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Discovery, Development, and Clinical Applications of Bortezomib

Discovery, Development, and Clinical Applications of Bortezomib

Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. Bortezomib (PS-341, Velcade), the first proteasome inhibitor evaluated in human clinical trials, has been approved by the US Food and Drug Administration for use in patients with refractory or relapsed multiple myeloma. Preclinical study results show that bortezomib suppresses tumor cell growth, induces apoptosis, overcomes resistance to standard chemotherapy agents and radiation therapy, and inhibits angiogenesis. Phase I study results established the antitumor activity of bortezomib, administered alone or in combination with standard chemotherapy agents, in patients with advanced hematologic malignancies or solid tumors, usually without additive toxicities. The results of phase II studies further supported the antitumor activity of bortezomib in patients with refractory or relapsed multiple myeloma and non- Hodgkin’s lymphoma; less impressive results were observed in patients with stage IV renal cell cancer. Studies evaluating bortezomib in earlier stages of multiple myeloma, including first-line therapy, are under way. Evidence suggests that certain prognostic factors, such as older age and bone marrow containing more than 50% plasma cells, may be useful in predicting response and survival time in multiple myeloma patients receiving bortezomib. Further studies of bortezomib are needed to establish its full spectrum of activity, the ideal regimens for various tumor types, and clinically useful prognostic indicators that predict successful outcomes.

