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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2108-2121 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.106 Phase I Trial of the Proteasome Inhibitor Bortezomib in Patients With Advanced Solid Tumors With Observations in Androgen-Independent Prostate CancerFrom The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Millennium Pharmaceuticals, Inc, Cambridge, MA. Address reprint requests to Christopher J. Logothetis, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0427, Houston, TX 77030; e-mail: clogothe{at}mdanderson.org
PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m2/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m2).
RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m2 (diarrhea, hypotension) occurring at an average 1-hour post-dose of CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m2. Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.
The ubiquitin-proteasome pathway plays an essential role in the proteolysis of most intracellular proteins in eukaryotic cells. At the heart of this pathway is the 26S proteasome, an adenosine triphosphate–dependent, multicatalytic protease, that degrades damaged, oxidized, or misfolded proteins, as well as regulatory proteins that govern the cell cycle, transcription factor activation, apoptosis, and cell trafficking.1-11
The ordered degradation of key regulatory proteins (p53, p21, p27, cyclins) is required for progression through the cell cycle and mitosis.3 In addition, the activation of the nuclear factor-kappa B (NF- The dipeptidyl boronic acid bortezomib (N-pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid; Millennium Pharmaceuticals, Inc, Cambridge, MA), formerly known as PS-341, is a specific and reversible inhibitor of the proteasome, with a unique pattern of growth-inhibitory and cytotoxic activity against many human cancer cell lines, leading to accumulation of cells in the G2-M phase followed by apoptosis.7
We focused on patients with advanced AIPCa since many of the previously described NF- Preclinical studies showed that bortezomib is rapidly and widely distributed into the extravascular compartment, resulting in plasma levels below 5 ng/mL within 30 to 60 minutes after intravenous (IV) administration. In cynomolgus monkeys, bortezomib produced a dose-dependent inhibition of peripheral blood proteasome activity and predictable sudden severe toxicity when the peripheral blood 20S proteasome inhibition (PI) exceeds 80%.23 The availability of an ex vivo assay for 20S proteasome activity24 made possible the design of a cautious dose-escalation scheme in this phase I study. The primary objective of our study was to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of bortezomib administered IV bolus once-weekly for 4 of 5 weeks. Secondary objectives were to: (1) assess the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in this schedule, (2) evaluate the relationship between toxicity and whole blood 20S PI, and (3) seek preliminary evidence of antitumor activity.
Eligibility Eligibility criteria included: histologically documented advanced solid malignancies refractory to conventional therapy; age  18 years; Zubrod performance status (PS)  2; life expectancy 3 months; adequate organ function (absolute neutrophil count 1,500/µL; platelet count 100,000/µL; total bilirubin 1.5 mg/dL; ALT and AST levels 2.5 times the upper normal limit; creatinine clearance of 50 mL/min), and left ventricular ejection fraction of 50%. Patients with AIPCa had to have serum testosterone 50 ng/dL and progressive disease at least 4 weeks following antiandrogen withdrawal (6 weeks for bicalutamide), defined as either new sites of bone metastases on bone scintigraphy, 25% increase in the sum of the products of diameters of any measurable lesion, or rising PSA level on three consecutive measurements done at least 1 week apart. Testicular androgen suppression (luteinizing hormone-releasing hormone analog) was continued on all patients who did not have an orchiectomy. Patients were excluded if they had chemotherapy or radiotherapy within 4 weeks of study entry; strontium-89 or immunotherapy within 12 weeks of study entry; inflammatory bowel disease; serious medical or psychiatric illness; uncontrolled CNS metastases; significant atherosclerotic disease (peripheral vascular disease requiring surgical management or history of myocardial infarction, heart failure, cerebrovascular accident or transient ischemic attack within 2 years of study entry); electrocardiographic evidence of acute ischemia or significant conduction abnormality; hypertension requiring treatment with calcium-channel-blockers, beta- or alpha-blockers; or longstanding diabetes mellitus. Pregnant or lactating women were ineligible. All patients gave written informed consent in accordance with federal guidelines before enrollment in the study.
Dosage and Dose Escalation
Bortezomib was not administered on scheduled days if there was:
Drug Administration and Supportive Care
Definitions of DLT and MTD
Pretreatment and Follow-Up Studies
Response Criteria
Bioanalytical Methods
Bortezomib Measurement To 100 µL of sample plasma 10 µL of IS at 0.1 ng/µL were added for total concentration of 10 ng/mL. For standards we added 10 µL IS at 0.1 ng/µL, and 10 µL bortezomib to a final concentration of 0.5, 1, 3, 10, 30, and 100 ng/mL. For quality controls we added 10 µL IS and 10 µL bortezomib to a final concentration of 0.5 and 5 ng/mL and vortex to mix. Plasma samples were extracted with 400 µL of ice-cold acetonitrile, 0.1% formic acid. We then evaporated 400 µL of supernatant to dryness in turbovap 96 (approximately 1 hour at 40 l/min; 80°C), reconstituted with 100 µL of 90:10 H2O:ACN, 0.1% formic acid and vortexed gently to mix. Following centrifugation at 5,000 x g in bench top centrifuge the supernatant was transferred to 96 well polypropylene plate and sealed with polypropylene mat. A 20 µL sample was injected into analysis system.
Instrumentation and Conditions Protein precipitation has been demonstrated to be a reproducible method of sample preparation for the analysis of bortezomib in human plasma. Bortezomib is accurately quantitated in human plasma with this method. The lower limit of quantitation has been established as 0.5 ng/mL. The upper limit of quantitation has been established as 100,000 ng/mL. For all of the standards and quality controls tested, coefficient of variation (% deviation) did not exceed 10%. Accuracy was within 15% of theoretical for all standards and quality controls.
20S PI Assay A spectrofluorometric assay was used to assess the level of proteasome activity in blood and tissue biopsies, as previously described.24 Biopsy tissue, approximately 5 mg, was diluted (10:1) with cold phosphate-buffered saline, homogenized, then lysed with 5 mmol/L EDTA (pH 8.0) for 1 hour and processed the same as the whole blood samples for 20S PI determination.
Pharmacokinetic Analysis
Pharmacodynamic Analysis
Statistical Analysis The Fisher's exact test for categoric variables and the nonparametric Mann-Whitney test for continuous variables were carried out whenever appropriate. The Spearman correlation test was used to test the relationship between dose and 20S PI. Univariate and multivariate regression analysis was performed to examine the relationship between 20S PI and categoric grades of specific toxicites (diarrhea, constipation, vomiting, fatigue, hypotension, and neuropathy) and the predictive effects of various covariates (such as age, PS, baseline IL-6 level, albumin, PSA, and hemoglobin) for each type of toxicity. The Wilcoxon rank sum test was used to compare 20S PI with different degrees of toxicity. The Classification and Regression Tree recursive partitioning method, a computer-intensive nonparametric statistical method, was used to search for optimal cutoff value of 20S PI as predictor of outcome variable (ie, toxicity).33 A P value less than .05 was considered significant. All statistical analyses were performed using Splus.34
Fifty-four patients were enrolled; one patient withdrew consent before receiving any drug. Pretreatment characteristics of the 53 patients who received at least one dose of bortezomib are shown in Table 1. Most patients (n = 48; 91%) had AIPCa, and 43 patients (84%) had prior chemotherapy. The characteristics of the 48 AIPCa patients are shown in Table 2.
In all, 128 cycles of bortezomib were delivered; the median number of cycles administered was two (range 0.25 to 15 cycles). One patient was dosed according to his average weight and BSA. Four patients did not complete one cycle (three for rapid disease progression and one for DLT at 2.0 mg/m2). Thirty-one patients completed at least two cycles.
DLT and MTD
Toxicity
Diarrhea and Other Gastrointestinal Symptoms The incidence and severity of diarrhea were dose- and time-dependent. The diarrhea started approximately 12 to 18 hours after bortezomib administration and continued for 1 to 2 days thereafter. In cycle 1, 20 of 53 patients developed diarrhea. Fifteen of these 20 patients were treated at dose levels 1.45 mg/m2/dose. At 1.45 and 1.6 mg/m2/dose levels the diarrhea was usually grade 1 to 2 and self-limited. Only one of 13 patients treated at the 1.6 mg/m2/dose level had grade 3 diarrhea for 1 day that was aborted with loperamide at subsequent bortezomib doses. Patients treated at 1.8 to 2.0 mg/m2/dose levels were instructed to start taking loperamide with the first episode of diarrhea, thereby limiting the diarrhea to grade 1 to 2 for all but two patients treated at the 2.0 mg/m2/dose level, who developed grade 3 diarrhea despite loperamide. Nausea and vomiting were grade 1 to 2 and easily controlled with anti-nausea medications. The rate and severity of nausea did not increase during subsequent treatment cycles. Constipation was generally grade 1 to 2 (one patient developed grade 3 constipation after loperamide treatment).
Fatigue
Cardiovascular Toxicity One patient developed grade 3 hypotension on cycle 3 associated with new onset atrial fibrillation. Hypertension was less common (11 of 53 patients during cycle 1) and was grade 1 to 2 in all but one patient with grade 3 toxicity. Arrhythmia. Only one patient developed significant arrhythmia during cycle 1 (grade 3 atrial fibrillation and hypotension, related to cancer-induced hypoxia, as described earlier). Clinically insignificant arrhythmias were seen in 21 of 53 patients during cycle 1 (mostly sinus bradycardia or tachycardia, or atrial and ventricular premature complexes on routine ECGs). No other ECG abnormalities were noted. The frequency and severity of cardiac arrhythmias did not increase during the second or subsequent treatment cycles. The only significant late cardiac toxicity was one episode of grade 3 atrial fibrillation in a 68-year-old patient during cycle 3, with history of hypertension, emphysema, and palpitations. He presented with diarrhea, nausea, dehydration, and atrial fibrillation that spontaneously converted to normal sinus rhythm after IVFs. The event was clinically attributed to the patient's underlying medical condition, though bortezomib could not be excluded as a causative agent.
Hematologic Toxicities Ten patients developed phlebitis along the long line during cycle 1, treated with topical antiseptics and antibiotics. Only one patient developed low extremity deep vein thrombosis, possibly related to an inferior vena cava filter placed 5 months earlier. Neurologic toxicity potentially attributable to the drug was seen in a minority of patients during the first cycle. New or worse sensory neuropathy grade 1 and 2 was observed in one patient each, at 0.8 and 2.0 mg/m2/dose levels, respectively. One patient at the 1.6 mg/m2/dose level developed ischemic cerebral infarct, considered unrelated as a result of comorbidities. One patient, at the 2.0 mg/m2/dose level, developed serious neurotoxicity (grade 3 syncope) related to bortezomib, as previously described. Subsequent cycles of therapy were not associated with worsening neuropathy except in two patients requiring discontinuation of bortezomib. Both patients had AIPCa and prior KAVE chemotherapy; one patient had pre-existing grade 1 peripheral neuropathy that progressed to grade 2 after the second cycle of treatment, while the second patient developed sudden onset, grade 3 left hip and right shoulder pain, numbness, and dysesthesia with normal motor function during cycle 2. Neurologic evaluation was consistent with acute inflammatory polyradiculopathy. His symptoms improved with discontinuation of bortezomib and short course of steroids.
Pharmacokinetic/Pharmacodynamic Analysis
Plasma profiles were subsequently evaluated using a two-compartment PK model. Overall, the bortezomib plasma profiles in the 24 patients evaluated were quite similar. The majority of the plasma profiles are described by a two-compartment pharmacokinetic model with a rapid initial distribution half-life (t1/2  : 0.22 to 0.46 hours), followed by a more sustained terminal elimination half-life (t1/2ß > 10 hours) and a large (> 500 L) volume of distribution. These results, along with tissue distribution data from animal studies, suggest that after IV administration, bortezomib is rapidly distributed into the extravascular tissues, cleared slowly from them, returning to the systemic circulation to be eliminated by the hepatic and renal routes. We further analyzed the relationship between a measure of body size (BSA) and bortezomib clearance in patients having PK assessments at doses ranging from 1.45 to 2.0 mg/m2 (Fig 2). Substantial scatter was observed suggesting no relationship between patient size and drug clearance over this narrow dose range.
A spectrofluorometric assay measuring the whole blood 20S PI24 served as a guide for dose escalation in this study. The level of 20S PI was low and variable for the patients treated at the lowest dose levels (0.13 to 0.6 mg/m2), probably related to the sensitivity of the assay at low level of inhibition, as the detection limit is 13% inhibition for the ChT:T ratio method.24 Data were more consistent for the remaining dose levels (0.75 to 2.0 mg/m2). Maximum percent 20S PI was seen 1 hour after bortezomib in Cycle 1. One-hour after first treatment, 20S PI data from 43 patients were used in a sigmoid maximum obtainable effect (Emax) PD model. Figure 3 displays the observed dose-response relationship between bortezomib (mg/m2) and 20S PI. The Emax model showed a relatively steep dose-response curve up to 1.3 mg/m2, followed by a tendency to plateau for higher doses, with a calculated ED50 of 0.89 mg/m2 and an Emax of 92%. Similar results were obtained modeling the 1-hour post-dose data according to total dose (mg) and for subsequent days of treatment during cycle 1 (data not shown).
Figure 4 displays the time course of mean percent 20S PI relative to pretreatment baseline in cycle 1 by dose group. A trend was seen across all dose groups with maximum mean percent 20S PI occurring at 1 hour post-dose and a sequential return toward pre-dose baseline from 1 to 6, 6 to 24, and 24 hours post-dose on all treatment days. Overall, there was a dose-dependent increase in the level of 20S PI (Spearman correlation coefficient = 0.89; P < .00001), with similar rates of return toward baseline activity. However, PI was partially reversible with a trend towards decreased rate of recovery of proteasome activity with subsequent weeks of therapy. Tolerance or tachyphylaxis to the effects of bortezomib did not develop. The clinical relevance of an incomplete recovery of proteasome activity is unknown at this time, but may be an explanation for the trend in increased toxicity (diarrhea and fatigue) seen with subsequent weeks and cycles of treatment.
The 20S proteasome activity was measured in tumor samples obtained 2 hours after bortezomib administration from patients with prostate mass (n = 2), lymph node (n = 1), and bone marrow aspirate/biopsy (n = 2) and compared to the level of 20S activity in a matched pretreatment tumor sample and the percent change in 20S activity in blood samples taken before and 1 hour post-bortezomib treatment. For each patient the pretreatment blood proteasome activity was taken as a reference of 100%. In the limited number of patients evaluated, the degree of post-treatment 20S PI in tumor tissue (70% to 90%) was similar to that seen in the peripheral blood (70% to 80%) of the same patient, with the exception of bone marrow biopsy where the 20S PI was approximately half (40% compared to 80%) of that seen in peripheral blood.
Relationship of Bortezomib Pharmacokinetics and Pharmacodynamics
Relationship of Bortezomib Pharmacodynamics and Toxicity Using the Classification and Regression Tree recursive partitioning method33 we found that 20S PI 58% was associated with a statistically significant increased probability to develop grade 1 diarrhea (P = .03), vomiting (P = .05), and fatigue (P = .04), while such a correlation could not be demonstrated for hypotension or constipation. This may reflect the rarity of hypotensive episodes and the presence of other factors contributing to constipation (ie, analgesics, antidiarrheal medications). The level of 20S PI was the only significant predicitive factor for toxicity (diarrhea, constipation, vomiting, hypotension, or fatigue) in the multivariate analysis (independent of age, PS, or baseline IL-6, albumin, hemoglobin, or PSA). The only exception was that patients with higher pretreatment PSA had an increased probability to develop fatigue, probably reflecting higher tumor burden.
