The potential role of proteasome inhibitors in the treatment of lung cancer.
Bortezomib (PS-341, Velcade, Millennium Pharmaceuticals, Cambridge, MA) is a novel inhibitor of the proteasome. The proteasome plays a critical role in the degradation and, therefore, regulation of many proteins involved in cell cycle regulation, apoptosis, and angiogenesis. Bortezomib inhibits the growth of lung cancer cell lines in vitro and in vivo in athymic nude mouse xenografts. Bortezomib produces a G(2)-M arrest, increases in cyclin A and cyclin B, increases in p21, and increases apoptosis in these preclinical models. Phase I studies established that a dose of 1.4 mg/m(2) given i.v. on days 1, 4, 8, and 11 of a 3-week cycle produced acceptable toxicity and serum levels that resulted in proteasome inhibition. Phase II studies showed high-response rates in refractory multiple myeloma. These response rates were sufficiently high to allow accelerated approval of bortezomib by the Food and Drug Administration for this indication. Phase II trials in both non-small cell lung cancer and small cell lung cancer are in progress. A number of Phase I combination studies are also underway. Hopefully, bortezomib will show sufficient activity in lung cancer to improve survival in this dread disease.
Bunn
Paul A
PA
University of Colorado Cancer Center, Denver, Colorado, USA. paul.bunn@uchsc.edu
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001897:Boronic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D002986:Clinical Trials as Topic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib