Abstract
The dipeptide boronic acid analogue VELCADE™ (Bortezomib; formerly known as PS-341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a multicatalytic enzyme that mediates many cellular regulatory signals by degrading regulatory proteins or their inhibitors. The proteasome is, thus, a potential target for pharmacological agents. Bortezomib, the first proteasome inhibitor to reach clinical trials, has shown in vitro and in vivo activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib–mediated proteasome blockade is dose-dependent and reversible. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies.
Abbreviations | ||
MTD: | = | maximum tolerated dose |
ICAM: | = | intracellular adhesion molecule |
VCAM: | = | vascular cell adhesion molecule |
IAP: | = | inhibitor of apoptosis |
CLL: | = | chronic lymphocytic leukemia |
CTEP: | = | Cancer Therapy Evaluation Program |
BMSCs: | = | bone marrow stromal cells |