Publications by authors named "Jean-Pierre Bergerat"

45 Publications

[Pertuzumab and solid tumors: perspectives].

Bull Cancer 2014 Dec;101(12):1114-21

Hôpital de Hautepierre, Hôpitaux universitaire de Strasbourg, Département d'oncologie et hématologie médicale, 1, avenue Molière, BP 49, 67200 Strasbourg, France.

Over the past decade, trastuzumab was the only available monoclonal anti-HER2 antibody for the treatment of HER2 positive breast and gastric cancer. Recently, pertuzumab added to docetaxel and trastuzumab showed dramatic overall survival improvement in first line treatment of HER2 positive metastatic breast cancer. Pertuzumab is the first approved monoclonal antibody in a new class of drugs called dimerization inhibitors. This agent was also approved in association with trastuzumab for neoadjuvant HER2-positive breast cancer treatment. However, pertuzumab development was not confined to breast cancer and in the present review, we will focus on biological rational, preclinical data and clinical trial results of pertuzumab in solid tumors excluding breast cancer.
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http://dx.doi.org/10.1684/bdc.2014.2026DOI Listing
December 2014

First report of trastuzumab treatment after postoperative Takotsubo cardiomyopathy.

Anticancer Res 2014 Jul;34(7):3579-82

Breast Diseases Center, Department of Obstetrics and Gynaecology, Hautepierre Hospital, CHRU, University Hospital Strasbourg, Strasbourg; France

Background: Trastuzumab is a humanized monoclonal antibody used for the treatment of HER2-positive breast cancer. Cardiotoxicity is a well-known adverse event of trastuzumab use but little has been documented regarding its use in patients with a history of cardiac disease.

Case Report: We describe a case in which trastuzumab treatment was administered to a 40-year-old female patient with early breast cancer after acute heart failure secondary to postoperative Takotsubo cardiomyopathy. After one year of follow-up with close monitoring by echocardiography, there have been no heart-related symptoms. Additional surgery was performed because of positive resection margins at first surgery, without complications, despite the risk of recurrence of Takotsubo cardiomyopathy.

Conclusion: Trastuzumab can be safely administered after acute heart failure secondary to postoperative Takotsubo cardiomyopathy.
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July 2014

Isolated cerebellar metastasis from prostate adenocarcinoma diagnosed by 18F-fluorocholine PET/CT: a rare but not impossible complication.

Eur J Nucl Med Mol Imaging 2014 Feb 1;41(2):397-8. Epub 2013 Oct 1.

Biophysics and Nuclear Medicine, University Hospitals of Strasbourg, Strasbourg, France,

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http://dx.doi.org/10.1007/s00259-013-2577-6DOI Listing
February 2014

Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells.

PLoS One 2013 2;8(5):e63466. Epub 2013 May 2.

INSERM U1113, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Androgen receptor (AR) signaling pathway remains the foremost target of novel therapeutics for castration-resistant prostate cancer (CRPC). However, the expression of constitutively active AR variants lacking the carboxy-terminal region in CRPC may lead to therapy inefficacy. These AR variants are supposed to support PCa cell growth in an androgen-depleted environment, but their mode of action still remains unresolved. Moreover, recent studies indicate that constitutively active AR variants are expressed in primary prostate tumors and may contribute to tumor progression. The aim of this study was to investigate the impact of constitutively active AR variants on the expression of tumor progression markers. N-cadherin expression was analyzed in LNCaP cells overexpressing the wild type AR or a constitutively active AR variant by qRT-PCR, Western blot and immunofluorescence. We showed here for the first time that N-cadherin expression was increased in the presence of constitutively active AR variants. These results were confirmed in C4-2B cells overexpressing these AR variants. Although N-cadherin expression is often associated with a downregulation of E-cadherin, this phenomenon was not observed in our model. Nevertheless, in addition to the increased expression of N-cadherin, an upregulation of other mesenchymal markers expression such as VIMENTIN, SNAIL and ZEB1 was observed in the presence of constitutively active variants. In conclusion, our findings highlight novel consequences of constitutively active AR variants on the regulation of mesenchymal markers in prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063466PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3642121PMC
December 2013

Duration of adjuvant trastuzumab treatment in routine practice.

