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.

greater 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. 

 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; IÎºÎ², an inhibitor of nuclear factor-kappa beta (NF-ÎºÎ²); 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 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] 


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-ÎºB.[16,18-21] NF-ÎºB 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-Î±, 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.

-Two phase I trials have evaluated singleagent bortezomib for the treatment of refractory and/or relapsed hematologic malignancies and solid tumors.[23- 25] Orlowski and colleagues[23] evaluated a twice-weekly regimen of bortezomib in patients with refractory hematologic malignancies; the maximum tolerated dose was 1.04 mg/m

 administered twice weekly for 4 weeks of a 6-week cycle. Proteasome inhibition was dose-dependent, with the maximum tolerated dose providing 60% ± 1% inhibition; proteasome activity returned toward baseline within 72 hours. Electrolyte disturbances, particularly hyponatremia and hypokalemia, and cytopenias were common at the maximum tolerated dose; thrombocytopenia was the most common maximum tolerated dose- related cytopenia, but patients experienced a recovery of their platelet counts to their baseline level or higher before starting the next cycle. Evidence of antitumor activity was noted for 9 of 9 assessable patients with multiple myeloma, with 1 patient obtaining a complete response.

Twice-weekly bortezomib was also evaluated in patients with advanced solid tumors.[24] The original publication of this study suggested a maximum tolerated dose of 1.56 mg/m2 administered twice weekly for 2 weeks of a 3-week cycle; however, the dose recommended for further clinical study by the principal investigator was 1.3 mg/m2.[25] Again, PI was dose dependent, with the 1.3 mg/m2 maximum tolerated dose providing 65% inhibition and the 1.56 mg/m2 maximum tolerated dose producing 68% inhibition.[24] Cytopenias were less common with this regimen, with only one episode of grade 3 anemia reported with bortezomib 1.3 mg/m2.[24] Although grades 3/4 neutropenia and thrombocytopenia were not reported at this dose, bortezomib 1.56 mg/m2 was associated with the development of these hematologic toxicities as well as dose-limiting toxicities of grade 3 diarrhea and grade 3 sensory neuropathy. Diarrhea and sensory neuropathy may also have been dose related. In this heavily pretreated patient population, one patient with non-smallcell lung cancer (NSCLC) had a partial response and three patients (nasopharyngeal carcinoma, malignant melanoma, and renal cell carcinoma, one each) experienced stable disease. The median duration of stable disease was 4 months (range: 2.5-5 months). Several ongoing phase I or I/II studies are evaluating different regimens in both hematologic malignancies and solid tumors, including bortezomib once weekly for 4 weeks repeated every 6 weeks and twice weekly every other week.[26-28]

Bortezomib in Combination With Chemotherapy

-Several phase I studies have evaluated bortezomib combined with various chemotherapy agents for the treatment of hematologic malignancies and solid tumors (Table 1).[29-33] For example, bortezomib combined with liposomal doxorubicin (Doxil) was evaluated in 41 patients with refractory hematologic malignancies.[29] This combination was selected because preclinical study results suggested that PI by bortezomib may enhance tumor sensitivity to anthracyclines by downregulating the activation of the NF-ÎºB and p44/42 MAPK pathways.[6]

During cycle 1, grade 3 or 4 adverse events at the maximum tolerated dose included thrombocytopenia, constipation, neuropathy, and hyperglycemia; however, repeated administration of the first-cycle maximum tolerated dose necessitated dose reductions and delays.[29] Therefore, the dose recommended for phase II trials (ie, bortezomib 1.3 mg/m2 twice weekly for 2 weeks and liposomal doxorubicin 30 mg/m2 on day 4, with cycles repeated every 3 weeks) was lower than the maximum tolerated dose reported during cycle 1. This combination displayed disease activity not only in patients with multiple myeloma, but also in patients with acute myelogenous leukemia, non- Hodgkin's lymphoma (NHL), Hodgkin's disease, myelodysplastic syndromes, and chronic lymphocytic leukemia. As in phase I studies evaluating bortezomib alone, PI was dose dependent and did not increase with the use of liposomal doxorubicin.[29] Phase I studies assessed bortezomib combined with either gemcitabine, gemcitabine and carboplatin (Paraplatin), irinotecan, or 5-FU/leucovorin, in patients with solid tumors (see Table 1).[30-33] Various doses of bortezomib and gemcitabine were evaluated; the maximum tolerated dose was bortezomib 1 mg/m2 and gemcitabine 1,000 mg/m2.[30] Table 1 lists the toxicities at the maximum tolerated dose. One patient with relapsed metastatic NSCLC experienced a partial response despite previous treatment with numerous chemotherapy agents, including gemcitabine. Activity of bortezomib in NSCLC was also reported with gemcitabine and carboplatin.[31] The maximum tolerated dose in this trial was bortezomib 1 mg/m2, gemcitabine 1,000 mg/m2, and carboplatin at an area under the concentration-time curve of 5 (see Table 1). Four patients experienced a partial response and seven patients experienced stable disease.[ 31] In the irinotecan-bortezomib trial, the maximum tolerated dose was bortezomib 1.3 mg/m2 and irinotecan 125 mg/m2.[32] Although concern about additive toxicities, particularly diarrhea, exists with this combination, no grade 3 or 4 adverse events were reported at the maximum tolerated dose. Two patients, one with gastroesophageal junction adenocarcinoma (unconfirmed) and one with ovarian cancer, achieved a response (unspecified). Weekly 5-FU/leucovorin has also been evaluated with bortezomib (see Table 1).[33] The maximum tolerated dose was bortezomib 0.7 mg/m2 with 5-FU 500 mg/m2, and leucovorin 20 mg/m2. One patient with esophageal cancer experienced a partial response and eight patients with either colorectal cancer or anal cancer experienced stable disease.[33] Several other phase I or I/II studies are evaluating bortezomib in combination with chemotherapy agents, including liposomal doxorubicin, docetaxel, and carboplatin.[34-37] The results of these and ongoing phase I trials evaluating single-agent bortezomib are eagerly awaited and may define the optimal regimen of bortezomib as a single agent or in combination with other agents.


Phase II clinical trials have evaluated bortezomib administered twice weekly for 2 weeks, with cycles repeated every 3 weeks, as treatment of solid tumors (bortezomib alone) or hematologic malignancies (bortezomib alone or in combination with dexamethasone) (Table 2).[25,38-44] The largest study, the SUMMIT trial, evaluated bortezomib in 202 patients with multiple myeloma who had received a median of six prior therapies (see Table 2).[25,38] Of 193 assessable patients, 7 patients (4%) achieved a complete response, 12 (6%) acheived a near complete response, and 34 (18%) achieved a partial response; responses occurred independent of the number and type of previous therapies.[38] Additionally, response rates in patients with a chromosome 13 abnormality, a poor prognostic indicator, and patients without this abnormality did not differ.[25] The median time to disease progression in all 202 patients receiving bortezomib was 7 months, which was significantly longer than the median time to disease progression (3 months) with the last prior treatment patients had received before study entry (

 = .01).[38] Table 2 lists the grade 3 and 4 toxicities associated with bortezomib administration. A smaller study (the CREST trial) evaluated bortezomib in 54 patients with relapsed or refractory multiple myeloma who had received a median of three prior therapies.[39] Bortezomib 1 or 1.3 mg/m

 was administered using the same schedule as that in the SUMMIT trial (see Table 2).[39] The overall response rate (complete plus partial response) in 53 assessable patients was 30% and 38% for the 1- and 1.3-mg/m

 groups, respectively, with one complete response observed at each dose level.[39] The median time to disease progression was 212 days for the 1-mg/m

 group.[39] In both the SUMMIT and CREST trials, patients with disease progression or stable disease after two and four cycles, respectively, could receive dexamethasone 20 mg orally on the day of and the day after bortezomib administration; 78 patients in the SUMMIT trial and 28 patients in the CREST trial received dexamethasone.[ 40] The addition of dexamethasone improved response rates in 18% and 33% of patients in the SUMMIT and CREST trials, respectively, including patients refractory to dexamethasone alone. The median time to disease progression for these patients was 5.7 months (SUMMIT) and 6.8 months (CREST). Importantly, the addition of dexamethasone did not increase toxicities associated with single- agent bortezomib.[40] A phase II study evaluated bortezomib 1.3 mg/m

 in patients with mantle cell lymphoma (MCL) who had received 0 to 2 prior therapies.[41] Of 13 assessable patients, 5 patients (38.5%) experienced a partial response and 5 patients (38.5%) experienced stable disease. Five patients experienced treatment-limiting fluid retention and/or dyspnea. Therefore, the investigators modified the protocol to exclude patients with preexisting fluid retention or dyspnea.[41] Two additional phase II studies have evaluated 1.5 mg/m

 bortezomib in patients with relapsed or refractory NHL.[42,43] In one study, patients with MCL experienced a 48% response rate (complete, 26%; partial, 22%). Responses were also observed in other B-cell lymphomas, including one complete response (follicular lymphoma) and two partial responses (one diffuse large cell lymphoma, one Waldenstrm's macroglobulinemia).[ 42] A second study produced similar results, with an overall response rate of 55%, including a 7% complete response rate (follicular lymphoma) and 48% partial response rate (17% follicular lymphoma, 21% MCL, 3% small-cell lymphocytic lymphoma-chronic lymphocytic leukemia, 7% marginal zone lymphoma).[ 43] Toxicities in both studies were manageable, with the most common grade 3 or 4 toxicities being thrombocytopenia and lymphopenia, respectively (see Table 2).[42,43] Bortezomib 1.5 mg/m

 has also been evaluated in patients with stage 4 renal cell carcinoma who had received minimal pretreatment (median: 1 prior therapy).[ 44] Dose escalation to 1.7 mg/m

 was permitted beginning with cycle 2 in patients who developed less than or equal to grade 2 toxicities during cycle 1. Twenty-one patients received a total of 74 treatment cycles: 34 cycles at 1.7 mg/m

. One patient had a partial response, and six patients had stable disease; enrollment in this study was ceased because of a lack of response. Toxicities reported were similar to toxicities reported in other trials (see Table 2). Although 10% of patients experienced grades 3 or 4 neuropathy, the incidence for all grades of neuropathy was 47%. A correlation between the number of doses given or the cumulative dose of bortezomib and the development of neuropathy was not observed. Kondagunta and colleagues[45] conducted a similar study in 37 metastatic renal cell cancer patients who had either received no prior therapy (49%) or cytokine therapy alone (51%). Bortezomib 1.5 mg/m

 was administered to the first 25 patients enrolled in the study; however, the dose was decreased to 1.3 mg/m

 for the subsequent 12 patients, because more than 50% of the patients receiving bortezomib 1.5 mg/m

 required toxicity-related dose reductions, primarily due to grade 2 or 3 peripheral neuropathy, fatigue, thrombocytopenia, and anemia. A partial response was observed in 4 patients (11%) and stable disease in 14 patients (38%). In the four patients with a partial response, durations of response ranged from 8 to more than 20 months. The median time to disease progression was 1.4 months and the median survival time was 7.5 months (median follow-up: 11.7 months [range: 3.7- 20.9 months]). Peripheral neuropathy occurred in 27% of all patients, 28% of patients receiving bortezomib 1.5 mg/m

. The authors concluded that only a small portion of patients with renal cell carcinoma are likely to respond to bortezomib therapy and do not recommend routine use of bortezomib in this patient population.[45] 

 Bortezomib has also been evaluated in patients with hepatocellular carcinoma, soft tissue sarcoma, and NSCLC.[46-49] Preliminary results of these studies suggest promising activity of bortezomib in patients with metastatic or recurrent sarcomas and advanced NSCLC.[46-49] 

 The results of a retrospective multivariate analysis have reported predictors of response to bortezomib in patients with refractory or relapsed multiple myeloma.[50] Older age (ie, ≥ 65 years) was associated with a lower response rate and longer time to treatment response; however, age was not predictive of duration of response, time to disease progression, or overall survival time.[50] Elevated levels of C-reactive protein and the presence of more than 50% plasma cells in the bone marrow were predictive of a longer time to treatment response. Low albumin levels and Karnofsky performance scale scores were predictors of shorter response duration and overall survival time. Additionally, elevated levels of C-reactive protein and abnormal cytogenetics were found to be predictors of shorter time to disease progression, and the presence of more than 50% plasma cells in bone marrow and low platelet counts were associated with a decreased overall survival time.[50] Another predictor of response may be an increase in bone alkaline phosphatase level without an increase in gamma glutaryl transferase level, which occurred in patients with multiple myeloma who responded to combination therapy with bortezomib, thalidomide (Thalomid), and dexamethasone.[ 51] Finally, pharmacogenomics may predict time to disease progression after treatment with bortezomib; preliminary results indicate that numerous genes associated with proliferation, survival, signaling, and the UPP correlate with time to disease progression.[50] Although these prognostic factors may enable clinicians to predict which patients will have a better response to bortezomib, their use is currently limited to patients with refractory or relapsed multiple myeloma. Future studies are warranted to address the clinical applicability of these prognostic factors to other types of malignancies. 


Studies of bortezomib have usually investigated eight or fewer cycles. Berenson and colleagues[52] evaluated the long-term use of bortezomib, with or without dexamethasone, in 59 patients with refractory or relapsed multiple myeloma initially treated with eight cycles of bortezomib, with or without dexamethasone. Bortezomib alone (median duration: 12 cycles; range: 7-24 cycles) or in combination (median duration: 5 cycles, range: 0-17 cycles) appeared to be well tolerated.[52] Interestingly, the incidence of peripheral neuropathy, gastrointestinal complaints (eg, nausea, vomiting, constipation), fatigue, rash, and neutropenia decreased in patients receiving more than eight cycles of bortezomib; however, the incidence of lower-extremity edema increased compared with patients who received eight or fewer cycles of bortezomib.[ 38,52] Possible explanations for these differences in adverse events include improved management of adverse events, smaller sample size, number of patients receiving dexamethasone, and bias in reporting only responding patients. Although bortezomib has been administered for as long as 32 cycles in some patients, the optimal duration of therapy with this agent has not been defined.[52] The phase III, international, multicenter Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial is also evaluating longterm bortezomib therapy in patients with earlier-stage relapsed or refractory multiple myeloma (patients having received one to three prior therapies).[53] Patients receive induction therapy with either (1) bortezomib 1.3 mg/m

 twice weekly for 2 weeks, with cycles repeated every 3 weeks for 8 cycles, followed by weekly bortezomib for 4 weeks, with cycles repeated every 5 weeks for 3 cycles; or (2) oral dexamethasone 40 mg/d on days 1 through 4, 9 through 12, and 17 through 20 repeated every 5 weeks for 4 cycles, followed by 40 mg/d on days 1 through 4 every 28 days for 3 cycles. Depending on the response, patients in either treatment arm may continue therapy for up to 10 months.[54] A planned interim analysis demonstrated a 58% improvement in median time to disease progression (bortezomib, 5.7 mo vs dexamethasone, 3.6 mo; 

 < .0001). Patients treated with bortezomib had a higher incidence of grade 3 or 4 hematologic, gastrointestinal, and nervous system adverse events, whereas patients treated with dexamethasone had a higher incidence of grade 3 or 4 psychiatric, metabolic, and infectious adverse events.[53] Based on time to disease progression and an early survival advantage for bortezomib, the data monitoring committee recommended that the study be closed early and bortezomib offered to all patients treated on the dexamethasone arm. 

Quality of Life and Cost-Effectiveness of Bortezomib


Bortezomib has primarily been evaluated in patients with advanced or refractory cancers. In these patients, the goals of therapy are usually costeffective prolongation of survival and improvement of quality of life. In the SUMMIT trial, quality of life was assessed using validated quality-of-life questionnaires (eg, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire- C30).[55] Responding patients experienced a decrease in disease symptoms, pain, fatigue, and an overall improvement in their quality of life compared with baseline.[55] These improvements may have been associated with an increase in normal immunoglobulin levels, improved hemoglobin levels and platelet counts, better renal function, and decreased requirement for red blood cell transfusions, all of which were observed in responding patients. However, quality- of-life data by its nature is subjective and was collected in an unblinded manner. Furthermore, no internal control group existed, and bortezomib's effect on quality of life in nonresponding patients was not reported. Despite these limitations, results of the SUMMIT trial showed bortezomib to be cost-effective compared with best-supportive care or thalidomide, with a marginal cost-per-lifeyear gain of $49,807 and $21,758, respectively.[56] 

 Proteasome inhibition is a new and promising treatment option for certain patients with cancer. The proteasome inhibitor bortezomib is the first agent in this novel class of antineoplastics to be studied in clinical trials and receive FDA approval. Preclinical study results suggest that bortezomib has a unique mechanism of action and may display selective targeting of malignant cells over normal cells. Furthermore, these study results suggest that bortezomib may overcome resistance of cancer cells to standard chemotherapy agents and radiation therapy in patients with relapsed or refractory disease. Results of studies evaluating bortezomib in patients with renal cell carcinoma are mixed.[44] Additionally, the use of bortezomib in combination with chemotherapy may allow for the use of lower doses of cytotoxic chemotherapy agents, which may minimize toxicity and decrease the likelihood of developing drug resistance.[57,58] Bortezomib has been investigated primarily as a salvage therapy. However, current and future trials are now and will be investigating bortezomib as first-line therapy.[59,60] Finally, a fuller understanding about the regulation of the cell cycle and interactions among various proteins may lead to the use of bortezomib in combination with other targeted, nonstandard chemotherapy agents.[61]

Dr. Dalton has received grant support from Millennium Pharmaceuticals, Inc.

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Dreicer R, Roth B, Petrylak D, et al: Phase I/II trial of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer (abstract/poster 4654). Proc Am Soc Clin Oncol 23:418, 2004.


 Aghajanian C, Dizon D, Yan XJ, et al: Phase I trial of PS-341 and carboplatin in recurrent ovarian cancer (abstract 1815). Proc Am Soc Clin Oncol 22:452, 2003.


 Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003.


 Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Cancer 127:165-172, 2004.


 Jagannath S, Richardson P, Barlogie B, et al: Phase II trials of bortezomib in combina tion with dexamethasone in multiple myeloma: assessment of additional benefits to combination in patients with sub-optimal response to bortezomib alone (abstract/poster 2341). Proc Am Soc Clin Oncol 22:582, 2003.


 Assouline S, Belch A, Sehn L, et al: A phase II study of bortezomib in patients with mantle cell lymphoma (abstract/poster 3358). Blood 102:902a-903a, 2003.


