Bortezomib

Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. It is approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

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History

Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogen, which soon changed name to ProScript. After promising preclinical results, the drug (PS-341) was used in a small Phase I clinical trial in patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite itself was bought by Millennium Pharmaceuticals in October 1999. At this stage, the project had a low priority amongst the other projects at the company. This changed significantly when one of the first patients to be treated in the clinical trial achieved a complete response and was still alive 4 years later. At the time this was a remarkable result. Later clinical trials showed that a complete response would be expected for 15% of patients in a similar condition, when treated with bortezomib. In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved by the FDA for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.

^[1]

Pharmacology

  The boron atom in bortezomib binds the catalytic site of the 26S proteasome^[2] with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitinylated proteins, and also cleanses the cell of abnormal or misfolded proteins. Clinical and preclinical data support a role in maintaining the immortal phenotype of myeloma cells, and cell-culture and xenograft data support a similar function in solid tumor cancers. While multiple mechanisms are likely to be involved, proteasome inhibition may prevent degradation of pro-apoptotic factors, permitting activation of programmed cell death in neoplastic cells dependent upon suppression of pro-apoptotic pathways.

Bortezomib is rapidly cleared following intravenous administration.^[3] Peak concentrations are reached at about 30 minutes. Drug levels can no longer be measured after an hour. Pharmacodynamics are measured by measuring proteasome inhibition in peripheral blood mononuclear cells. The much greater sensitivity of myeloma cell lines and mantle cell lines to proteasome inhibition compared with normal peripheral blood mononuclear cells and most other cancer cell lines is poorly understood.

The drug is a tripeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with boric acid instead of a carboxylic acid. Peptides are written N-terminus to C-terminus, but as peptide synthesis procedes C-terminus to N-terminus, peptide drugs are illustrated C to N, as in this case.

Side effects

Bortezomib is associated with peripheral neuropathy in 30% of patients; occasionally, it can be painful. This can be worse in patients with pre-existing neuropathy. In addition, myelosuppression as neutropenia and thrombocytopenia can also occur and be dose limiting. However, relative to other treatment options for patients with advanced disease (eg, bone marrow transplantation), these side effects are mild. Bortezomib is associated with a high rate of shingles (reactivation of the chickenpox virus in a nerve distribution, also referred to as zoster).^[4]

GI effects and aesthenia are the most common adverse events ^[5]

References

1. ^ Adams, J. and Kauffman, M. (2004). "Development of the Proteasome Inhibitor Velcade™ (Bortezomib)". Cancer Invest. 22 (2): 304-11. doi:10.1081/CNV-120030218. PMID 15199612. Retrieved on 2007-08-29.
2. ^ Bonvini P, Zorzi E, Basso G, Rosolen A (2007). "Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma". Leukemia 21 (4): 838-42. doi:10.1038/sj.leu.2404528. PMID 17268529.
3. ^ Voorhees PM, Dees EC, O'Neil B, Orlowski RZ (2003). "The proteasome as a target for cancer therapy". Clin. Cancer Res. 9 (17): 6316-25. PMID 14695130.
4. ^ Oakervee HE, Popat R, Curry N, et al (2005). "PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma". Br. J. Haematol. 129 (6): 755-62. doi:10.1111/j.1365-2141.2005.05519.x. PMID 15953001. Retrieved on 2007-07-04.
5. ^ http://www.velcade.com/full_prescrib_velcade.pdf

• Millennium Pharmaceuticals website on Velcade™
• Multiple Myeloma Research Foundation article on Velcade™
• International Myeloma Foundation article on Velcade™
• U.S. Food and Drugs Administration on Velcade™
• Dedicated website for European audience
• Presentation at 2006 ASCO of the PINNACLE Study on MCL by Dr. Goy, with video/slides