Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome. This drug is thought to inhibit many proteins (known as proteasomes) that cancer cells need to survive and multiply. It has been shown to have anti-tumor activity in B cell malignancies.

Bortezomib is “indicated” (recommended) for single-agent use in the treatment of patients with multiple myeloma who have received at least two prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types.

Bortezomib (VELCADE®, formerly PS-341) was approved for the treatment of patients with relapsed or refractory multiple myeloma in May 2003 by the US Food and Drug Administration and in April 2004 by the Committee for Proprietary Medicinal Products of the European Union. In December 2006 the FDA approved Bortezomib for treatment of mantle cell lymphoma.

Bortezomib binds to the proteasome and does so “reversibly” (this is a chemical term that means that the bortezomib molecule can come free under different micro-cellular chemical conditions.) Normal healthy (non-cancer) cells are not as prone to damage from this binding after the Bortezomib comes off, as cancer cells are. Malignant cells suffer a breakdown even after inhibition of the proteasome for a short time.

Research has found that lymphoma patients who had become resistant to standard treatment respond well to a combination of bortezomib and obatoclax.

Other boron compounds are of interest in both prevention of cancer (chemoprevention) and treatment of cancer (chemotherapy, or at least “targeted therapy”)

A Proteasome Inhibitor

This class of drug, proteasome inhibitors, stops proteasomes, which are large protein complexes.  Bortezomib was the first Proteasome inhibitor to be approved for use.

The word proteasome refers to a protein complex present in all cells. In cellular metabolism, the ubiquitin-proteasome pathway is involved in degrading proteins in cell cycle contol and growth of tumors. The idea of proteasome inhibitors is to put a roadblock in this pathway and encourage the cells to die – a process called apoptosis.

Inhibitors are a unique class of anti-cancer drugs and they are under development, particularly for advanced cancer.

In September 2008, the European Commission approved the use of Bortezomib in combination with melphalan and prednisone for treatment of multiple myeloma. A Phase III study published in the New England Journal of Medicine showed that this combination worked better in myeloma patients than if the bortezomib was not included.

A recent Italian study found encouraging results in lab-scale exposure of malignant liver cells to Bortezomib.

More

Like every drug, bortezomib has potential side effects and they differ in nature and intensity in different patients.

The following side effects occur in greater than 30% of patients who have taken bortezomib for treatmet of cancer. Most are similar to the side effects of other chemotherapy agents.

• Fatigue
• Peripheral neuropathy: characterized by decreased sensation and paresthesia (numbness and tingling of the hands and feet).
• Nausea and vomiting
• Diarrhea
• Poor appetite
• Constipation
• Low platelet count
• Fever
• Anemia

Less common side effects are arthralgia (joint pain) headache, insomnia, edema (swelling of body parts), muscle pain, and low white blood cell count. (This can put you at increased risk for infection.)

Blood tests of patients have found lower than normal concentrations of electrolytes such as sodium, potassium, magnesium, and calcium.

Patients have also reported:

• Shortness of breath
• Dizziness
• Dehydration
• Upper respiratory tract infection
• Cough
• Bone pain
• Anxiety
• Heartburn
• Abdominal pain
• Itching
• Blurring of visiom

The FDA’s webpage on bortezomib.

Proteasome inhibitors are also used in therapy for immune system disorders, and there are ideas that bortezomib affects elements of the immune system through different biochemical pathways than the drug works against cancer. There are suggestions bortezomib might someday be used to facilitate tissue grafts (which often provoke immune responses) and in therapy for multiple sclerosis and arthritis.

Complete Atrioventricular Block Secondary to Bortezomib Use in Multiple Myeloma

A Case of Disseminated and Fulminant Plasmacytomas That Developed during Bortezomib Treatment