Agreater understanding of cancer molecular biology has led to the development of several agents that target specific intracellular signal transduction pathways involved in cancer cell development and progression.[1] One pathway, the ubiquitin-proteasome pathway (UPP), is primarily responsible for the systematic degradation of cell cycle regulatory proteins and has recently received considerable attention.[2,3] In cancer cells, the UPP is essential to the mechanisms underlying tumorigenesis and metastasis, including cell cycle arrest, apoptosis, and angiogenesis.[ 2] Disruption of the UPP, particularly in rapidly dividing cancer cells, can potentially arrest or retard cancer progression by interfering with mechanisms that confer malignant properties to the cell.[4-6] Furthermore, disruption of the UPP may interrupt and potentially reverse mechanisms of de novo and acquired resistance to chemotherapy or radiation therapy.[6] A variety of proteasome inhibitors, both natural and synthetic, have been shown to disrupt the UPP pathway.[4- 6] In 2003, the first proteasome inhibitor, bortezomib (PS-341, Velcade), was approved by the US Food and Drug Administration (FDA) for the treatment of recurrent and/or refractory multiple myeloma. In 2004, the European Commission also approved the use of bortezomib for this indication in European Union member countries.[7] This article reviews proteasome function and inhibition, the results of preclinical studies demonstrating tumoricidal effects of proteasome inhibition (PI), and the results of phase I and II clinical trials evaluating bortezomib in the treatment of various hematologic malignancies and solid tumors. Proteasome Function and Inhibitors Cellular homeostasis and the ability of cells to function in their environment depend on the systematic degradation of regulatory proteins and their inhibitors.[4] The majority of proteins in eukaryotic cells are degraded by the UPP, which consists of a ubiquitin-conjugating system and proteasome.[6,8] For a protein to be recognized by a proteasome, several ubiquitin molecules must first attach to the side of the target protein, a process carried out by a cascade of enzymes; this polyubiquinated sidechain flags the protein for destruction by a proteasome.[5] Proteasomes are responsible for degrading more than 80% of all cellular proteins- including several important proteins that regulate tumor cell survival, proliferation, invasion and metastasis, angiogenesis, and apoptosis-such as the cyclin B1 cell-cycle regulatory protein; the p53 tumor suppressor gene; the p21 and p27 cyclin-dependent kinase inhibitors; Iκβ, an inhibitor of nuclear factor-kappa beta (NF-κβ); the p44/42 mitogen-activated protein kinase (MAPK); and the bax proapoptotic protein.[4-6] Proteasome inhibition results in accumulation of these cellular proteins, resulting in antitumor effects, such as cell-cycle arrest, apoptosis, and downregulation of angiogenesis.[ 6] Because proteasomes are essential components of eukaryotic cell protein degradation, PI would seemingly kill both normal and malignant cells. However, all cells do not respond similarly to PI. The results of several preclinical studies suggest that malignant cells are more susceptible to PI than are normal cells.[9,10] The molecular basis for this differential susceptibility of cells to PI remains undetermined, although several interesting theories are being investigated.[5,6,9] For a more in-depth discussion of UPP and PI, refer to the article entitled "Pharmacology, Pharmacokinetics, and Practical Applications of Bortezomib" in this supplement. Numerous natural and synthetic compounds inhibit the activity of proteasomes. Many of these compounds bind to and interfere with the chymotrypsin- like activity (one of three types of proteolytic activity within the proteasome) of the proteasome.[4,9] However, many of these inhibitors also lack specificity for the proteasome, have poor metabolic stability, or bind irreversibly to the proteasome.[ 4,5] An ideal proteasome inhibitor would exhibit metabolic stability, enzyme specificity, reversible binding to the proteasome, and selective cytotoxicity toward malignant cells.[2] The natural proteasome inhibitors include lactacystin, expoxyketones (epoxomicin and eponemycin), and TMC-95 cyclic peptides. The synthetic compounds include the peptide vinyl sulfones, peptide aldehydes (MG132 and PSI), and the peptide boronic acids.[4,5] The peptide aldehydes were one of the first groups of proteasome inhibitors discovered. However, their fast dissociation rate from the proteasome and their rapid transportation out of the cell by the multidrug resistance (MDR) transporter limited their usefulness as a therapeutic strategy.[9] Because of these limitations, the peptide boronic acids, were developed by replacing an aldehyde group with boronic acid; peptide boronic acids have a slower dissociation rate and up to 1,000-fold higher potency than those of the peptide aldehydes.[4,5] The peptide boronic acids are selective for proteasomes and form covalent and reversible complexes within the chymotrypsin- like site of proteasomes, thereby inhibiting proteasome activity.[ 5,11] Bortezomib Bortezomib is a peptide boronic acid and the first proteasome inhibitor to be approved for use in humans. The results of a preclinical study by the National Cancer Institute (NCI) in 60 cancer cell lines determined that bortezomib had substantial in vitro cytotoxicity against multiple human tumors.[11] The NCI also compared the mechanism of cytotoxicity of bortezomib with that of 60,000 compounds and determined bortezomib's mechanism to be unique.[11] Although the exact mechanism of cytotoxicity of bortezomib and other proteasome inhibitors has yet to be fully elucidated, inhibition of proteasomes by these agents affects numerous cellular pathways, all of which result in increased apoptosis of affected cells.[11] Preclinical Data
The NCI study results showing the cytotoxic activity of bortezomib led to the evaluation of this agent in numerous murine xenograft models, representing a wide variety of malignancies (eg, multiple myeloma and colorectal, pancreatic, prostate, and ovarian cancers).[10-14] In these models, bortezomib decreased tumor volume, confirming its in vivo effectiveness as an antineoplastic agent. Bortezomib also demonstrated an increased tumoricidal effect in human xenografts when combined with various standard chemotherapy agents, including cisplatin, docetaxel (Taxotere), fluorouracil (5-FU), gemcitabine (Gemzar), irinotecan (Camptosar), and paclitaxel.[12-15] Results of preclinical studies of multiple myeloma cell lines have also demonstrated the ability of bortezomib to circumvent chemotherapy or radiation resistance and inhibit angiogenesis.[ 16-22] The primary mechanism by which bortezomib overcomes drug resistance may be the downregulation of NF-κB.[16,18-21] NF-κB activity in resistant myeloma cell lines is higher than that in nonresistant cell lines.[16] Bortezomib also downregulates or disrupts other resistance pathways or mechanisms, such as the p44/42 MAPK pathway, topoisomerase II-α, Bcl-2, or the transcription of genes involved in DNA damage repair.[18,19] Furthermore, bortezomib is not a substrate for the multidrug resistance protein, a protein that is overexpressed in tumors resistant to a variety of chemotherapy agents.[19] Bortezomib's effects on the tumor microenvironment include disruption of cellular adhesion of cancer cells to bone marrow stromal cells; this adhesion is recognized as a principal promoter of tumor cell growth and survival. Cell-cell adhesion initiates the production of growth factors (eg, interleukin-6) that stimulate tumor resistance to chemotherapy.[17,18] Finally, bortezomib has been shown to inhibit tumor angiogenesis, probably as a result of decreased vascular endothelial cell growth factor secretion and high levels of endothelial cell apoptosis. In preclinical models, bortezomib markedly decreased microvessel density and inhibited the activity of proangiogenic cytokines (eg, vascular endothelial growth factor [VEGF]).[16,22] The ability of bortezomib to inhibit tumor cell proliferation, selectively induce apoptosis in proliferating cells, alter the tumor microenvironment, inhibit angiogenesis, and overcome resistance to standard therapies encouraged investigators to initiate clinical trials with this agent.

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