 Goy A, Younes A, McLaughlin P, et al: Update on a phase 2 study of bortezomib in patients with relapsed or refractory indolent or aggressive non-Hodgkin’s lymphoma (abstract/ poster 6581). Proc Am Soc Clin Oncol 23:575, 2004.


 O’Connor OA, Wright J, Moskowitz CH, et al: Marked clinical activity of the novel proteasome inhibitor bortezomib in patients with relapsed follicular and mantle cell lymphoma (abstract/poster 6582). Proc Am Soc Clin Oncol 23:576, 2004.


 Davis NB, Taber DA, Ansari RH, et al: Phase II trial of PS-341 in patients with renal cell cancer: A University of Chicago Phase II Consortium Study. J Clin Oncol 22:115-119, 2004.


 Kondagunta GV, Drucker B, Schwartz L, et al: Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol. 22:3720-3725, 2004.


 Hegewisch-Becker S, Sterneck M, Schubert U, et al: Phase I/II trial of bortezomib in patients with unresectable hepatocellular carcinoma (HCC) (abstract/poster 4089). Proc Am Soc Clin Oncol 23:334, 2004


 Maki RG, Kraft A, Demetri GD, et al: A phase II multicenter study of proteasome inhibitor PS-341 (LDP-341, bortezomib) for untreated recurrent or metastatic soft tissue sarcoma (STS); CTEP study 1757 (abstract 3291). Proc Am Soc Clin Oncol 22:819, 2003.


 Stevenson JP, Nho CW, Johnson SW, et al: Phase II/pharmacodynamic trial of PS-341 (bortezomib, Velcade) in advanced non-small cell lung cancer (abstract/poster 7145). Proc Am Soc Clin Oncol 23:649, 2004.


 Fanucchi M, Belt RJ, Fossella F, et al: Phase 2 study of bortezomib ± docetaxel in previously treated advanced non–small cell lung cancer patients: interim analysis (abstract/ poster 7107). Proc Am Soc Clin Oncol 23:640, 2004 .


Richardson PG, Barlogie B, Berenson J, et al: Prognostic factors for response parameters and overall survival in patients with multiple myeloma (MM) following treatment with bortezomib (abstract 1629). Paper presented at the Annual Meeting of the American Society of Hematology; San Diego, December 6-9, 2003.


Articles

Proteasome inhibition is a novel, targeted approach in cancertherapy. Both natural and synthetic proteasome inhibitors selectivelypenetrate cancer cells, disrupting the orderly destruction of key regulatoryproteins involved in tumorigenesis and metastasis. Disrupting theorderly destruction of regulatory proteins causes an imbalance of theseproteins within the cell, which interferes with the systematic activationof signaling pathways required to maintain tumor cell growth and survival;therefore, cellular replication is inhibited and apoptosis ensues.

Discovery, Development, and Clinical Applications of Bortezomib

Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasome inhibitor with antitumor activity against a number of hematologic and nonhematologic malignancies. Based on the results of phase II clinical trials, bortezomib received accelerated US Food and Drug Administration approval on May 13, 2003, for the treatment of multiple myeloma patients whose disease has progressed after they have received at least two prior conventional therapies. The results of phase III studies evaluating bortezomib as first- or second-line therapy, or in combination with other commonly prescribed therapies in multiple myeloma patients, are eagerly awaited. Studies assessing the antitumor effects of bortezomib in other hematologic malignancies and solid tumors are also under way. A thorough understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of this novel compound is essential for appropriate prescribing and monitoring of bortezomib therapy. Bortezomib is rapidly distributed into tissues after administration of a single dose, with an initial plasma distribution half-life of less than 10 minutes, followed by a terminal elimination half-life of more than 40 hours. Maximum proteasome inhibition occurs within 1 hour and recovers close to baseline within 72 to 96 hours after administration. Bortezomib is primarily metabolized by oxidative deboronation to one of two inactive enantiomers that are further processed and eliminated, both renally and in bile. Bortezomib has been shown to be a substrate of several cytochrome P450 isoenzymes using in vitro systems. Adverse effects of bortezomib are generally mild and effectively managed with supportive care. Bortezomib should be administered with caution to patients with preexisting fluid retention and patients with baseline platelet counts of less than 70,000/Î¼L. Dose reductions are recommended for patients experiencing peripheral neuropathy, grade 3 or higher nonhematologic toxicities, or grade 4 hematologic toxicities. Formal drug interaction studies have not been performed, but bortezomib has been administered in combination with a variety of antitumor agents without significant alterations to its pharmacokinetic or pharmacodynamic profile.

ormal cellular function and homeostasis depend on precisely controlled intracellular processes, including the systematic and highly regulated degradation of proteins that control cellular division, growth, function, and death.[1-3] For example, regulation of the cell cycle depends on the orderly degradation of cyclins and inhibitors of the cyclin-dependent kinases.[1] If the systematic degradation of proteins is interrupted, regulatory proteins accumulate within the cell, creating an imbalance in the number of proteins required to elicit certain cellular functions, such as progression from the G1 to the S phase of the cell cycle or activation of signal transduction pathways.[ 4,5] In eukaryotic cells, the ubiquitinproteasome pathway (UPP), comprising a ubiquitin-conjugating system and the proteasome, is primarily responsible for the degradation of cellular proteins and plays an important role in many basic cellular processes.[ 5-7] The list of cellular proteins controlled by the UPP is growing rapidly and includes, in addition to the cell-cycle regulatory proteins (eg, cyclins, cyclin-dependent kinase inhibitors), proteins involved in chromatid separation, oncogenes and tumor suppressor genes, and transcriptional activators and inhibitors.[5,7-10] Another important function of the UPP is the selective removal of mutated and denatured or misfolded proteins, as well as proteins damaged by stress, oxidation, chemicals, or viral infection.[ 1,8,10] Aberrations in the UPP have been implicated in the pathogenesis of many diseases, including certain malignancies. For example, degradation of the p53 tumor suppressor gene or p27 inhibitor of cyclin-dependent kinases can promote tumorigenesis of various malignancies, including uterine, colon, breast, and prostate cancers.[ 1,7,8] Inhibiting the activity of the proteasome, one of the key constituents of the UPP, can block cellular growth and division, ultimately leading to cell death. Because the proteasome is responsible for degrading more than 80% of cellular proteins in eukaryotic cells, its inhibition would seem incompatible with life.[5] However, the results of preclinical and early-phase clinical studies show that proteasome inhibition (PI) can arrest the growth of tumor cells, induce apoptosis, inhibit angiogenesis, and increase the sensitivity of tumor cells to chemotherapy or radiation therapy, without having a major deleterious effect on nontumor cells.[3,11-13] Based on these results, a number of synthetic PIs have been developed and evaluated as antitumor agents. Bortezomib (PS-341, Velcade), the first proteasome inhibitor to be evaluated in humans, received US Food and Drug Administration (FDA) approval for the treatment of patients with multiple myeloma previously treated with two or more therapies and with disease progression on the last therapy.[5,14-17] This article summarizes the pharmacology, pharmacokinetics, and current practical applications of bortezomib. 

 To understand more clearly the mechanism of action of bortezomib (Figure 1), a basic understanding of the proteasome's role in the UPP and the consequences of PI are required.[ 1,18] 


Protein degradation by the UPP involves two discrete and successive steps: (1) tagging of the substrate (protein to be destroyed) by covalent attachment of multiple ubiquitin molecules, and (2) degradation of the tagged protein by the 26S proteasome.[ 7,8] Ubiquitin molecules are attached to the target protein by the sequential activity of three enzymes: E1, E2, and E3. E1, the ubiquitinactivating enzyme, activates the ubiquitin molecule through an adenosine 5'-triphosphate (ATP)-dependent reaction and transfers it to one of many different E2 or ubiquitin-conjugating enzymes. The ubiquitin molecule is then transferred to the target protein in a step that requires the E3 enzyme (ubiquitin protein ligase). Eukaryotic cells contain hundreds of E3 enzymes, each with the ability to recognize different degradation signals on proteins. Ubiquinated proteins are then recognized and degraded by the 26S proteasome.[ 1,6-9] The 26S proteasome is a multifunctional proteolytic complex that consists of a proteolytic core particle, the 20S proteasome, and two 19S regulatory particles.[7] The 20S core particle consists of four stacked rings: two identical outer rings (Î± rings) and two identical inner rings (Î² rings). The Î± and Î² rings are composed of seven distinct subunits, giving the 20S complex the general structure of Î± 

. The proteolytic sites are localized on the Î²1, Î²2, and Î²5 subunits of the two inner Î² rings. Each end of the 20S core is capped with a 19S regulatory particle, which recognizes polyubiquinated proteins, cleaves the polyubiquitin chain from the target protein (the polyubiquitin chain can then be disassembled by deubiquitinating enzymes and recycled into the UPP), unfolds proteins that would be unable to fit through the narrow proteasomal channel, and opens the channel in the Î± ring to permit entry of the target protein into the proteolytic chamber. The opening of the channel requires metabolic energy, and each 19S regulatory particle contains six different ATPase subunits that provide energy upon hydrolysis by ATP. After the protein is degraded by the 20S core particle, short peptides are released into the cytosol of the cell. Because the active sites (Î² subunits) of the proteasome are confined to the inner cavity of the 20S core particle, uncontrolled degradation of cellular proteins cannot occur.[1,2,6-9] The beta subunits of the 20S core particle contain three types of proteolytic sites: chymotrypsin-like sites, trypsin-like sites, and caspase-like sites.[1,6,9] These sites differ in their specificity for the types of protein residues (eg, hydrophobic residues and acidic residues) at which they cleave. Although the 26S proteasome has several active sites, inhibition of all three sites is not required to significantly reduce protein processing. Specific inhibition of the chymotrypsin-like site by bortezomib significantly reduces protein processing (Ki = 0.6 nM). Most inhibitors of chymotrypsin-like sites are more highly hydrophobic and cell-permeable than inhibitors of the trypsin- or caspase-like sites, which contain charged residues; therefore, most proteasome inhibitors act predominantly on the chymotrypsinlike sites and to a much lesser degree on the other two sites.[1] 


Various natural and synthetic proteasome inhibitors-all of which bind to and directly inhibit the active sites within the 20S core particle of the proteasome-have been identified.[ 1,5,11-13] Impeding the degradation of regulatory proteins through PI results in accumulation of several important regulatory proteins, including the inhibitor of nuclear factorkappa beta (NF-ÎºB), IÎºB, the p53 tumor suppressor gene, the p21 and p27 cyclin-dependent kinase inhibitors, and the bax protein.[1,5,13,19- 22] Accumulation of these proteins leads to decreased NF-ÎºB activity, increased p53-mediated transcription of genes important in apoptosis and dysregulation of the cell cycle, increased p21- and p27-mediated induction of cell cycle arrest, and promotion of apoptosis by inhibition of Bcl-2 by bax.[1,5,13,19-22] Proteasome inhibition also downregulates the p44/42 mitogen-activated protein kinase (MAPK)-induced signals required for tumorigenesis.[1,5] As a result of these and other incompletely understood effects of PI, proteasome inhibitors inhibit tumor cell proliferation, induce apoptosis, and inhibit angiogenesis. As mentioned previously, the results of several preclinical studies have shown cancer cells to be more sensitive to the effects of PI than are normal cells. For example, patientderived chronic lymphocytic leukemia cells are about 10 times more sensitive to PI than are normal human lymphocytes.[20] Although the biologic basis for the enhanced susceptibility of cancer cells to PI has not been fully elucidated, several hypotheses exist, including a greater sensitivity of rapidly proliferating cells (eg, tumor cells) to PI and more efficient uptake and slower inactivation of proteasome inhibitors by tumor cells.[1,5] Other theories focus on the deregulation of various UPP functions during the malignant transformation of a cell. For example, low levels of the bax proapoptotic protein resulting from an upregulation of UPP activity have been associated with higher Gleason scores in prostate cancer patients.[22] Proteasome inhibition blocks the degradation of this protein, resulting in higher intracellular levels and increased apoptosis.[22] In addition to producing antitumor effects, proteasome inhibitors sensitize both chemosensitive and chemoresistant cancer cells to conventional chemotherapy.[ 5,12,13,18,19,23,24] For example, the combination of bortezomib with irinotecan (Camptosar) was more effective in inhibiting tumor growth in mice than either irinotecan or bortezomib alone.[23] Combined with subtoxic doses of bortezomib, melphalan (Alkeran), doxorubicin, and mitoxantrone (Novantrone) exhibit cytotoxic effects on chemoresistant multiple myeloma cell lines at drug concentrations 100,000- to 1,000,000-fold lower than concentrations required for cytotoxicity in the absence of bortezomib.[24] Proteasome inhibitors also play a role as radiation therapy sensitizers. In a mouse colon cancer model, a single dose of radiation therapy and bortezomib produced significantly lower tumor volumes and increased apoptosis rates compared with radiation therapy alone.[25] These combination therapies did not increase cytotoxic or radiotoxic effects on normal bone marrow cells in healthy, cancer- free individuals. The mechanisms by which proteasome inhibitors reverse chemotherapy or radiation therapy resistance are not completely understood, although downregulation of NF-ÎºB has been shown to play an important role in abrogating drug resistance.[5,23] For example, NF-ÎºB activity in multiple myeloma cell lines resistant to melphalan, mitoxantrone, and doxorubicin is greater than NF-ÎºB activity in nonresistant multiple myeloma cell lines; treatment with subtoxic doses of bortezomib attenuated NF-ÎºB activity, sensitizing the resistant cells to treatment with these agents.[22] Proteasome inhibitors may also downregulate other resistance pathways, including the p44/42 MAPK pathway, which is activated by certain chemotherapy agents, such as the taxanes and anthracyclines. In a murine xenograft model of breast cancer, proteasome inhibitors have been shown to block doxorubicin-mediated activation of the p44/42 MAPK pathway, which correlates with increased apoptosis and antitumor efficacy.[5] Proteasome inhibitors have shown a broad spectrum of activity in preclinical models. The dipeptide boronic acid bortezomib is a specific and reversible inhibitor of the chymotrypsin- like activity of the 26S proteasome. While many other proteasome inhibitors have been synthesized and tested in preclinical models, bortezomib is the only one to be clinically evaluated in cancer patients and approved for clinical use.[1,5,13-17] 

 Bortezomib is a potent, selective, and reversible inhibitor of the chymotrypsin- like activity of the 26S proteasome (see Figure 1). Preclinical and early-phase study results revealed that bortezomib was active against a broad range of hematologic and solid tumors, with tolerable effects on normal tissues.[3-5,11-14] The results of a phase I dose-determining study by Aghajanian and colleagues[3] showed that PI increases with increasing doses of bortezomib, with approximately 65% PI occurring after administration of the manufacturer-recommended dose of 1.3 mg/m

. Maximum inhibition of 20S activity occurs within 1 hour after bortezomib administration; 20S activity returns toward baseline within 72 to 96 hours.[26,27] No significant difference in the mean percentage of PI was observed with administration of subsequent doses on days 4, 8, and 11, suggesting that 72 hours between administration is sufficient for recovery of proteasome function in normal tissues.[3] 

 The pharmacokinetics of bortezomib have not been fully characterized in multiple myeloma patients.[16] The pharmacokinetics have been investigated in two phase I studies in patients with solid tumors receiving combination therapy of bortezomib and irinotecan or gemcitabine (Gemzar).[28,29] After intravenous (IV) bolus administration, bortezomib quickly distributes into tissues from the plasma.[17,27,28,30] The distribution half-life is less than 10 minutes, followed by a long elimination half-life (> 40 hours).[27] In animal studies using radiolabeled bortezomib, bortezomib was rapidly distributed into nearly all tissues, with the exception of adipose tissue and certain tissues in the brain protected by the blood-brain barrier.[30] Following extensive tissue distribution of radiolabeled bortezomib, a slow terminal elimination rate was observed, with only 65% (females) to 85% (males) of the total dose recovered from monkeys after 144 hours.[30] Plasma protein binding of bortezomib is considered moderate (approximately 83%) and was not shown to be concentration dependent over the concentration range studied (100 to 1,000 ng/mL).[17] The results of in vitro studies suggest that bortezomib is metabolized primarily through oxidative deboronation (the removal of boronic acid from the parent compound), which can be mediated by multiple cytochrome P450 system isoenzymes, including 3A4, 2C19, 1A2, 2D6, and 2C9.[16,17,31] Deboronation produces two inactive enantiomers that subsequently undergo further metabolic processing and are eliminated by both renal and hepatic routes.[30,32] More than 30 inactive metabolites have been identified in animal and human studies. Pharmacokinetics studies of bortezomib in patients with renal or hepatic insufficiency have not been completed; however, studies evaluating bortezomib in these patient populations are under way with the National Cancer Institute's Organ Dysfunction Group.[17,33] Clinical trials included patients with creatinine clearance values ranging from 13.8 to 220 mL/min.[17] No correlation between creatinine clearance and maximum PI at 1 hour, the incidence of grade 3 or 4 adverse effects, or discontinuation rates have been observed.[ 33] Patients with reduced renal function have displayed response and treatment discontinuation rates comparable to those in patients with more normal renal function and were able to receive a comparable number of bortezomib doses.[33] The pharmacokinetics in patients either undergoing hemodialysis or with a creatinine clearance value less than 13 mL/min have not been completely described.[17] The appropriate dosage of bortezomib in patients who were more than 30% above their ideal body weight was calculated based on average body weight ([actual body weight - ideal body weight]/2); however, the effectiveness of this method for determining an appropriate dose in obese patients is unknown.[34] Bortezomib use has not been evaluated in pediatric patients, although a pharmacokinetics study of bortezomib administered to pediatric patients is under way.[17] 

 Based on the results of two phase II clinical trials, the SUMMIT and CREST trials, bortezomib received accelerated FDA approval on May 13, 2003, for the treatment of multiple myeloma patients whose disease has progressed after they have received at least two prior conventional therapies.[ 16,17,35] Studies evaluating bortezomib as first- and second-line therapy for multiple myeloma patients, including a phase III, multicenter, randomized trial comparing bortezomib with high-dose dexamethasone in relapsed multiple myeloma patients, are under way.[14,16,35] Additional phase I or II studies evaluating bortezomib alone or combined with standard chemotherapy agents as multiple myeloma treatment and as treatment of solid tumor and other hematologic malignancies have shown promising results.[36-42] For a more indepth discussion of the clinical uses of bortezomib, refer to the article entitled "Discovery, Development, and Clinical Applications of Bortezomib" found in this supplement. Because bortezomib is a novel, first-in-class proteasome inhibitor approved for use in relapsed or refractory multiple myeloma, clinicians prescribing or monitoring bortezomib therapy should be educated about its effects in humans. Although additional studies are needed to define more clearly the effects of bortezomib administered either alone or in combination with other antitumor agents for various cancers, the results of phase I and II studies have provided useful information about monitoring the toxicity of bortezomib in relapsed or refractory multiple myeloma patients whose disease has relapsed or whose disease is refractory to conventional therapies. 


In the SUMMIT and CREST phase II trials, the most common adverse effects in multiple myeloma patients receiving bortezomib 1.3 mg/m

, included fatigue (65%), nausea (64%), diarrhea (51%), thrombocytopenia (43%), anorexia (43%), peripheral neuropathy (37%), vomiting (36%), pyrexia (36%), anemia (32%), peripheral edema (25%), and dyspnea (22%).[16,17] Table 1 lists the severe (grades 3 and 4) adverse effects observed in these trials.[16,17] Most toxicities were mild to moderate in severity (grades 1 or 2) and did not require discontinuation or delay of bortezomib therapy. 

 Treatment was withheld in patients experiencing grade 3 or higher nonhematologic toxicities or grade 4 hematologic toxicities.[14] Retreatment with a 25% dose reduction (ie, reduced from 1.3 to 1.0 mg/m

 were not permitted) was allowed in patients who experienced a lessening in the severity of the adverse effect to a grade 1 or lower level.[14] Bortezomib-related toxicities that required treatment discontinuation, including peripheral neuropathy (5%), thrombocytopenia (4%), fatigue (2%), and diarrhea (2%), developed in 18% of patients.[17] In another phase II trial in mantle cell lymphoma patients receiving bortezomib, Assouline and colleagues[ 43] reported five cases of severe fluid retention in patients with baseline dyspnea or peripheral edema. Two patients died: one died of grade 4 acute vascular leak syndrome and the other died of progressive disease with severe edema. The other three patients experienced dyspnea and peripheral edema or hypoxia and peripheral edema. Based on these results, the authors amended their study to exclude patients with baseline dyspnea or fluid retention. Interestingly, less than 5% of multiple myeloma patients enrolled in the SUMMIT and CREST trials experienced grade 3 or 4 dyspnea or edema; presumably these patients showed no signs of fluid retention at study entry.[17] Nevertheless, patients with preexisting fluid retention, especially in the presence of dyspnea or hypoxia, should not receive bortezomib therapy, and patients should be instructed to report any signs of fluid retention promptly to their caretaker. Because of the potential need for dosage adjustment or requirement for premedication, several adverse events associated with bortezomib merit further discussion, including peripheral neuropathy, hypotension, thrombocytopenia, and gastrointestinal effects.

 Risk factors for the development of hypotension after bortezomib therapy include (1) history of syncope, (2) concomitant use of medications known to lower blood pressure (ie, antihypertensive agents), and (3) dehydration.[ 17] Hydration status should be assessed and corrected, if necessary, before and throughout bortezomib therapy, especially in patients experiencing nausea and/or vomiting. Additionally, patients receiving antihypertensive medications should be closely monitored to determine if antihypertensive medication dosage adjustment is necessary. Mineralocorticoids were effective in minimizing the hypotensive effects of bortezomib therapy in some patients.[17] Finally, patients and/or caregivers should be instructed to report signs or symptoms of hypotension (eg, lightheadedness, dizziness, syncope) immediately to a healthcare professional, maintain adequate hydration, and exercise caution when operating machinery, including automobiles. In patients experiencing grade 3 hypotension, the bortezomib dose should be discontinued until symptoms resolve, at which time a 25%- reduced dose of bortezomib may be implemented (see Table 2).[17]

 in these trials experienced a median 60% decrease in their baseline platelet count during therapy regardless of initial baseline platelet count, baseline serum myeloma paraprotein (M-protein) level, or degree of multiple myeloma bone marrow involvement.[ 46] The onset of thrombocytopenia most commonly occurred after cycles 1 or 2 and continued throughout therapy.[17] Platelet counts typically reached a nadir on day 11 and rose to a normal count by day 21. Cerebral and gastrointestinal hemorrhages secondary to bortezomib- induced thrombocytopenia were rarely reported.[17] Patients with a baseline platelet count of less than 70,000/Î¼L had an increased risk of developing grade 4 thrombocytopenia.[ 46] Furthermore, patients with greater bone marrow involvement (ie, > 50% plasma cells) or higher Mprotein levels (> 31 g/L) usually had lower baseline platelet counts and lower platelet count nadirs. Thrombocytopenia caused by bortezomib therapy presumably results from an inhibition of thrombopoiesis, an NF-ÎºB-dependent process, rather than direct bone marrow toxicity; therefore, supportive care, rather than discontinuation of bortezomib therapy, may be adequate for controlling bortezomib's effects on platelet production.[46] Platelet counts should be monitored throughout bortezomib therapy, and therapy should be discontinued in patients with platelet counts less than 25,000/Î¼L (grade 4 thrombocytopenia) until the platelet count returns to normal.[17] Bortezomib can be reinitiated at a 25%-reduced dose when platelet counts return to baseline levels. Patients and/or caregivers should be educated about the risks of bleeding and instructed how to manage a bleeding episode.

-Gastrointestinal adverse effects, including nausea, vomiting, diarrhea, constipation, and/or anorexia, are common in patients receiving bortezomib therapy. Nausea, vomiting, and diarrhea should be anticipated and may warrant premedication with antiemetics or antidiarrheals.[ 16] Ensuring adequate hydration and electrolyte levels in patients experiencing nausea, vomiting, diarrhea, or constipation helps to reduce the consequences of these adverse effects. Although therapy discontinuation due to gastrointestinal adverse effects was required in only 5% of patients, grade 3 or 4 events occurred in 21% of patients.[17]

Dose Modifications Due to Adverse Effects


The recommended bortezomib dose for multiple myeloma is 1.3 mg/m2 administered as a 3- to 5-second IV bolus.[14,17] Administration is repeated twice weekly for 2 weeks, with a minimum of 72 hours between doses to allow for restoration of proteasome function in normal cells.[17] Each cycle of four doses is followed by a 10-day rest (ie, bortezomib is administered on days 1, 4, 8, and 11, followed by no administration on days 12 through 21). Dose modifications are recommended to manage peripheral neuropathy, grade 3 nonhematologic toxicities, and grade 4 hematologic toxicities (see Table 2).[17] 


