Peptide-chlorambucil conjugates combat pgp-dependent drug efflux.

Cancer drugs, such as the ovarian cancer drug adriamycin, are effective at slowing disease progression and improving remission rates in patients. However, drug resistance often arises, limiting the activity of these agents in some patients. In particular, efflux pumps, which export drugs out of cells, limit the efficacy of a variety of anticancer agents. While inhibitors to block these pumps currently exist, they are usually not used clinically because they alter other drug properties. Here, we report a novel inhibitor of drug efflux that only reduces pump activity temporarily. This decreases the risk that it will alter drug function and cause nonspecific toxicity. P-glycoprotein efflux pumps are commonly overexpressed by malignant cells and are a major contributing factor to the development of drug resistance. Many therapeutics containing basic nitrogens, hydrophobic character, or aromaticity are efficiently eliminated from cells, and Pgp inhibitors must often be coadministered to limit this process. How...