Bortezomib

Systematic (IUPAC) name
[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid
Identifiers
CAS number	179324-69-7
ATC code	L01XX32
PubChem	CID 387447
DrugBank	APRD00828
ChemSpider	343402
Chemical data
Formula	C19H25BN4O4
Mol. mass	384.237 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	n/a
Protein binding	83%
Metabolism	Hepatic, CYP extensively involved
Half-life	9 to 15 hours
Excretion	?
Therapeutic considerations
Licence data	EU EMA:link, US FDA:link
Pregnancy cat.	D(US)
Legal status	? Prescription only
Routes	Intravenous
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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^[1] and mantle cell lymphoma. In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease.

[edit] History

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 was 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.^[2]

[edit] Pharmacology

Bortezomib bound to the core particle in a yeast proteasome. The bortezomib molecule is in the center colored by atom type (carbon = cyan, nitrogen = blue, oxygen = red), surrounded by the local protein surface. The blue patch is catalytic threonine residue whose activity is blocked by the presence of bortezomib.

[edit] Structure

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

[edit] Mechanism

The boron atom in bortezomib binds the catalytic site of the 26S proteasome^[3] 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.

[edit] Pharmacodynamics

Bortezomib is rapidly cleared following intravenous administration.^[4] 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.

[edit] Costs

[edit] UK

NICE recommended against Velcade in Oct 2006 due to its cost.^[5]

The company proposed a cost reduction for multiple myeloma,^[6] and this was taken up in the UK.^[7]

[edit] 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.^[8]

GI effects and asthenia are the most common adverse events.^[9]

[edit] 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.^{[10][11][12][13]}

[edit] Therapeutic Efficacy

Two open-label, phase III trials established the efficacy of bortezomib 1.3mg/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.^[14]. Another trial demonstrated the superiority of bortezomib 1.3mg/m² over a high-dose dexamethasone regimen.^[14]

[edit] 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.^[15][16] In laboratory studies, it was found that bortezomib killed multiple myeloma cells more efficiently when combined, for example, with histone deacetylase inhibitors,^[17] thapsigargin,^[18] or celecoxib.^[19] However, the therapeutic efficacy of any of these latter combinations has not yet been confirmed in cancer patients.

[edit] References

[edit] External links

• 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

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Bortezomib".