Although formal drug interaction studies of bortezomib have not been conducted, the results of phase I or II clinical trials evaluating bortezomib in combination with other chemotherapy agents, including docetaxel (Taxotere), gemcitabine, or irinotecan (Camptosar), have shown no alteration in the pharmacokinetics or pharmacodynamics (ie, degree of 20S PI) of any of these drugs when concurrently administered.[17,28,47-50] Additionally, toxicities associated with the combination of bortezomib and dexamethasone were similar to toxicities of bortezomib or dexamethasone alone, suggesting that no interaction occurs with concomitant administration of these agents.[51] Results of in vitro studies demonstrate that bortezomib is a substrate of several isoenzymes in the cytochrome P450 system.[17] Further studies are warranted to characterize the disposition of bortezomib when administered with other substrates or inhibitors of the P450 metabolic system. 

 Proteasome inhibition is a promising new anticancer therapy that inhibits one target, but affects multiple pathways. Bortezomib, which possesses highly selective and reversible PI activity, is the first commercially available proteasome inhibitor. The adverse effects of bortezomib are generally well tolerated and, with standard supportive care measures, manageable. The most common severe adverse effects include peripheral neuropathy, fluid retention, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea. Bortezomib is currently approved for the treatment of multiple myeloma in patients whose disease has progressed after they have received at least two prior therapies. Ongoing studies are evaluating the efficacy and safety of bortezomib as first- or second-line treatment of multiple myeloma and in the treatment of other malignancies.

Dr. Schwartz has acted as a speaker for Millennium Pharmaceuticals, Inc.

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Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasomeinhibitor with antitumor activity against a number of hematologic andnonhematologic malignancies.

Pharmacology, Pharmacokinetics, and Practical Applications of Bortezomib

hroughout my career, I have collaborated with many colleagues who share a common goal of mapping and reversing the molecular mechanisms involved in the malignant transformation of plasma cells and resistance of myeloma cells to chemotherapy drugs. Over the years, I have had the privilege of participating in and witnessing the discovery of numerous promising molecular targets, which has led to the development of many unique antitumor drugs; however, the marketing of a compound that significantly impacts the lives of cancer patients is still rare. One such compound that recently entered the market is bortezomib (PS-341, Velcade), a proteasome inhibitor with impressive antitumor activity in multiple myeloma and promising activity in other hematologic malignancies and solid tumors. Research regarding the antitumor benefits of proteasome inhibition, including reversal of de novo or acquired chemotherapy and radiation therapy resistance, led to the development and clinical use of bortezomib. Bortezomib induces apoptosis and increases sensitivity or reverses resistance to standard chemotherapy agents in a wide variety of cancer cell lines, with relatively few toxic effects on normal cells. As a single agent or in combination with irinotecan (Camptosar), gemcitabine (Gemzar) with or without carboplatin (Paraplatin), liposomal doxorubicin (Doxil), or fluorouracil/leucovorin, bortezomib has demonstrated activity against multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's disease, acute myelogenous leukemia, chronic lymphocytic leukemia, non-small-cell lung cancer, prostate cancer, and other human tumor xenografts. The clinical development of bortezomib has been rapid and compelling, with promising results observed in patients with relapsed or refractory multiple myeloma. The results of a phase II trial evaluating bortezomib in 202 multiple myeloma patients with highly refractory disease showed a 27% overall response rate, including a 3.6% complete response rate, 6.2% near complete response rate, and 17.6% partial response rate. Based on the results of this and other phase II trials, the US Food and Drug Administration approved bortezomib as treatment of multiple myeloma in patients whose disease has progressed after they have received at least two prior conventional therapies. The most common adverse effects reported with bortezomib in clinical trials included gastrointestinal events (ie, nausea, vomiting, diarrhea, constipation, anorexia), asthenia, thrombocytopenia, peripheral neuropathy, pyrexia, and anemia. Most toxicities were mild to moderate in severity. Bortezomib should be administered with caution in patients with preexisting fluid retention or baseline platelet counts of less than 70,000/Î¼L. Patients with preexisting peripheral neuropathy, a history of neurotoxic drug use, or cardiovascular instability should be monitored closely during therapy. This supplement, based on a symposium held at the 8th Annual "Making A Difference in Oncology" (MADONC) conference, summarizes the clinical development and applications of bortezomib. In the first article (see page 4), Laura Jung, Lisa Holle, and I summarize the preclinical, phase I, and phase II clinical trials of bortezomib, including predictors of response in patients with relapsed or refractory multiple myeloma and the effects of bortezomib on quality of life in responding patients. The second article (see page 14), by Rowena Schwartz and Terri Davidson, focuses on the pharmacology of bortezomib, including its mechanism of action, pharmacokinetics, pharmacodynamics, and toxicities. Recommendations for prescribing and monitoring bortezomib therapy are also provided. Bortezomib is the first treatment in more than a decade to be approved for patients with multiple myeloma. It is the first in a new class of antitumor agents, the proteasome inhibitors, which hold promise as treatment for a variety of hematologic malignancies and solid tumors, including tumors resistant to cytotoxic drugs. In addition to their use as an antitumor agent, proteasome inhibitors have potential as treatment of several noncancer diseases, including neurodegenerative diseases, cystic fibrosis, and various immune or inflammatory responses, the pathogeneses of which include proteasomes. We eagerly await the results of current and planned studies assessing this compound in various tumor types and other diseases.

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Throughout my career, I have collaborated with manycolleagues who share a common goal of mappingand reversing the molecular mechanisms involvedin the malignant transformation of plasma cells and resistanceof myeloma cells to chemotherapy drugs. Over theyears, I have had the privilege of participating in andwitnessing the discovery of numerous promising moleculartargets, which has led to the development of manyunique antitumor drugs; however, the marketing of a compoundthat significantly impacts the lives of cancer patientsis still rare.

ONCOLOGY Vol 18 No 14_Suppl_11 | Oncology

Discovery, Development, and Clinical Applications of Bortezomib

Pharmacology, Pharmacokinetics, and Practical Applications of Bortezomib

Proteasome Inhibition in Hematologic Malignancies: Clinical Update and Practical Applications