Use of novel proteosome inhibitors as a therapeutic strategy in lymphomas current experience and emerging concepts.
Precedent from preclinical experiments coupled with two pivotal phase 2 studies in myeloma has focused attention on a potential role for ubiquitin-proteasome pathway in modulating a number of events that occur commonly in the neoplastic process involving proteins in the regulation of cells cycling, growth and differentiation. This influence is vested in the proteasomes which are large complexes of proteolytic enzymes responsible for degradation of many of these intracellular messengers. Logically interest has centred on molecules having the capacity to influence, by degradation, such molecules and although a number of agents are in development bortezomib is the only one currently in clinical use. Velcade, formerly PS-341, is a novel dipeptide boronic acid capable of reversibly inhibiting the 26S proteasome through a range of activities. The latter are anti-proliferative and proapoptotic with the latter blocking nuclear transcription via NF-kappa B in addition to down regulating adhesion and inhibiting angiogenesis. Additional changes are mediated in protein folding within the endoplasmic reticulum and contribute to cell death. These concepts are given focus by considering their introduction into treatment of lymphoreticular malignancy.
Abayomi
Emmanuel Akinola
EA
Faculty of Health Sciences, Stellenbosch University, Tygerberg Academic Hospital, South Africa.
Sissolak
Gerhard
G
Jacobs
Peter
P
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D025801:Ubiquitin / Q000378:metabolism
D001897:Boronic Acids; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D025801:Ubiquitin; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease