Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas

Luca Paoluzzi, Owen A. O'Connor

Research output: Contribution to journalReview article

22 Citations (Scopus)

Abstract

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, bortezomib (formerly known as PS341), 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 cancer, especially select hematological malignancies. 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. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity 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 bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, 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.

Original languageEnglish (US)
Pages (from-to)13-23
Number of pages11
JournalBioDrugs
Volume20
Issue number1
DOIs
StatePublished - Apr 11 2006
Externally publishedYes

Fingerprint

Mantle-Cell Lymphoma
Proteasome Inhibitors
Proteasome Endopeptidase Complex
Non-Hodgkin's Lymphoma
B-Cell Chronic Lymphocytic Leukemia
Lymphoma
Therapeutics
Drug Therapy
Phase II Clinical Trials
Lymphoma, Large B-Cell, Diffuse
Hematologic Neoplasms
Ubiquitin
Cell Cycle Checkpoints
Protease Inhibitors
Drug-Related Side Effects and Adverse Reactions
Multiple Myeloma
Cell Adhesion
Bortezomib
Histology
Radiotherapy

ASJC Scopus subject areas

  • Biotechnology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas. / Paoluzzi, Luca; O'Connor, Owen A.

In: BioDrugs, Vol. 20, No. 1, 11.04.2006, p. 13-23.

Research output: Contribution to journalReview article

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