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Annals of Oncology Advance Access originally published online on January 21, 2008
Annals of Oncology 2008 19(5):871-876; doi:10.1093/annonc/mdm569
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

breast cancer

A phase I/II study of bortezomib and capecitabine in patients with metastatic breast cancer previously treated with taxanes and/or anthracyclines

P. Schmid1,*, D. Kühnhardt2, P. Kiewe3, S. Lehenbauer-Dehm2, W. Schippinger4, R. Greil5, W. Lange6, J. Preiss7, N. Niederle8, P. Brossart9, W. Freier10, S. Kümmel11, H. Van de Velde12, A. Regierer2 and K. Possinger2

1 Medical Oncology, Imperial College London, Charing Cross Hospital, London, UK
2 Department of Oncology and Haematology, Charite Campus Mitte, Berlin
3 Department of Haematology, Oncology and Transfusion Medicine, Charite Campus Benjamin Franklin, Berlin, Germany
4 Department of Oncology and Haematology, Universitaetsklinikum, Graz
5 3rd Medical Department of Oncology and Haematology, Private Medical University Hospital Salzburg, Salzburg, Austria
6 Department of Oncology and Haematology, Johanniter-Krankenhaus Rheinhausen, Duisburg
7 Department of Oncology and Haematology, Caritasklinik St Theresia, Saarbrücken
8 Department of Oncology and Haematology, Klinikum Leverkusen, Leverkusen
9 Department of Oncology and Haematology, Universitätsklinikum, Tübingen
10 Practice for Oncology and Haematology, Hildesheim
11 Department of Gynecology and Obstetrics, University of Duisburg-Essen, Duisburg, Germany
12 Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

* Correspondence to: Dr P. Schmid, Charing Cross and Hammersmith Hospital, Imperial College London, Fulham Palace Road, London W6 8RF, UK. Tel: +44-20-8846-1418; Fax: +44-20-8846-1433; E-mail: p.schmid{at}imperial.ac.uk


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Background: Proteasome inhibitors are a novel class of compounds entering clinical trials as a method to increase tumour sensitivity to standard chemotherapy. This phase I/II trial was carried out to evaluate the combination of capecitabine and the proteasome inhibitor bortezomib in anthracycline and/or taxane-pretreated patients with metastatic breast cancer.

Patients and methods: A total of 35 patients were treated with bortezomib (1.0–1.3 mg/m2 on days 1, 4, 8 and 11) and capecitabine (1500–2500 mg/m2 on days 1–14) in 3-week intervals for up to eight cycles.

Results: The maximum tolerated doses (MTDs) were bortezomib 1.3 mg/m2 and capecitabine 2500 mg/m2. The treatment was generally well tolerated and associated with toxic effects that were consistent with the known side-effects of the individual agents. The intent-to-treat overall response rate was 15% and an additional 27% of patients had stable disease (SD). In the 20 patients treated at the MTD, the response rate was 15% and 40% had SD. Median time to progression and overall survival were 3.5 months [95% confidence interval (CI) 1.9–4.4] and 7.5 months (95% CI 5.6–14.6), respectively. Median duration of response was 4.4 months.

Conclusion: The combination of bortezomib and capecitabine is well tolerated and has moderate antitumour activity in heavily pretreated patients.

Key words: bortezomib, capecitabine, chemotherapy, metastatic breast cancer, phase I study, proteasome inhibition


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
Breast cancer remains the leading cause of death from cancer among women worldwide, accounting for >400 000 deaths per year. Currently available treatments are unable to eradicate metastatic breast cancer (MBC). Consequently, treatment goals are to prolong survival, prolong disease control and to provide better palliation for patients. Though an expanding array of active agents has become available, overall survival (OS) has changed little in the last 30 years. While response rates between 20% and 40% for single-agent treatment and 40%–60% in combination regimens are routinely achieved in previously untreated patients, response rates decrease significantly in patients previously exposed to chemotherapy.

Patients with MBC who have progressed after anthracyclines and taxanes have limited treatment options. The oral fluoropyrimidine capecitabine has shown significant single-agent activity in MBC that has progressed during or after anthracycline and/or taxane therapy, achieving response rates between 9% and 14% in phase III trials and a median progression-free survival (PFS) of 4.1–4.4 months [1–3].

Further therapeutic advances require new strategies that are on the basis of an understanding of breast cancer biology. The ubiquitin–proteasome pathway plays an important role in regulating the cell cycle, neoplastic growth and metastasis [4]. A number of key regulatory proteins are temporally degraded during the cell cycle by the proteasome, and the ordered degradation of these proteins is required for the cell to progress through the cell cycle and undergo mitosis [5–7]. Some of these factors have also been reported to inhibit the apoptotic response to chemotherapy and thus contribute to drug resistance.

Bortezomib (VELCADE, Millennium Pharmaceuticals, Inc., Cambridge, MA and Johnson & Johnson Pharmaceutical Research & Development LLC, Raritan, NJ) is a first-in-class, highly selective and potent inhibitor of the 26S proteasome. Preclinical research has shown that bortezomib may block chemotherapy-induced activation of the anti-apoptotic survival factor nuclear factor-kappa B (NF-{kappa}B) and augment the apoptotic response to chemotherapeutic agents. Bortezomib also appeared to increase the stabilisation of the cell cycle regulators p21 and p27, as well as the tumour suppressor p53. In preclinical models of breast and other cancers, bortezomib inhibited tumour growth and demonstrated anti-angiogenic properties [8–12]. Bortezomib exhibited the greatest activity when combined with standard chemotherapeutic agents, including irinotecan, docetaxel or 5-fluorouracil (5-FU), indicating its potential additive/synergistic role in overcoming resistance to conventional chemotherapy. This phase I/II study was therefore carried out to evaluate the combination of capecitabine and bortezomib in pretreated patients with MBC.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 funding
 Acknowledgements
 References
 
study design
This phase I/II study was conducted at 11 centres in Germany and Austria. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Harmonised Tripartite Guidelines for Good Clinical Practice, in compliance with local regulations, and with the institutional review boards of each participating centre.

objectives
The primary objectives were to determine the maximum tolerated disease (MTD) for bortezomib and capecitabine and to evaluate the objective response rate. Secondary objectives included evaluation of time to progression (TtP), duration of response (DR), OS and safety.

patient population
Eligible patients had to have histologically confirmed MBC and one or two prior lines of chemotherapies for metastatic disease including anthracyclines and/or taxanes. Patients were required to have measurable disease. All patients had to have adequate haematological, renal and hepatic function [haemoglobin > 8 g/dl; absolute neutrophil count (ANC) > 1.5 x 109/l; platelets > 75 x 109/l; serum bilirubin level < 1.5 x upper limit of normal (ULN) and serum creatinine level ≤ ULN], a Karnofsky performance status ≥60 and an estimated life expectancy ≥12 weeks. Written informed consent was required before enrolment.

Exclusion criteria included brain metastases, bone metastases as the only site of metastases, radiotherapy within 4 weeks before study entry, a history of other prior malignancies (except for curatively treated nonmelanoma skin cancer or carcinoma in situ of the cervix), significant cardiac disease or any other serious medical or psychiatric conditions which would impair the ability of the patient to receive protocol treatment. Pregnant or lactating women were ineligible.

study treatment
Patients were treated with bortezomib (1.0–1.3 mg/m2 as i.v. injection on days 1, 4, 8 and 11) and capecitabine (750–1250 mg/m2 twice daily orally on days 1–14) in 3-week cycles. Within the phase I part, doses were assigned at registration according to the dose escalation scheme (Table 1). For the phase II part, the MTDs were used. Treatment was planned for eight cycles unless there was evidence of unacceptable toxicity or disease progression. Patients received prophylactic anti-emetic therapy with 5-hydroxytryptamine 3-antagonists before each application of bortezomib.


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  		Table 1. Dose escalation and DLTs (phase I part)

 
dose escalation
Dose escalation and determination of the MTD were on the basis of the occurrence of dose-limiting toxicities (DLTs) during cycle 1. DLT were defined as (i) any grade 3 or 4 non-haematologic toxicity other than nausea or vomiting, (ii) febrile neutropenia or grade 4 neutropenia for >4 days, (iii) grade 4 thrombocytopaenia or thrombocytopaenia of any grade associated with bleeding or (iv) any grade 2 and more toxicity (other than nausea, vomiting, alopecia or anaemia) that persisted over day 35 of the first cycle.