Anticancer Res 2012 Oct;32(10):4585-8

Strasbourg University Hospital, Strasbourg, France.

Background: Trastuzumab is used for the adjuvant (postoperative) treatment of (HER2)-positive early breast cancer. The duration of treatment is set at one year. The goal of our study was to examine the effective duration of trastuzumab treatment in routine clinical practice.

Patients And Methods: We performed a retrospective review of all patients with early breast cancer, treated with trastuzumab at our hospital between 2005 and 2008. Data concerning patterns of use and safety were collected from patient charts and pharmacy records.

Results: The cohort comprised of 96 patients, with a median age of 50 years (range=25-79 years). The majority of patients (63.5%) had node-negative disease. Besides trastuzumab, most patients underwent chemotherapy (before or after surgery). Trastuzumab was administered every three weeks and the median duration of treatment was 52 weeks (range=6-81 weeks). Only half of the patients received the monoclonal antibody for 52 weeks, 36.6% had therapy more than 52 weeks and 12.5% discontinued treatment before 52 weeks due to adverse effects (8.4%) and refusal (4.1%). Two (2.1%) patients discontinued trastuzumab therapy because of cardiotoxicity, a recognized side-effect of the monoclonal antibody. Regarding treatment durations of more than 52 weeks, 15/35 were due to the off-label use of trastuzumab in the neoadjuvant setting (before surgery). The 3-year rate of disease-free survival was 91.6%.

Conclusion: Half of the patients completed the 52-week treatment of trastuzumab after surgery for early breast cancer. Trastuzumab was well-tolerated and the rate of discontinuation due to cardiotoxicity was low, compared to published results.
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October 2012

Risk of hormone escape in a human prostate cancer model depends on therapy modalities and can be reduced by tyrosine kinase inhibitors.

PLoS One 2012 6;7(8):e42252. Epub 2012 Aug 6.

Translational Research Department, Institut Curie, Paris, France.

Almost all prostate cancers respond to androgen deprivation treatment but many recur. We postulated that risk of hormone escape--frequency and delay--are influenced by hormone therapy modalities. More, hormone therapies induce crucial biological changes involving androgen receptors; some might be targets for escape prevention. We investigated the relationship between the androgen deprivation treatment and the risk of recurrence using nude mice bearing the high grade, hormone-dependent human prostate cancer xenograft PAC120. Tumor-bearing mice were treated by Luteinizing-Hormone Releasing Hormone (LHRH) antagonist alone, continuous or intermittent regimen, or combined with androgen receptor (AR) antagonists (bicalutamide or flutamide). Tumor growth was monitored. Biological changes were studied as for genomic alterations, AR mutations and protein expression in a large series of recurrent tumors according to hormone therapy modalities. Therapies targeting Her-2 or AKT were tested in combination with castration. All statistical tests were two-sided. Tumor growth was inhibited by continuous administration of the LH-RH antagonist degarelix (castration), but 40% of tumors recurred. Intermittent castration or complete blockade induced by degarelix and antiandrogens combination, inhibited tumor growth but increased the risk of recurrence (RR) as compared to continuous castration (RR(intermittent): 14.5, RR(complete blockade): 6.5 and 1.35). All recurrent tumors displayed new quantitative genetic alterations and AR mutations, whatever the treatment modalities. AR amplification was found after complete blockade. Increased expression of Her-2/neu with frequent ERK/AKT activation was detected in all variants. Combination of castration with a Her-2/neu inhibitor decreased recurrence risk (0.17) and combination with an mTOR inhibitor prevented it. Anti-hormone treatments influence risk of recurrence although tumor growth inhibition was initially similar. Recurrent tumors displayed genetic instability, AR mutations, and alterations of phosphorylation pathways. We postulated that Her-2/AKT pathways allowed salvage of tumor cells under castration and we demonstrated that their inhibition prevented tumor recurrence in our model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042252PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412862PMC
January 2013

Insulin-like growth factor type 1 receptor (IGF-1R) exclusive nuclear staining: a predictive biomarker for IGF-1R monoclonal antibody (Ab) therapy in sarcomas.

Eur J Cancer 2012 Nov 7;48(16):3027-35. Epub 2012 Jun 7.

CHU Strasbourg, 1, Avenue Molière, 67000 Strasbourg, France.

Aims: A minority of patients with advanced sarcoma achieve prolonged progression free survival (PFS) with insulin growth factor type 1 receptor (IGF-1R) monoclonal antibody (Ab) therapy. A biomarker identifying those patients beforehand would be useful to select patients for the development of these agents.

Methods: This single centre series includes patients with unresectable or metastatic soft tissue sarcomas (STS), Ewing sarcoma (ES) and osteosarcoma treated with IGF-1R Ab (R1507, IMC-A12, SCH 717454 and CP-751.871) in the Centre Léon Bérard. Tumour samples were analysed by immunohistochemistry for expression of IGF-1R, insulin-like growth factor binding protein type 3 (IGFBP-3), Ki67, epidermal growth factor receptor (HER1) and human epidermal growth factor receptor 2 (HER2). Predictive factors for PFS and overall survival (OS) were investigated.

Results: All tumour samples had a positive IGF-1R immunostaining on 60% to 100% of tumour cells. IGFBP-3 immunostaining was observed in 12 (75%) samples with 5% to 100% of positive cells. IGF-1R immunostaining was nuclear (n=9, 56%), cytoplasmic (n=4, 25%), or nuclear +cytoplasmic (n=3, 19%). Neither IGFBP-3 expression, nor Ki67 was correlated to PFS. HER2 and HER1 staining were positive in 0 and 2 samples respectively (both primary resistant to IGF-1R Ab therapy). Exclusive intra-nuclear immunoreactivity for IGF-1R was significantly associated with a better PFS (p=0.01) and OS (p=0.007).

Conclusion: Exclusive nuclear localisation of IGF-1R is an easily testable biomarker associated with a better PFS and OS for patients treated with IGF-1R Ab therapy. Nuclear localisation of IGF-1R in tumour cells might be a hallmark of pathway activation.
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http://dx.doi.org/10.1016/j.ejca.2012.05.009DOI Listing
November 2012

Bevacizumab plus microtubule targeting agents in heavily pre-treated ovarian cancer patients: a retrospective study.

Bull Cancer 2011 Oct;98(9):80-9

CHU Hautepierre, Department of Oncology & Hematology, Strasbourg, France.

OBJECTIVES. As vascular endothelial growth factor (VEGF) is expressed in ovarian cancer, we assessed the efficacy and safety of bevacizumab (a monoclonal antibody targeting VEGF) plus microtubule targeting agents for heavily pre-treated ovarian carcinoma patients. METHODS. We retrospectively reviewed 43 patients with recurrent epithelial ovarian carcinoma. Combined treatment included bevacizumab with paclitaxel in 32 (74%), docetaxel in 10 (23%), and vinorelbine in one (2.3%) patients, respectively. RESULTS. The median number of combined treatment was six cycles (range 1-29). On RECIST criteria, the objective response rate (ORR) was 40% (16% CR and 24% PR). Clinical benefit (complete response [CR] plus partial response [PR] and stable disease [SD] lasting ≥ 3 months) was 74% (CI95%: 46.7-77%). Median duration of treatment and overall survival were 3.9 months (range 0.2-14.4 months) and 20.1 months (CI95%: 13.8-20.1) respectively. No toxic death was reported. Grade 3-4 toxicity occurred in 30% of patients. Gastrointestinal perforations and fistula occurred in 3 (7%) and 6 (14%) patients, respectively. CONCLUSION. Although being active in terms of ORR, bevacizumab plus microtubule targeting agents - mainly taxanes - leads to a high rate of gastro-intestinal perforations and fistula in heavily pre-treated ovarian carcinoma patients.
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http://dx.doi.org/10.1684/bdc.2011.1436DOI Listing
October 2011

Off-label use of oxaliplatin in patients with metastatic breast cancer.

Anticancer Res 2011 May;31(5):1765-7

Pharmacy, Hôpital Hautepierre, Strasbourg, France.

Background: Oxaliplatin is an anticancer agent only approved for treatment of colorectal cancer, but that has shown some activity in metastatic breast cancer in phase II studies. Herein, we examine the off-label use of oxaliplatin in unselected patients with metastatic breast cancer.

Patients And Methods: A retrospective review was performed of all patients with metastatic breast cancer treated with oxaliplatin at our hospital between February 2003 and November 2009. Data concerning patterns of use, safety and activity were collected from patient charts.

Results: The cohort comprised 30 female patients with a median age of 49 (range, 34-68 years) and a median of two involved organs (range, 1-4). All patients had been pretreated for metastatic breast cancer (median number of previous lines: 3; range:1-6). Oxaliplatin was only given in association either with fluorouracil and folinic acid (n=23) or with gemcitabine (n=7). The most commonly used dose was 100 mg/m(2) given every other week or every 3 weeks. As of December 15, 2009, the median duration of treatment was 4 (range, 0.75-11) months. Most of the discontinuations occured due to disease progression (n=11) and adverse effects or worsening condition (n=8). Twelve (40%) patients presented side-effects related to oxaliplatin use including hematotoxicity (n=8), gastrointestinal disorders (n=4) and neuropathies (n=2). Among patients evaluable for antitumoral activity (n=15), one patient achieved a complete response and one patient demonstrated a partial response. Most of the patients (57%) continued to be treated by chemotherapy after oxaliplatin. Median overall survival for the evaluable patients was 10 (range, 1-51) months.

Conclusion: In our population of heavily pretreated women with metastatic breast cancer, off-label use of oxaliplatin was of little worth. This off-label treatment was not the last therapeutic option for most of these patients.
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May 2011

New strategies for medical management of castration-resistant prostate cancer.

Oncology 2011 16;80(1-2):1-11. Epub 2011 May 16.

Department of Hematology and Oncology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.
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http://dx.doi.org/10.1159/000323495DOI Listing
September 2011

[Potential clinical impact of therapeutic education in patients treated with anticancer drugs].

Bull Cancer 2011 Feb;98(2):176-81

Hôpitaux universitaires de Strasbourg, pôle d'oncologie et d'hématologie, France.

The aim of our work was to assess the potential clinical impact of therapeutic education in patients treated with anticancer drugs. One hundred-one ambulatory adult patients (mean age: 60 years, range: 24-88) treated by anticancer chemotherapy were included. The occurrence of adverse events was reported by 83% of the patients. Twenty-one percent (14/67) of the patients were not compliant with their supportive care treatment, 60% (60/101) took over-the-counter medications (one contraindication identified) and 14% (14/101) claimed they had received no counsel on risk behaviour (UV exposure, lack of contraception, driving) from health care professionals. Overall, 11% (44/397) of adverse events were associated with a lack of information. Twelve percent (4/33) of the calls to the doctor, 6% (1/17) of the visits to the physician and 21% (3/14) of the hospitalizations could be associated with a lack of therapeutic education. These data enlighten the importance of therapeutic education of cancer patients treated by chemotherapy.
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http://dx.doi.org/10.1684/bdc.2011.1308DOI Listing
February 2011

Successful treatment of a granulocytic sarcoma of the uterine cervix in complete remission at six-year follow-up.

J Oncol 2010 29;2010:812424. Epub 2010 Apr 29.

Department of Hematology and Oncology, Centre des Hôpitaux Universitaires de Strasbourg, BP 67000, Strasbourg, France.

Background. Localized granulocytic sarcoma of the uterine cervix in the absence of acute myelogenous leukemia (AML) at presentation is very rare, its diagnosis is often delayed, and its prognosis almost always ominous evolving into refractory AML. Case. We present the case of a 30-year-old woman with vaginal bleeding and a large cervical mass. Further evaluation confirmed the presence of a granulocytic sarcoma but failed to reveal systemic involvement. Results. AML type chemotherapy followed by radiotherapy of the uterus led to a durable complete remission. She remains in complete remission six years after diagnosis. Conclusion. Granulocytic sarcoma of the cervix is a rare entity for which early intensive AML type therapy is effective.
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http://dx.doi.org/10.1155/2010/812424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862322PMC
July 2011

Severe intoxication with methotrexate possibly associated with concomitant use of proton pump inhibitors.

Anticancer Res 2010 Mar;30(3):963-5

Pharmacy, Hôpital Hautepierre, avenue Molière, 67000 Strasbourg, France.

Background: Delayed elimination of methotrexate associated with serious side-effects has been attributed to the co-administration of benzimidazole proton pump inhibitors.

Patients And Methods: We have retrospectively analyzed the causes of delayed methotrexate elimination in patients who had received the rescue agent glucarpidase to evaluate the potential implication of benzimidazoles.

Results: Between 2002 and 2008, six patients (mean age: 30 years; range: 4-74 years) were treated with glucarpidase. Delayed elimination associated with impaired renal function occured after the first cycle except in 2 patients (2nd and 8th administration of high-dose methotrexate). The possible causes of delayed elimination identified were: insufficient hydration (n=1) and drug-drug interactions (n=5). The potential drug-drug interactions included the co-administration of piperacillin/tazobactam (n=1) and proton pump inhibitors (omeprazole, n=3; esomeprazole, n=2). Impaired elimination of methotrexate was not observed either in the 3 patients who were treated further or during the previous cycles of the 2 pretreated patients in relation to the absence of co-prescription of proton pump inhibitors.

Conclusion: In line with the recent literature and given the prohibitive cost of glucarpidase, we have advocated the cessation of proton pump inhibitors administration during methotrexate treatment.
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March 2010

A V530I Mutation in c-KIT Exon 10 Is Associated to Imatinib Response in Extraabdominal Aggressive Fibromatosis.

Sarcoma 2010 17;2010:458156. Epub 2010 Mar 17.

Pôle d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, 67098 Strasbourg, France.

Aggressive fibromatosis (AF) or desmoid tumor is a rare condition, characterized by deep tissue invasion by a monoclonal fibroblastic neoplasm, developed from musculoaponeurotic structures. Surgery is the treatment of choice, but negative margins can hardly been achieved in large tumors, and can lead to major functional disability. AF medical therapy includes nonsteroids anti-inflammatory drugs, tamoxifen, with inconsistent results. Several reports of imatinib efficacy in AF appear in the literature. Here, we describe for the first time a V530I KIT exon 10 mutant that was associated to a dramatic imatinib response in an extraabdominal aggressive fibromatosis. The previously discovered V530I substitution was characterized in the core binding factor AML, but had never been reported in any other condition, so far. In this paper, we discuss the KIT exon 10 mutations or polymorphisms that have been described in a variety of KIT-related conditions, including acute myelogenous leukemia, mastocytosis, and aggressive fibromatosis.
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http://dx.doi.org/10.1155/2010/458156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841250PMC
July 2011

Role of cationic channel TRPV2 in promoting prostate cancer migration and progression to androgen resistance.

Cancer Res 2010 Feb 26;70(3):1225-35. Epub 2010 Jan 26.

Institut National de la Santé et de la Recherche Médicale, U-800, Equipe labellisée par la Ligue Nationale contre le cancer, France.

Castration resistance in prostate cancer (PCa) constitutes an advanced, aggressive disease with poor prognosis, associated with uncontrolled cell proliferation, resistance to apoptosis, and enhanced invasive potential. The molecular mechanisms involved in the transition of PCa to castration resistance are obscure. Here, we report that the nonselective cationic channel transient receptor potential vanilloid 2 (TRPV2) is a distinctive feature of castration-resistant PCa. TRPV2 transcript levels were higher in patients with metastatic cancer (stage M1) compared with primary solid tumors (stages T2a and T2b). Previous studies of the TRPV2 channel indicated that it is primarily involved in cancer cell migration and not in cell growth. Introducing TRPV2 into androgen-dependent LNCaP cells enhanced cell migration along with expression of invasion markers matrix metalloproteinase (MMP) 9 and cathepsin B. Consistent with the likelihood that TRPV2 may affect cancer cell aggressiveness by influencing basal intracellular calcium levels, small interfering RNA-mediated silencing of TRPV2 reduced the growth and invasive properties of PC3 prostate tumors established in nude mice xenografts, and diminished expression of invasive enzymes MMP2, MMP9, and cathepsin B. Our findings establish a role for TRPV2 in PCa progression to the aggressive castration-resistant stage, prompting evaluation of TRPV2 as a potential prognostic marker and therapeutic target in the setting of advanced PCa.
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http://dx.doi.org/10.1158/0008-5472.CAN-09-2205DOI Listing
February 2010

Potential pharmacokinetic interactions affecting antitumor drug disposition in cancer patients.

Anticancer Res 2009 Nov;29(11):4741-4

Pharmacy, Hôpital Hautepierre, avenue Molière, 67000 Strasbourg, France.

Aim: The extent of potential pharmacokinetic drug-drug interactions affecting anticancer agents disposition has not been specifically investigated. The prevalence of this type of interaction in adult ambulatory patients receiving systemic chemotherapy in our institution was examined.

Patients And Methods: The medication list of 200 consecutive cancer patients receiving intravenous chemotherapy was prospectively collected by means of the prescriptions (chemotherapy, supportive care, medications for comorbidities) and a questionnaire (over-the-counter products). Interacting drugs had to have been taken in the previous 7 days. Data concerning the type of cancer and the nature of the comorbidities were also collected. Potential pharmacokinetic drug interactions affecting the activity of the anticancer agent were identified using the guide of drug interactions of the French drug agency (June 2007) and the literature.

Results: A total of 200 patients (mean age 60 years; range 17-96 years) entered the study and 73.5% were female. The most common cancer types were breast cancer (41%), non-Hodgkin's lymphomas (17.5%), and gastrointestinal tumors (12.5%). The majority of the patients (58.5%) had a comorbid illness (cardiovascular diseases, hypothyroidism, diabetes, depression). The median number of medications per patient was 4 (range 1-14). All the patients received systemic chemotherapy but 29 (14.5%) also took anticancer drugs at home. Nine potential pharmacokinetic interactions were found in nine patients (frequency: 4.5%; 95% confidence interval: 1.6-7.4%). Most of the interactions (7/9) involved fluconazole that might alter the metabolism of oxazaphosphorines or the elimination of bortezomib and paclitaxel. One association was contraindicated. Five interactions were not associated with a published clinical effect. No interaction with an enzyme or drug transporter inducer (e.g., rifampin, St. John's wort) was encountered.

Conclusion: The frequence of potential pharmacokinetic interactions affecting the disposition of antitumor drugs was low in this population of ambulatory adult cancer patients and mostly involved the antifungal agent fluconazole.
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November 2009

Identification of novel truncated androgen receptor (AR) mutants including unreported pre-mRNA splicing variants in the 22Rv1 hormone-refractory prostate cancer (PCa) cell line.

Hum Mutat 2010 Jan;31(1):74-80

Signalisation et Cancer de la Prostate, Physiopathologie et Médecine Translationnelle, Université de Strasbourg, 67000Strasbourg, France.

Advanced prostate cancer (PCa) has emerged as a public health concern due to population aging. Although androgen deprivation has proven efficacy in this condition, most advanced PCa patients will have to face failure of androgen deprivation as a treatment. Mutations in the androgen receptor (AR) from tumor cells have been shown to induce androgen independency both in PCa cell lines and in the clinic. We have investigated the molecular events leading to androgen independency in the 22Rv1 cell line, a commonly used preclinical model of PCa. Besides AR mutants that have been described so far, including nonsense mutations, recent data have focused on AR pre-mRNA aberrant splicing as a new mechanism leading to constitutively active truncated AR variants. In this article, we describe two novel variants arising from aberrant splicing of AR pre-mRNA, characterized by long mRNA transcripts that encode truncated, constitutively active proteins. We also describe several new nonsense mutants that share ligand independency and transcriptional activity. Finally, we show that alongside these mutants, 22Rv1 cells also express a mutant AR lacking exon 3 tandem duplication, a major feature of this cell line. By describing unreported AR mutants in the 22Rv1 cell line, our data emphasize the complexity and heterogeneity of molecular events that occur in preclinical models, and supposedly in the clinic. Future work on the 22Rv1 cell line should take into account the concomitant expression of various AR mutants.
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http://dx.doi.org/10.1002/humu.21138DOI Listing
January 2010

Paralytic ileus possibly associated with interaction between ritonavir/lopinavir and vincristine.

Pharm World Sci 2009 Dec 10;31(6):619-21. Epub 2009 Sep 10.

Department of Pharmacy Pharmacology, Hôpital de Hautepierre, Strasbourg, France.

Case Description: A French Caucasian man aged 39 with HIV infection was treated with abacavir/lamivudine and ritonavir/lopinavir. The patient (normal renal and liver functions) was diagnosed with a Burkitt lymphoma for which he was treated with cyclophosphamide day 1 to 5; doxorubicin day 1; methotrexate day 10; and vincristine day 1 and 8. At day 12, he suffered from abdominal pain associated with constipation. Paralytic ileus was diagnosed by study imaging. Ileus lasted 10 days necessitating parenteral feeding. Later on, a further cycle of chemotherapy with etoposide replacing vincristine was given and was well tolerated.

Conclusion: We speculate that an interaction between ritonavir/lopinavir and vincristine was responsible for this severe toxicity. Vincristine is transported by P-gp and is metabolized via CYP3A5. Ritonavir is a potent CYP3A5 isoenzyme and P-gp inhibitor. Lopinavir is also a P-gp inhibitor. Ritonavir and lopinavir might have delayed vincristine elimination. Clinicians should be aware of this possible interaction.
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http://dx.doi.org/10.1007/s11096-009-9323-yDOI Listing
December 2009

Adjuvant chemotherapy in elderly patients with colorectal cancer. A retrospective analysis of the implementation of tumor board recommendations in a single institution.

Crit Rev Oncol Hematol 2010 Jun 26;74(3):211-7. Epub 2009 Jun 26.

Pôle d'Hématologie et d'Oncologie, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, 67098 Strasbourg, France.

Background: A number of studies have shown that elderly cancer patients were denied optimal anticancer treatment because of age. Colorectal cancer is among the most frequent cancers in Western countries, and adjuvant chemotherapy has proven efficacy and tolerance in this condition. This study was undertaken to explore the current approaches to adjuvant chemotherapy in elderly cancer patients in a single institution.

Patients And Methods: We retrospectively analyzed all patients' files that were discussed in the gastro-intestinal tumor board of the Hôpitaux Universitaires de Strasbourg during 3 years (2004-2006). The recorded variables included sex, age, tumor stage, cancer location colon vs rectum, number of comorbidities, occurrence of an oncogeriatric assessment, type and tolerance of chemotherapy. We investigated the reason to not administer adjuvant therapy in patients whom should have received this treatment if guidelines had to be applied.

Results: A total of 193 consecutive patients' files were extracted from colorectal cancer patients that had been discussed in the gastro-intestinal tumor board. Among these, we isolated patients over 70 years old who were proposed with either adjuvant chemotherapy (group A, n=65) or follow up (group B, n=128). The median age in group A was 75.3 years old. Tumor board recommendations were in accordance with guidelines in 91% of cases. Chemotherapy was delivered in 44 pts (76%) and completed in 42 (95%). The median age in group B was 78.6 years old, and in this group tumor board proposal met the guidelines in 83% of cases. In the logistic regression model, disease stage was the major variable leading to adjuvant treatment recommendation, age and comorbidities being of lesser importance.

