The primary objective of this project is to evaluate the potential of 2(3)-tertbutyl-4-hydroxyanisole (BHA) in protecting against the toxicities of several anticancer drugs. BHA is a phenolic antioxidant that not only inhibits lipid peroxidation, but also induces high levels of activity of key enzymes in major pathways of non-oxidative detoxification, and elevates tissue concentrations of non-protein sulfhydryl compounds [primarily glutathione (GSH)]. BHA administration confers protection against a variety of toxic chemicals. Thus it is anticipated that BHA may protect against certain toxicities of antitumor drugs. The ability of BHA to protect mice against the acute lethal toxicity of adriamycin will be evaluated under conditions of maximal induction of detoxification enzymes as well as under conditions where BHA acts primarily as an antioxidant. The effects of BHA on the antitumor activity of adriamycin, on adriamycin-induced cardiac damage, and on biochemical and enzymological changes postulated to be involved in the mechanism of adriamycin cardiotoxicity will also be investigated. [The effects of BHA on adriamycin gut toxicity will be examined.] Special attention has been given to the requirements for therapeutic activity as well as to the basis of toxicity. Some of the biochemical studies may provide further information relevant to the mechanisms of dose-limiting toxicities of adriamycin.
| Odom, A L; Hatwig, C A; Stanley, J S et al. (1992) Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine. Biochem Pharmacol 43:831-6 |
