Proteasome inhibition: a new approach for the treatment of malignancies.
Since last years, the proteasome has emerged as a real and exciting target for anticancer therapy. Velcade (bortezomib, formerly known as PS341) remains the first selective proteasome inhibitor that has demonstrated significant preclinical activity in several tumor models and a significant efficacy in patients with refractory or relapsed multiple myeloma, resulting in an accelerated approval in US and Europe in such a setting. The major biological effect of bortezomib is the inhibition of the nuclear transcription factor NFkappaB, with subsequent inhibition of the growth tumor cells, induction of apoptosis, inhibition of angiogenesis and of cellular adhesion. The better understanding of the role of proteasome in the regulation of tumor cell growth has led to the development of new therapeutic approaches, notably in patients with multiple myeloma but also seems to hold interesting promises in other hematologic malignancies and solid tumors. This review provides a summary of the rationale for using proteasome inhibitors and an update on available and ongoing clinical studies involving human malignancies.
Spano
Jean-Philippe
JP
Département d'oncologie médicale, Groupe Hospitalier Pitié-salpêtrière, Assistance Publique/Hôpitaux de Paris, Paris, France. jean-philippe.spano@psl.ap-hopparis.fr
Bay
Jacques-Olivier
JO
Blay
Jean-Yves
JY
Rixe
Olivier
O
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D045744:Cell Line, Tumor / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004354:Drug Screening Assays, Antitumor; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011323:Primates; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012377:Rodentia
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib