Proteasome inhibition: potential benefits in the treatment of cancer

AbstractProteasome inhibition is a novel and promising strategy for the treatment of cancer. Bortezomib is a boronic acid dipeptide that potently and reversibly inhibits the 26S proteasome. Following intravenous (IV) injection, bortezomib is cleared with a rapid initial half-life of less than 10 min followed by a longer elimination half-life of 5–15 h. A pharmacodynamic assay has been developed to measure bortezomib activity at the level of the proteasome. Data from phase I trials show that bortezomib induces predictable, dose-related, reversible inhibition of proteasome activity. A phase I trial designed to evaluate the safety and pharmacodynamics of bortezomib administered as a twice-weekly IV bolus for 2 weeks followed by a 1-week rest was conducted in 43 patients with advanced solid tumours. Dose-limiting toxicities (DLTs) at the dose of 1.56 mg/m2 included diarrhoea and sensory neuropathy. A partial response was seen in one patient with non-small cell lung cancer. In a second phase I trial, bortezomib was administered twice weekly for 4 weeks followed by a 2-week rest to 27 patients with refractory haematological malignancies. DLTs included fatigue, hyponatraemia, and hypokalaemia. Among nine patients with myeloma, there was one complete response and a reduction in paraprotein level and/or marrow plasmacytosis in the remaining eight. Additionally, two partial responses were seen in patients with lymphoma. Thus, in phase I testing, bortezomib demonstrated promising clinical activity. It is biologically active and generally well tolerated. Based on these promising early results, bortezomib is now being actively investigated for the treatment of multiple myeloma, non-Hodgkin's lymphoma, and a variety of solid tumours