Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and XXXX .

@entity1 @entity1893 @entity137 @entity706 @entity5 @entity1072 @entity1582 @entity1892 @entity1583 @entity1073 @entity1749
Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, @entity1749 (formerly known as @entity1749 ), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of @entity5 , especially select @entity1583 . The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. @entity1749 was recently approved by the US FDA for the treatment of relapsed or refractory multiple @entity1582 . In addition, @entity1749 has also shown encouraging results in the treatment of select types of @entity1893 ( @entity1893 ). Ongoing phase II clinical trials in pretreated @entity1 are exploring @entity1749 in different histologies of @entity1893 and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in @entity1 with follicular, marginal zone, and @entity1073 ; in these populations, durable complete and partial remissions have been reported. The @entity137 profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ @entity1749 in the conventional treatment of @entity706 . The apparent lack of activity in different subtypes of @entity706 , such as @entity1072 and diffuse large @entity1892 , as well as a lack of understanding about the best way to combine @entity1749 with standard therapies for indolent @entity1893 , raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.
