Bortezomib (originally PS-341 and marketed as Velcade by Millennium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be tested in humans. The boron atom within bortezomib catalytically binds the active site of the 26S proteasome with high affinity and specificity, thereby resulting in cell cycle arrest and apoptosis. In normal cells, the proteasome is involved in degradation of ubiquitylated proteins that have been tagged for destruction because they are damaged or unneeded by the cell. However, in cancerous cells, proteasome activity degrades pro-apoptotic proteins such as p53 that would normally result in programmed cell death of the dysfunctional cells. Proteasome inhibitors such as bortezomib interrupt this process, resulting in destruction of cancerous cells.

Bortezomib 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.

• Acids
• Acids, Noncarboxylic
• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Boron Compounds
• Boronic Acids
• Cytochrome P-450 CYP1A2 Inhibitors
• Cytochrome P-450 CYP1A2 Inhibitors (moderate)
• Cytochrome P-450 CYP1A2 Substrates
• Cytochrome P-450 CYP2C19 Inhibitors
• Cytochrome P-450 CYP2C19 Inhibitors (moderate)
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Inhibitors
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (weak)
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors (moderate)
• Cytochrome P-450 CYP3A4 Substrates
• Hypotensive Agents
• Myelosuppressive Agents
• Pyrazines
• QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying)

For treatment of multiple myeloma in patients who have not been successfully treated with at least two previous therapies.

• Mantle Cell Lymphoma (MCL)
• Multiple Myeloma (MM)

Bortezomib is a drug that inhibits the mammalian 26S proteasome. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Tumor cells, that is, rapidly dividing cells, appear to be more sensitive to proteasome inhibition.

83% over the concentration range of 100-1000 ng/ml.

The pathways of elimination of bortezomib have not been characterized in humans.

The mean elimination half-life of bortezomib after first dose ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced malignancies.

• 102 L/h [patients with multiple myeloma following the first dose for doses of 1 mg/m2]
• 112 L/h [patients with multiple myeloma following the first dose for doses of 1.3 mg/m2]
• 15 - 32 L/h [patients with multiple myeloma following subsequent doses for doses of 1 and 1.3 mg/m2]

Cardiovascular safety pharmacology studies in monkeys show that lethal IV doses are associated with decreases in blood pressure, increases in heart rate, increases in contractility, and ultimately terminal hypotension. In monkeys, doses of 3.0 mg/m² and greater (approximately twice the recommended clinical dose) resulted in progressive hypotension starting at 1 hour and progressing to death by 12 to 14 hours following drug administration.

• Humans and other mammals

• Citrus fruits - Patients should avoid taking extra vitamin C (ascorbic acid) supplements and vitamin C-containing multi-vitamins during their bortezomib therapy. Ascorbic Acid may diminish the therapeutic effect of Bortezomib.
• Green Tea - Green Tea may diminish the antineoplastic effect of Bortezomib. Avoid concurrent use of green tea extract and other green tea products during treatment with bortezomib.

1. Adams J, Kauffman M: Development of the proteasome inhibitor Velcade (Bortezomib). Cancer Invest. 2004;22(2):304-11. [PubMed:15199612 ]
2. Bonvini P, Zorzi E, Basso G, Rosolen A: Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma. Leukemia. 2007 Apr;21(4):838-42. Epub 2007 Feb 1. [PubMed:17268529 ]
3. Voorhees PM, Dees EC, O'Neil B, Orlowski RZ: The proteasome as a target for cancer therapy. Clin Cancer Res. 2003 Dec 15;9(17):6316-25. [PubMed:14695130 ]
4. Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD: PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. [PubMed:15953001 ]
5. Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD, Maas J, Pien CS, Prakash S, Elliott PJ: Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res. 1999 Jun 1;59(11):2615-22. [PubMed:10363983 ]
6. Berkers CR, Verdoes M, Lichtman E, Fiebiger E, Kessler BM, Anderson KC, Ploegh HL, Ovaa H, Galardy PJ: Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib. Nat Methods. 2005 May;2(5):357-62. Epub 2005 Apr 21. [PubMed:15846363 ]

• L01XX — Other antineoplastic agents
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

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