Mitigating ‘normal cell’ toxicity of cancer chemotherapy while maintaining effective killing of cancer cells is essential to maintain acceptable therapeutic indices; however, most chemotherapy treatments are usually halted prematurely due to potentially life-threatening damage to normal tissues. In this issue, Ndolo et al. demonstrate that elevated lysosomal pH significantly enhanced the toxicity of 17-DMAG [17-dimethylaminoethylamino-17-demethoxy-geldanamycin], a lysosomotropic compound, by using chloroquine treatment of mice to quantitatively elevate lysosomal pH. Because many cancer cells are defective in acidification of the lysosomal compartment, altering the physicochemical properties of cytotoxic agents to be more lysosomotropic would increase their extra-lysosomal accumulation in cancer cells, whereas their lysosomal accumulation in normal cells may provide protection. These results provide an important advance toward our understanding of the optimal properties of chemotherapeutic agents that could lead to the discovery of novel agents with improved therapeutic indices.
See article at J Pharmacol Exp Ther 2010, 333:120–128.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics