These studies will examine the differential effect of aging as a contributing factor to drug-related changes in the morphological and biochemical parameters of neurotransmitter and neuropeptide neurons of the central (CNS) and autonomic nervous system (ANS) associated with anticancer agents. Drugs chosen for these studies are either currently being used in the clinic (WR-2721) or will enter clinical trials within the next year (BSO). An integrated methodological approach encompassing light microscopic immunocytochemistry and histochemistry, radioimmunoassay, radioenzymatic assays and HPLC will be used to identify changes in cholinergic, catecholaminergic and somatostatin systems. Tissues to be examined include the substantia nigra and striatum, locus coeruleus, cholinergic nuclei of the basal forebrain, superior cervical ganglia and adrenal gland. We will address two specific questions: first, does buthionine sulfoxine (BSO), an inhibitor of glutathione synthesis or the thiol-containing radiation protector, WR-2721 alter neurotransmitter or neuropeptide systems of the CNS or ANS; second, does advancing age provide a confounding variable in determining either acute or late-effect therapy- related drug toxicity in young (3, 6 months) and old (10, 20, 25, 30 months) mice? Our approach will be twofold. First, we will determine acute effects by comparing drug-related morphological and biochemical changes in neurotransmitter or neuropeptide neurons in young animals with similar data obtained in old mice. Second, we will determine late-effect toxicities by comparing morphological and biochemical changes in middle and old aged mice which have received treatments at earlier ages with age- matched, untreated controls. Data from these investigations will provide information fundamental to our understanding of the underlying mechanisms of the neurotoxicity of anticancer agents and will increase our awareness of potential age-related hazards associated with cancer therapy in man.
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