|Systematic (IUPAC) name|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||D (US)|
|Legal status||℞ Prescription only|
|Metabolism||Hepatic, CYP extensively involved|
|Half-life||9 to 15 hours|
|Mol. mass||384.237 g/mol|
| (what is this?)
Bortezomib (INN, originally codenamed PS-341; 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.
Origin and development 
Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, which soon changed its name to ProScript. After promising preclinical results, the drug (PS-341) was tested in a small Phase I clinical trial on patients with multiple myeloma cancer. ProScript ran out of money and was bought by Leukosite in May 1999. Leukosite in turn was bought by Millennium Pharmaceuticals in October 1999. At this point in time, the project had low priority amongst other projects at the company. This changed significantly when one of the first volunteers to receive the drug in the clinical trial achieved a complete response and were still alive four years later. At the time this was a remarkable result. Later clinical experimentation indicates the possibility of a complete response in 15% of patients in a similar condition, when treated with bortezomib.
In May 2003, seven years after the initial synthesis, bortezomib (Velcade) was approved in the United States by the Food and Drug Administration (FDA) for use in multiple myeloma, based on the results from the SUMMIT Phase II trial.
Another commercially available bortezomib product - Bortenat (Natco Pharma, India), reportedly contains substantially more active entity than declared, potentially and even more resulting in increase toxicity. Moreover, Bortenat has some other chemical and formulation deviations from the registered ethic product Velcade (Millennium Pharmaceuticals and Janssen-Cilag), with unclear clinical impact.
The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine and Leucine with a boronic acid instead of a carboxylic acid. Peptides are written N-terminus to C-terminus, and this convention is used here even though the "C-terminus" is a boronic acid instead of a carboxylic acid.
The boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitylated 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. Recently, it was found that bortezomib caused a rapid and dramatic change in the levels of intracellular peptides that are produced by the proteasome. Some intracellular peptides have been shown to be biologically active, and so the effect of bortezomib on the levels of intracellular peptides may contribute to the biological and/or side effects of the drug.
Pharmacokinetics and pharmacodynamics 
Bortezomib is rapidly cleared following intravenous administration. 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.
Adverse 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 causing neutropenia and thrombocytopenia can also occur and be dose-limiting. However, these side effects are usually mild relative to bone marrow transplantation and other treatment options for patients with advanced disease. Bortezomib is associated with a high rate of shingles, although prophylactic acyclovir can reduce the risk of this.
Drug interactions 
Green tea extract epigallocatechin gallate (EGCG), which had been expected to have a synergistic effect, was found by Encouse B. Golden, et al. to reduce the effectiveness of bortezomib.
Therapeutic efficacy 
Two open-label, phase II trials (SUMMIT and CREST) established the efficacy of bortezomib 1.3 mg/m2 (with or without dexamethasone) administered by intravenous bolus on days 1,4,8, and 11 of a 21-day cycle for a maximum of eight cycles in heavily pretreated patients with relapsed/refractory multiple myeloma. The phase III APEX trial demonstrated the superiority of bortezomib 1.3 mg/m2 over a high-dose dexamethasone regimen (eg. median TTP 6.2 vs 3.5 months, and 1-year survival 80% vs 66%).
Further improvement of anticancer potency 
Laboratory studies and clinical trials are investigating whether it might be possible to further increase the anticancer potency of bortezomib by combining it with novel types of other pharmacologic agents. For example, clinical trials have indicated that the addition of thalidomide, lenalidomide, inhibitors of vascular endothelial growth factor (VEGF), or arsenic trioxide might be beneficial. In laboratory studies, it was found that bortezomib killed multiple myeloma cells more efficiently when combined, for example, with histone deacetylase inhibitors, thapsigargin, or celecoxib. However, the therapeutic efficacy and safety of any of these latter combinations has not yet been evaluated in cancer patients.
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- Highlights Of Prescribing Information
- "Cancer drug benefits could be negated by healthy tea treatment". Belfast Telegraph. 3 February 2009. Retrieved 2009-08-14.
- http://www.news-medical.net/?id=45529 "Green tea may counteract anticancer effects of cancer therapy, bortezomib (Velcade)"
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- Myeloma patients campaigning for access to a life prolonging cancer drug
- 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