Antitumor Activity
When we analyzed the antitumor response in the 24 AIPCa patients treated at dose levels close to the MTD (
Effect of Therapy on Serum IL-6 Levels
The ubiquitin-proteasome pathway is the principal pathway for degradation of intracellular proteins that govern cell cycle, transcriptional factor activation, apoptosis, angiogenesis, and resistance to therapy.1-13 Bortezomib, a potent and selective proteasome inhibitor, induces apoptosis in androgen-dependent and androgen-independent (PC-3 and DU-145) cell lines, suppresses angiogenesis, invasion, and metastasis in PCa, and exhibits antitumor activity against PC-3 prostate cancer xenografts.7,12 Preclinical studies of bortezomib showed sudden, severe, and frequently irreversible toxicity at 80% whole blood proteasome innhibiton.23 Therefore, dosing regimens must be optimized to limit toxicity to normal tissues. We sought to determine the MTD, PK, and PD characteristics of weekly IV bortezomib. This clinical trial represents the first time that bortezomib was administered to humans, the first PK study, and the study that, to date, has involved the highest single dose/m2 in humans. The toxicities observed with bortezomib were generally modest at the recommended dose for phase II studies (1.6 mg/m2 once-weekly for 4 every 5 weeks). The use of the CRM permitted us to enroll large number of patients at dose levels near the MTD and provided us with a high degree of confidence regarding the expected toxicities at these dose levels. Most patients at 1.6 mg/m2 dose level received two or more cycles of bortezomib without experiencing significantly increased toxicities in the second cycle of treatment. As predicted, diarrhea was the most common toxicity; at higher doses, neurologic and cardiovascular side effects also occurred. The incidence and intensity of diarrhea increased with higher doses and subsequent weeks and cycles of therapy. Prompt use of loperamide was effective in avoiding severe diarrhea in all patients except those treated at the highest dose level. In this study, there was no evidence that resistance to loperamide occurred on subsequent cycles of therapy, though this should be studied further. At the 2.0 mg/m2 dose level, two of five patients developed DLT (grade 3 diarrhea and postural hypotension and syncope, reminiscent of autonomic dysfunction). In contrast to reports from other phase I studies,35,36 peripheral neuropathy was less frequent (8%), even though 39 (74%) of 53 patients had prior chemotherapy, including neurotoxic drugs. All episodes of new or worse neutopathy seen during the first two cycles occurred in patients previously treated with neurotoxic chemotherapy. The lower incidence of peripheral neuropathy in this study may be a reflection of the patient population treated or of the treatment schedule utilized. It is possible that the weekly schedule may be less neurotoxic. Further studies are needed to clarify the relationship between these toxicities and dose-schedules of bortezomib administration. Hypotension was generally modest and reversible with hydration, except in the patient treated at 2.0 mg/m2 dose level. The mechanism of hypotension remains unclear and does not appear to be related to adrenal dysfunction, infectious process, or cardiac arrhythmias/decompensation; possible explanations include autonomic nerve dysfunction as observed in the patient with DLT and/or dehydration. Based on our results, a dose of 1.6 mg/m2 is recommended as a starting dose in phase II studies testing a once-weekly for 4 of 5 weeks treatment cycle. The primary pharmacokinetic objective of this study was to complete the development of a specific, sensitive, and reproducible analytic method for measuring plasma concentrations of bortezomib. This became possible as a result of samples made available from this study. The method has a lower limit of quantitation of 0.5 ng/mL, and is currently being used in other clinical studies to characterize the pharmacokinetics of bortezomib. Bortezomib concentrations in plasma from 24 patients were determined throughout the development of the analytic method. The combination of PK data from all patients in a given dose group, obtained by different analytic methods, is done so with the understanding that the goal was to get an initial characterization of the kinetic disposition of bortezomib across all dose groups. The kinetic disposition of bortezomib appears to be described by a biphasic disappearance from the plasma with a rapid initial rate (< 10 minutes), followed by a slower terminal phase (on average > 20 hours). More pharmacokinetic data is needed to appropriately characterize the steady-state kinetics of multiple doses in humans. In this study, there appears to be no relationship between BSA and clearance of bortezomib. These data should be interpreted with caution though, given the small number of patients tested over a very narrow dose range. As a result of the limited nature of data obtained in this small study, we believe the data presented in this manuscript could at best be used to give a global view of the pharmacokinetics of bortezomib, rather than point to a specific relationship between BSA and bortezomib clearance. This will be examined in two ongoing phase II PK studies with much larger populations. The relationship between plasma concentration and proteasome inhibition over a 24-hour period was studied (Fig 5) and greater confidence in the data and correlation was obtained with the newer analytic method. With the dose and schedule employed, there appears to be a maximum level of 20S inhibition of 70% to 75%, which suggests that the inhibition of 20S activity is saturable. In the narrow dose range analyzed (1.45 to 2.0 mg/m2), the 24-hour measurements demonstrate a fairly homogeneous recovery of 20S activity, while the 1-hour concentrations demonstrate a heterogeneous eight-fold range in plasma concentration associated with a rather homogeneous response in reduction of 20S activity of approximately 70%. There is an obvious disconnect between plasma bortezomib pharmacology and suppression of 20S activity. It may be that the most interesting pharmacology occurs in the 0- to 1-hour interval, or more probably that the intercellular pharmacology is more informative than plasma bortezomib PK. Further, the observed clinically relevant efficacy and toxicity occurred at saturation (plateau) levels of 20S PI (65% to 80%) where there appears to be no relationship between plasma bortezomib concentration and 20S activity. Finally, as discussed earlier, there is insufficient data to assess relationship between bortezomib dose and PK parameters. Thus, there can be no dosing suggestion based on dose, plasma bortezomib concentration, AUC, or measurement of 20S plasma activity, as no data (at least presented in this manuscript) exists to support such a recommendation. The ex vivo PD assay could be used as predictor of toxicity up to 65% 20S PI. The ex vivo measurement of proteasome activity has little predictive value for toxicity at levels of proteasome inhibition greater than 65%; most adverse events occurred at doses between 1.6 to 2.0 mg/m2, which result in 65% to 75% 20S PI, but the severity of adverse events did not correlate with the degree of 20S PI at this range. Inhibition of the proteasome activity was partially reversible by the time of the next dose administration with this weekly schedule. This may explain the increased diarrhea and fatigue in subsequent weeks and cycles of treatment, and should be studied in phase II studies. In nonclinical studies, normal and tumor tissue 20S inhibition was found to correlate with the level of inhibition observed in the whole blood, therefore defending the use of the whole blood assay of proteasome activity as relevant. In our study, the 20S proteasome activity in biopsy samples paralleled that measured in peripheral blood. This suggests that blood 20S proteasome activity may be a reasonable surrogate marker for the drug activity in target tissues. Given the small number of biopsy specimen tested (two prostate, one lymph node, one bone marrow aspirate, and one biopsy) this observation requires further study.
This study incorporates prospective serial assessments of antitumor activity, peripheral blood proteasome inhibition, and downstream signaling on putative NF-
Our clinical observations support that bortezomib has manageable toxicities at 1.6 mg/m2 and may possess antitumor activity in AIPCa. The administration of bortezomib once-weekly for 4 of 5 weeks, resulted in dose-dependent proteasome inhibition, up to 65% 20S PI, which was associated with predictable toxicity. Bortezomib has biologic activity against AIPCa; however, the responses were generally modest and of short duration. Preclinical studies demonstrate synergy between bortezomib and chemotherapy, with bortezomib reversing the chemotherapy-induced and NF
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Julian Adams, Millennium Pharmaceuticals; Dixie Esseltine, Millennium Pharmaceuticals; Alexandria Petrusich, Millennium Pharmaceuticals. Acted as a consultant within the last 2 years: Dixie Esseltine, Millennium Pharmaceuticals. Performed contract work within the last 2 years: Dixie Esseltine, Millennium Pharmaceuticals. Received more than $2,000 a year from a company for either of the last 2 years: Julian Adams, Millennium Pharmaceuticals; Dixie Esseltine, Millennium Pharmaceuticals; Peter Elliot, Millennium Pharmaceuticals.
Supported in part by CaPCURE and Millennium Pharmaceuticals Inc. Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12–15, 2001. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
B), a key transcription factor, is dependent on proteasome-mediated degradation of the inhibitory protein I