At least three patients assessable for toxicity were treated at each dose level. If none of the first three patients experienced DLT, the next dose level was started. If DLT occurred in one patient, three additional patients were treated at the same level. Dose escalation was only continued, if DLT were observed in no more than one patient of the expanded cohort. If DLT occurred in more than or equal to two patients, dose escalation was stopped and subsequent patients were treated at the previous level. This dose level was defined as the MTD, if DLT occurred in less than or equal to one of six patients.

dose modification
Within the phase I part, dose modifications were not allowed during the first cycle. For subsequent cycles and phase II patients, treatment modifications were mandated for severe toxic effects. A new cycle was only started if ANC was ≥1.5 x 109/l, platelet count was ≥75 x 109/l and non-haematologic toxic effects had resolved to less than or equal to grade 1 (alopecia, nausea and vomiting excepted). If treatment had to be delayed for >2 weeks, the patient was withdrawn.

Within a course, doses of both capecitabine and bortezomib were reduced by 50%, if ANC was 0.5–0.99 x 109/l, and treatment was omitted for an ANC <0.5 x 109/l and/or a platelet count <50 x 109/l. The doses of both drugs were permanently reduced by 25% in patients who experienced febrile neutropenia, prolonged grade 4 neutropenia (>7 days), grade 4 thrombocytopaenia, any grade 3 non-haematologic toxicity or a second occurrence of grade 2 hand–foot syndrome (HFS), diarrhoea or stomatitis. If the toxicity reoccurred despite two dose reductions, the patient was withdrawn. The dose of bortezomib was reduced in case of ≥grade 2 sensory peripheral neuropathy. In case of any given grade 4 non-haematologic toxicity, the patient was discontinued.

assessments
Tumour lesions were measured using Response Evaluation Criteria in Solid Tumours at baseline and at the end of treatment cycles 2, 5 and 8. Adverse events and toxic effects were evaluated weekly and recorded for every cycle. They were graded using the National Cancer Institute Common Toxicity Criteria (version 2.0, dated 30 April 1999).

statistical analysis
The primary efficacy end point, objective response rate, was defined as the percentage of patients with complete response (CR; A complete response was defined as the disappearance of all target lesions determined by two observations not less than 4 weeks apart) or partial response (PR; A partial response required a greater than 30% decrease in the sum of the longest diameter (LD) of target lesions determined by two observations not less than 4 weeks apart). The sample size was estimated at 29 assessable patients assuming an objective response rate ≤10% as null hypothesis, a true response rate of 30%, a power of 80% and a significance level of 5%.

TtP was defined as the time from registration until disease progression. Death was regarded as a progression event in those who died before disease progression. Subjects whose disease had not progressed at the time of analysis were censored using the last assessment date. DR was defined, for responding patients only, as the period of time from registration to the first observation of disease progression. OS was calculated from the date of registration to the date of death for any reason. Standard descriptive methods were applied. Analyses were carried out on an intent-to-treat population including all patients without major violation of eligibility criteria. Efficacy data were reported separately for the overall cohort and for patients treated at the MTD. OS and TtP were estimated by the Kaplan–Meier method. Categorical variables were described by contingency table methods and percentages. Continuous variables were described by mean and median values, standard deviations and minimum and maximum values.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 funding
 Acknowledgements
 References
 
patient characteristics
A total of 35 patients were enrolled onto the study. Two patients had to be withdrawn before first study dose administration due to the requirement of radiotherapy for impending spinal compression and impairment of renal function, respectively. They were excluded from both safety and efficacy analyses. All remaining 33 patients were assessable for safety, and 29 patients were assessable for efficacy. Four patients were discontinued after the first cycle for reasons other than disease progression (patient request after experiencing grade 3 nausea (n = 1), peripheral neuropathy (n = 1), pneumonia (n = 1) and myocardial infarction (n = 1)).

Patient characteristics at the time of study registration are summarised in Table 2. The median age was 58 years (range, 38–75). Most patients (84%) had visceral-dominant disease. The mean number of involved sites at the study entry was 3 (range, 1–5). All but one patient had received prior anthracycline treatment, and 74% had prior taxane therapy.


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  		Table 2. Patient baseline characteristics

 
efficacy
Objective PR were observed in 5 of the 33 patients in the intent-to-treat population (15%) (Table 3). No patient had a CR. Nine additional women (27%) had stable disease (SD, defined as a less than 30% decrease or less than 20% increase in the sum of LD of target lesions, four unconfirmed) and two had SD ≥6 months for a clinical benefit (CR + PR + SD ≥ 6 months) of 21%. Out of the 20 assessable patients treated at the MTD, 3 had a PR (15%), 8 SD (40%) and 2 had SD ≥6 months for a clinical benefit of 25%. Median TtP based on Kaplan–Meier estimate was 3.5 months [range, 1–25.3; 95% confidence interval (CI) 1.9–4.4]. The median duration of objective response was 4.4 months (range, 3.2–25.3). Median survival was 7.5 months (range, 1–25.3; 95% CI 5.6–14.6).


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  		Table 3. Treatment efficacy results

 
chemotherapy administration
A total of 97 cycles were administered. The mean number of cycles per patient was 2.7 (median, 2; range, 1–8). Twenty-six women required dose modifications or treatment delay (79%); 24 patients (73%) in the bortezomib dose and 20 patients (61%) in the capecitabine dose. Most common reasons for dose modifications were HFS (n = 9), diarrhoea (n = 6), thrombocytopaenia (n = 6), patient request (n = 5), neutropenia (n = 4), peripheral neuropathy (n = 4) and fatigue (n = 3, more than one reason possible). Treatment was discontinued prematurely in 12 patients (36%); reasons for early discontinuation were peripheral neuropathy (n = 3), diarrhoea (n = 3), HFS (n = 2), unspecified patient request (n = 2), nausea (n = 2), hyperbilirubinemia (n = 1) and infection (n = 1, more than one reason possible).

The delivered dose intensities (DIs) for capecitabine and bortezomib, defined as actual/planned dose, are listed in Table 4. For bortezomib, the delivered relative DI was higher at dose levels using 1.0 mg/m2 (range, 0.91–0.93) compared with dose levels using 1.3 mg/m2 (range, 0.72–0.78), resulting in similar mean delivered doses for all dose levels. For capecitabine, the delivered relative DI was substantially lower at 2500 mg/m2 (0.49) compared with 2000 mg/m2 (range, 0.80–0.94), resulting in an absolute delivered dose that was almost 25% lower at dose level 4 (1228 mg/m2) compared with dose level 3 (1608 mg/m2).


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  		Table 4. Treatment administration: planned dose, mean actual dose and mean relative DI for bortezomib and capecitabine

 
safety
Treatment-related adverse events are summarised in Table 5. Most common grade 3 adverse events were thrombocytopaenia (n = 9), diarrhoea (n = 6), HFS (n = 4) and peripheral neuropathy (n = 4). All other treatment-related adverse events occurred in ≤3 women. No grade 4 non-haematologic toxicity occurred.


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  		Table 5. Treatment-related adverse events (n = 33, patients enrolled and treated)

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
funding
 Acknowledgements
 References
 
Patients with MBC who have progressed after anthracyclines and taxanes have limited treatment options. So far, only few cytotoxic agents or combinations have shown considerable activity for this group of patients, and capecitabine seems to be one of the most active compounds. Bortezomib has shown only limited activity against solid tumours when used as a single agent [13–16], but is a potentially promising agent for combination therapy as it might sensitise tumour to conventional chemotherapy and radiotherapy.

Our results demonstrate that capecitabine and bortezomib can be combined safely. The combination therapy was generally well tolerated and associated with toxic effects that were consistent with the known side-effects of the individual agents [1–3]. The MTDs were capecitabine 2500 mg/m2 and bortezomib 1.3 mg/m2, and these doses were subsequently used in the phase II part of the trial. Detailed analysis of treatment administration revealed, however, that patients treated at the MTD frequently required dose modifications or treatment delay (17 patients, 85%). The need for treatment modifications increased with the number of given cycles, resulting in a substantial decrease in the mean DI (range, 93.0%–94.8% during cycle 1; 52.3%–71.4% during cycle 2 and 39.6%–62.5% for subsequent cycles). Consequently, at the MTD the mean delivered doses and the relative DI for bortezomib and capecitabine were 26% and 51% lower than planned, respectively, and were similar or even lower compared with the other dose levels with lower planned bortezomib and/or capecitabine doses. Capecitabine 2000 mg/m2 and bortezomib 1.0 or 1.3 mg/m2 might therefore be more suitable for future studies of the combination.

With an objective response rate of 15%, a clinical benefit of 21% and a median PFS of 3.5 months, capecitabine/bortezomib demonstrated moderate activity in this prognostically unfavourable cohort of heavily pretreated women. In similar clinical settings, three randomised trials have recently evaluated the efficacy of capecitabine with or without an additional cytotoxic agent. They were able to demonstrate superior response rates and/or PFS for the combination therapy, ranging from 19.8% to 35% and 4.9 to 8.4 months, respectively, whereas single-agent capecitabine was associated with response rates of 9%–14% and a PFS between 4.1 and 4.4 months [1–3]. Although comparing trials can be problematic, it is relatively clear given the results from these studies that the combination of bortezomib and capecitabine does not provide a substantial advantage over single-agent capecitabine. This means that there either is no additive or synergistic antitumour activity for bortezomib and capecitabine in heavily pretreated breast cancer patients or the presented study failed to demonstrate an existing effect.

Indeed, there are a few caveats about the study design that might have affected the antitumour activity and could therefore be relevant for interpreting the results. First, most of the patients required treatment modifications and the resulting median doses of the study drugs were low, particularly for capecitabine (1464 mg/m2). In comparison, the median daily administered doses of capecitabine within recent randomised trials were 2000–2377 mg/m2 for single-agent therapy and 1875–2000 mg/m2 for combination therapy [1–3]. Secondly, a relatively large number of patients discontinued treatment early on their request without fulfilling stopping criteria for toxicity or experiencing disease progression. Consequently, the median number of cycles was only two, which is considerably lower to what was observed in other studies for both single-agent and combination therapy (range, 4–5) [1–3]. This might be partially explained by the observation that patients enrolled in this study had particularly aggressive metastatic disease with extremely poor prognosis, low probability of response to additional therapy and extensive pretreatment with pre-existing adverse effects and low acceptance of further toxic effects, but it could also reflect on the tolerability of the study treatment at the selected doses. Finally, the current schedule might be suboptimal for providing the maximum benefit of combining 5-FU-based therapy and bortezomib. Recent preclinical studies in lung and pancreatic cancer models demonstrated the relevance of scheduling for combining chemotherapy and bortezomib, showing increased activity when bortezomib was given simultaneously or after chemotherapy, but inhibitory effects when bortezomib was administered before chemotherapy [17, 18]. Although it is unclear whether these observations are relevant for MBC and 5-FU-based therapy, potential scheduling effects should be explored if the combination is further investigated.

On the other hand, the results of the trial might just reflect that bortezomib and capecitabine do not have additive or synergistic activity in an unselected and heavily pretreated cohort of MBC patients. As the proteasome–ubiquitin pathway affects the regulation of numerous cellular proteins, it is possible that some of them might interfere with the activity of 5-FU. It has been indicated that 5-FU-based combination chemotherapy partly acts by lowering the expression of Raf-1 and Akt through a proteasome-dependent pathway, thus inhibiting the survival and anti-apoptotic activity of their downstream enzyme targets [19]. Therapeutic inhibition of the proteasome function could potentially interfere with this mechanism and affect the efficacy of the treatment. Another potential interaction is that bortezomib might suppress the expression of uridine phosphorylase (UPase), which has been shown to play an important role in the antineoplastic activity of 5-FU and in the anabolism of capecitabine. Recent studies showed that UPase expression in breast cancer cells is induced by tumour necrosis factor (TNF)-alpha through a NF-{kappa}B-dependent pathway, enhancing cell sensitivity to 5'-deoxy-5-fluorouridine. This TNF-alpha-dependent induction of UPase could be suppressed by bortezomib [20]. It is unclear whether these factors are relevant for the present study, but the findings underline the relevance of elucidating the mechanism of action when combining proteasome inhibitors with standard chemotherapy. This is also important for selecting appropriate subgroups for combination therapy.

In conclusion, we were able to demonstrate that bortezomib and capecitabine can be combined safely, but the combination showed only moderate activity in heavily pretreated patients with MBC. We do therefore not recommend further investigations of this combination in an unselected cohort of MBC patients, unless there is a way of identifying patients that might have a benefit from the addition of bortezomib.


   funding
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
Acknowledgements
 References
 
Johnson & Johnson Pharmaceutical Research and Development (a division of Janssen-Cilag, Germany); Roche Pharmaceutical.


   Acknowledgements
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
References
 
The trial has been presented in part at the San Antonio Breast Cancer Symposium, San Antonio, TX, December 2005, and at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, June 2007.

Received for publication November 20, 2007. Accepted for publication November 26, 2007.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
1. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med (2006) 355(26):2733–2743.[Abstract/Free Full Text]

2. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol (2005) 23(4):792–799.[Abstract/Free Full Text]

3. Vahdat LT, Thomas E, Li R, et al. Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer (MBC) previously treated or resistant to an anthracycline and resistant to taxanes. J Clin Oncol. 2007 ASCO Annual Meeting Proceedings Part I. 2007; 25 (18 Suppl), 1006.

4. King RW, Deshaies RJ, Peters J-M, Kirschner MW. How proteolysis drives the cell cycle. Science (1996) 274:1652–1659.[Abstract/Free Full Text]

5. Sherr CJ. Cancer cell cycles. Science (1996) 274:1672–1677.[Abstract/Free Full Text]

6. Read MA, Neish AS, Luscinskas FW, et al. The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity (1995) 2:493–506.[CrossRef][Web of Science][Medline]

7. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T. The ubiquitin-proteasome pathway is required for processing the NF-{kappa}B1 precursor protein and the activation of NF-{kappa}B. Cell (1994) 78:773–785.[CrossRef][Web of Science][Medline]

8. Teicher BA, Ara G, Herbst R, et al. The proteasome inhibitor PS-341 in cancer therapy. Clin Cancer Res (1999) 5(9):2638–2645.[Abstract/Free Full Text]

9. Cusack JC, Liu R, Houston M, et al. Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. Cancer Res (2001) 61(9):3535–3540.[Abstract/Free Full Text]

10. Shah SA, Potter MW, McDade TP, et al. 26S proteasome inhibition induces apoptosis and limits growth of human pancreatic cancer. J Cell Biochem (2001) 82(1):110–122.[CrossRef][Web of Science][Medline]

11. Bold RJ, Virudachalam S, McConkey DJ. Chemosensitization of pancreatic cancer by inhibition of the 26S proteasome. J Surg Res (2001) 100:11–17.[CrossRef][Web of Science][Medline]

12. Pink M, Pien CS, Worland P, et al. PS-341 enhances chemotherapeutic effect in human xenograft models. Proc Am Assoc Cancer Res (2002) 43:158.

13. Milano A, Iaffaioli RV, Caponigro F. The proteasome: a worthwhile target for the treatment of solid tumours? Eur J Cancer (2007) 43(7):1125–33.[CrossRef][Web of Science][Medline]

14. Papandreou CN, Daliani DD, Nix D, et al. Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol (2004) 22:2108–2121.[Abstract/Free Full Text]

15. Yang CH, Gonzalez-Angulo AM, Reuben JM, et al. Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol (2006) 17(5):813–817.[Abstract/Free Full Text]

16. Lara PN, Chansky K, Davies AM, et al. Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327). J Thorac Oncol (2006) 1(9):996–1001.[Medline]

17. Mortenson MM, Schlieman MG, Virudachalam S, Bold RJ. Effects of the proteasome inhibitor bortezomib alone and in combination with chemotherapy in the A549 non-small-cell lung cancer cell line. Cancer Chemother Pharmacol (2004) 54(4):343–353.[Web of Science][Medline]

18. Fahy BN, Schlieman MG, Virudachalam S, Bold RJ. Schedule-dependent molecular effects of the proteasome inhibitor bortezomib and gemcitabine in pancreatic cancer. J Surg Res (2003) 113(1):88–95.[CrossRef][Web of Science][Medline]

19. Caraglia M, Marra M, Budillon A, et al. Chemotherapy regimen GOLF induces apoptosis in colon cancer cells through multi-chaperone complex inactivation and increased Raf-1 ubiquitin-dependent degradation. Cancer Biol Ther (2005) 4(10):1159–1167.[Web of Science][Medline]

20. Wan L, Cao D, Zeng J, et al. Modulation of uridine phosphorylase gene expression by tumour necrosis factor-alpha enhances the antiproliferative activity of the capecitabine intermediate 5'-deoxy-5-fluorouridine in breast cancer cells. Mol Pharmacol (2006) 69(4):1389–1395.[Abstract/Free Full Text]


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