Clinical update: proteasome inhibitors in solid tumors

The proteasome plays a critical role in regulating the cell cycle, neoplastic growth, and metastasis. Bortezomib (VELCADE; formerly PS-341, LDP-341, MLN341) is a novel dipeptide boronic acid that is the first proteasome inhibitor to have progressed to clinical trials. Preclinical research has shown that through the prevention of IkappaB degradation, bortezomib may block chemotherapy-induced NF-kappaB activation and augment the apoptotic response to chemotherapeutic agents. Bortezomib also appeared to increase the stabilization of p21 and p27, as well as transcription factor p53. In preclinical models of breast, lung, pancreatic, and ovarian tumor types, bortezomib inhibited tumor growth and demonstrated anti-angiogenic properties. Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, such as irinotecan, gemcitabine, and docetaxel, suggesting its potential additive/syngeristic role in overcoming resistance to conventional chemotherapy. Preliminary data from early clinical trials suggest that bortezomib can be given at pharmacologically active doses in combination with standard doses of chemotherapy with manageable toxicities. Responses have been seen and no evidence of additive toxicity has been exhibited in combination agent trials.