during out studies on the neurotoxicity of 2- and 5-nitroimidazoles in the mouse in order to select the least neurotoxic newly synthesized sensitizer to replace MISO for clinical use and thereby improved the potential therapeutic ratio. The studies proposed to investigate biochemical mechanism(s) of toxicity of nitroimidazoles will provide data on the cofactor and substrate changes produced by administration of such compounds in neuronal tissue in vivo in order to identify specific enzyme systems related to glycolysis for further investigation and to provide information on potential methods of protection. Overall, these investigations should provide information which will improve our understanding of the neurotoxicity of radiation sensitizers and which will guide our efforts to select the most effective replacement of MISO as an adjuvant agent in the clinical management of human solid tumors with radiation therapy.
| Williams, W M; Reichman, M; McNeill, T H (1988) Cerebral microvascular and parenchymal phospholipid composition in the mouse. Neurochem Res 13:743-7 |
| McNeill, T H; Koek, L L; Brown, S A et al. (1986) Effect of misonidazole on neurotransmitter systems. Int J Radiat Oncol Biol Phys 12:1067-70 |
