Use of proteasome inhibition in the treatment of lung cancer.
The proteasome plays a critical role in the degradation of proteins involved in the regulation of cell cycle, apoptosis, and angiogenesis. Bortezomib is the first in a new class of antineoplastic agents known as proteasome inhibitors to become available for clinical use. Bortezomib targets pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27kip1, p53, nuclear factor-kB, Bcl-2, and Bax. In in vitro and in vivo, growth inhibition and apoptosis have been observed in tumor cells following exposure to bortezomib. Currently, bortezomib is approved for the treatment of patients with relapsed and/or refractory multiple myeloma who have received > or =2 therapies and progressed on their most recent therapy. Efforts are now being directed toward exploring the use of bortezomib in the treatment of advanced non-small-cell lung cancer (NSCLC). Clinical trials using bortezomib as monotherapy or in combinations, such as with taxanes, gemcitabine and platinums, and novel agents are under way, and preliminary results have demonstrated activity with bortezomib as a single agent and in combination with chemotherapy in advanced NSCLC. In addition, pharmacogenomics and biomarker analysis are being used in an attempt to identify tumor types likely to respond to treatment with bortezomib.
Schenkein
David P
DP
Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA. david.schenkein@mpi.com
D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use
D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease