Clinical studies of reversal of drug resistance based on glutathione

The greater affinity of electrophiles for thiol groups than for hydroxyl or amine groups provides a teleological basis for the evolution of this mechanism to assist in the maintenance of cellular homeostasis. As the most abundant cellular non-protein thiol, glutathione (GSH) is pivotal in the protection of cells from electrophiles created during normal respiration and protection after exposure to environmental mutagens. Mutagens and many anti-cancer drugs, e.g. cisplatin and alkylating agents, have the same target, i.e. DNA. This suggested that one mechanism by which cancer cells might circumvent the action of cancer chemotherapeutic agents would be by increasing their cellular GSH and/or enhanced conjugation of these drugs to this abundant tripeptide. This chapter describes the abundant preclinical data that support this mechanism of resistance to platinum drugs and alkylating agents. This data was the rationale for the development of pharmacologic strategies to lower GSH and inactivate the glutathione-S-transferases to make anti-cancer drugs more effective. The positive outcome of preclinical studies to lower GSH and enhance the activity of melaphalan are described as is the status of on going clinical trials built around this data. (C) 1998 Published by Elsevier Science Ireland Ltd. All rights reserved.