Activation of adriamycin and other benzanthraquinones to drug free radicals has been demonstrated in microsomal systems. The reactions require NADPH as a cofactor and oxygen as a terminal acceptor. Theoretically, activation of these drugs in vivo also occurs by this mechanism. In microsomal systems, NADPH is the best cofactor for these reactions. This raises the question whether or not the hexose monophosphate shunt pathway provides the energy for the activation of these drugs in the intact cell since this pathway is the major source of cellular NADPH. Thus, the HMPS pathway which may normally protect the cell against oxidant damage may provide the cellular energy for the activation of drugs to drug free radicals with several reactive oxygen species being generated from molecular oxygen. Both the drug radical and the reactive oxygen species could then cause damage to the cell. In this study, we will determine the capacity of chemotherapeutic drugs to stimulate the HMPS pathway and to generate reactive oxygen species in several tissues. In this way we will determine whether or not the capacity of the drug to be activated to a radical in microsomal systems always correlates with the capacity to generate ROS in the intact cells. We will determine the type of ROS generated and whether or not these compounds produce oxidant damage to the cell.

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National Cancer Institute (NCI)
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Pathology B Study Section (PTHB)
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Ohio State University
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Sagone Jr, A L; Husney, R M; Davis, W B (1993) Biotransformation of para-aminobenzoic acid and salicylic acid by PMN. Free Radic Biol Med 14:27-35
Barton, K; Randall, G; Sagone Jr, A L (1989) The effects of the anti-tumor agent mezerein on the cytotoxic capacity and oxidative metabolism of human blood cells. Invest New Drugs 7:179-88
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Davis, W B; Husney, R M; Wewers, M D et al. (1988) Effect of O2 partial pressure on the myeloperoxidase pathway of neutrophils. J Appl Physiol 65:1995-2003
Sagone Jr, A L; Husney, R M (1987) Oxidation of salicylates by stimulated granulocytes: evidence that these drugs act as free radical scavengers in biological systems. J Immunol 138:2177-83
Alexander, M S; Husney, R M; Sagone Jr, A L (1986) Metabolism of benzoic acid by stimulated polymorphonuclear cells. Biochem Pharmacol 35:3649-51
Sagone Jr, A L (1985) Effect of hyperoxia on the carbohydrate metabolism of human lymphocytes. Am J Hematol 18:269-74
Conkling, P; Cornwell, D G; Sagone Jr, A L (1985) Effect of diethyldithiocarbamate (DDC) on human monocyte function and metabolism. Inflammation 9:149-61