In vivo effects of 1,3-bis(2-chloroethyl)-1-nitrosourea and doxorubicin on the cardiac and hepatic glutathione systems.

Doxorubicin and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) are anti-cancer drugs which have been used together in combination therapy of certain cancers. Each drug has been reported to affect intracellular glutathione stores and together, doxorubicin and BCNU have been shown to exert synergistic toxicity and to deplete completely the glutathione content of isolated hepatocytes. Cardiac and hepatic glutathione reductase activity was significantly inhibited following treatment in vivo with BCNU. Treatment of mice with both doxorubicin and BCNU resulted in increased mortality compared to either drug alone. There was, however, no depletion of hepatic or cardiac glutathione levels in vivo beyond that seen with either BCNU or doxorubicin alone. Diethyl maleate, a known glutathione depletor whose effects are enhanced by BCNU in vitro, also was unable to increase GSH depletion after BCNU in vivo. These discrepancies between in vivo and in vitro studies may be due to the presence of more effective compensatory mechanisms in the whole animal, or to differences in the metabolism and inactivation of these drugs.