Approximately 40,000 American men die annually from prostate cancer that has spread beyond the prostate gland. Standard treatment for this advanced prostate cancer consists of chemotherapy in which toxic drugs are given in doses that should potentially kill cancer cells while avoiding serious side effects. Unfortunately, the chemotherapy drugs tested to date as treatment for advanced prostate cancer have not resulted in any improvement in the life span of affected men. These treatments are also associated with often-severe side effects that limit how much and how often the drugs can be given. New treatments for prostate cancer therefore are desperately needed. In addition, a new way of giving the drugs so that they only reach prostate cancer cells and not normal cells would greatly decrease side effects. One new class of drugs, termed proteasome inhibitors, has recently been shown to kill a variety of different types of cells, including prostate cancer cells. The proteasome is a complex of proteins found inside cells whose function is to degrade other proteins that have either become damaged or that are involved in controlling how cells grow. Proteasome inhibitors prevent the normal degradation of these proteins and this causes the cells to die. The potent killing ability of the proteasome inhibitors, however, is not unique to prostate cancer cells. Normal, non-cancer cells also can be killed by these inhibitors. To target the killing ability of the proteasome inhibitors to prostate cancer cells only, we are chemically making changes to the proteasome inhibitor molecule to produce inactive drugs (prodrugs) that are themselves unable to kill normal or prostate cancer cells. These inactive prodrugs are designed so that they can be converted to killing agents only by prostate cancer cells at sites of prostate cancer throughout the body. This is based upon the unique ability of a protein, termed prostate-specific antigen (PSA) to convert the designed prodrug into a killing agent. Since PSA is produced at high levels only by prostate cancer cells and not by normal cells, this strategy represents a new way to target the killing ability of the proteasome inhibitors to prostate cancer cells while avoiding toxic side effects.