Bortezomib

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Bortezomib
Systematic (IUPAC) name
[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-
[(pyrazinylcarbonyl)amino]propyl]amino]butyl] boronic acid
Identifiers
CAS number 179324-69-7
ATC code L01XX32
PubChem 93860
DrugBank APRD00828
Chemical data
Formula C19H25BN4O4 
Mol. mass 384.24 g/mol
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, US
Pregnancy cat.

D(US)
Legal status

℞ Prescription only
Routes Intravenous

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.

Contents

[edit] History

Bortezomib was originally synthesized in 1995 (MG-341) at a company called Myogenics, 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]

[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 the catalytic threonine residue whose activity is blocked by the presence of bortezomib.
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 the catalytic threonine residue whose activity is blocked by the presence of bortezomib.

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 proceeds C-terminus to N-terminus, peptide drugs are illustrated C to N, as in this case.

[edit] 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 asthenia are the most common adverse events.[5]

[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.[6] [7] In laboratory studies, it was found that bortezomib killed multiple myeloma cells more efficiently when combined, for example, with histone deacetylase inhibitors,[8] thapsigargin,[9] or celecoxib.[10] However, the therapeutic efficacy of any of these latter combinations has not yet been confirmed in cancer patients.

[edit] 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. 
  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. 
  5. ^ Highlights Of Prescribing Information
  6. ^ Anargyrou K. et al (2008). "Novel anti-myeloma agents and angiogenesis.". Leuk. Lymphoma 49 (4): 677–689. doi:10.1080/10428190701861686. PMID 18398734. 
  7. ^ Richardson P.G. et al (2005). "Novel biological therapies for the treatment of multiple myeloma.". Best Pract. Res. Clin. Haematol. 18 (4): 619–634. doi:10.1016/j.beha.2005.01.010. PMID 16026741. 
  8. ^ Nawrocki S.T. et al (2006). "Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells.". Cancer Res. 66 (7): 3773–3781. doi:10.1158/0008-5472.CAN-05-2961. PMID 16585204. 
  9. ^ Nawrocki S.T. et al (2005). "Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis.". Cancer Res. 65 (24): 11658–11666. doi:10.1158/0008-5472.CAN-05-2370. PMID 16357177. 
  10. ^ Kardosh A. et al (2008). "Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl-celecoxib.". Cancer Res. 68 (3): 843–851. doi:10.1158/0008-5472.CAN-07-5555. PMID 18245486. 

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