Conclusions: In our series, elderly colorectal cancer patients are not undertreated. Efforts should be maintained to educate physicians with regard to feasibility of adjuvant chemotherapy in elderly patients.
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http://dx.doi.org/10.1016/j.critrevonc.2009.05.003DOI Listing
June 2010

Geriatric oncology, general practitioners and specialists: current opinions and unmet needs.

Crit Rev Oncol Hematol 2010 Jul 5;75(1):47-57. Epub 2009 Apr 5.

Department of Oncology and Hematology, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, Strasbourg, France.

Purpose: To describe the patterns of care of elderly cancer patients (ECPs) (>70 years old) and the factors affecting the referral by general practitioners (GPs) of patients to cancer specialists (SPs), in Alsace France.

Methods: A postal mail questionnaire was sent to a total of 2818 physicians including primary care physicians and specialists. The factors possibly responsible for a poor referral rate of ECPs and the factors affecting treatment implementation by specialists were explored. We also searched for unmet needs such as the incorporation of geriatric assessment into routine practice and continuous medical education (CME) programs.

Results: A total of 1217 questionnaires were returned (46.9%) from 1053 GPs and 214 SPs. Patients' age did not negatively impact referral to SPs as opposed to patients' performance status, wishes, and co-morbidities. Conversely, a significant decrease in patients' file presentation by SPs to tumor boards was observed for patients over 80 years old. Neither reimbursement nor SPs' waiting lists were an issue. The need for CME programs in geriatric oncology was emphasized by both GPs and SPs.

Conclusions: Age was not the governing variable that impacted patient referral. The need for CME in geriatrics was highlighted for both GPs and SPs.
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http://dx.doi.org/10.1016/j.critrevonc.2009.03.002DOI Listing
July 2010

Adriamycin, cisplatin, ifosfamide and paclitaxel combination as front-line chemotherapy for locally advanced and metastatic angiosarcoma. Analysis of three case reports and review of the literature.

Anticancer Res 2008 Sep-Oct;28(5B):3041-5

Department of Hematology and Oncology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Angiosarcoma represents 1 to 2% of soft tissue tumors. It originates from endothelial cells of small blood vessels and may affect a variety of organs, including the retroperitoneum, skeletal muscle, subcutis, liver, heart and breast. The outcome of angiosarcoma is poor for those patients in whom aggressive surgery cannot be considered. Chemotherapy, generally consisting of the combination of anthracyclines and ifosfamide, has little, but consistent effect. We report three cases of angiosarcoma in which first-line chemotherapy with adriamycin 40 mg/m2 day 1, ifosfamide 3 g/m2 day 1-2, cisplatin 35 mg/m2 day 1-2 and paclitaxel 175 mg/m2 day 3 led to clinically meaningful responses. The clinical relevance of incorporating paclitaxel in conventional soft tissue chemotherapy schedules in the light of both literature data and our experience is discussed. We emphasize the need for designing trials specifically dedicated to angiosarcomas, as this rare and severe condition may be a target for new antiangiogenic drugs.
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January 2009

Factors associated with overall and attributable mortality in invasive aspergillosis.

Clin Infect Dis 2008 Nov;47(9):1176-84

Pharmacie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Background: Invasive aspergillosis is associated with high death rates. Factors associated with increased mortality have not yet been identified in a large population of patients with various underlying conditions.

Methods: We retrospectively reviewed 385 cases of suspected or documented aspergillosis that occurred during a 9-year period. We identified 289 episodes that fulfilled the criteria for possible, probable, or proven invasive aspergillosis according to the international definition criteria and that was treated with an anti-Aspergillus active antifungal drug. Clinical and microbiological variables were analyzed for their effects on overall and attributable mortality. Significant variables in univariate analysis were introduced into a multivariate Cox model.

Results: Twelve-week overall and disease-specific survival rates were 52.2% (95% confidence interval, 46.5%-57.9%) and 59.8% (95% confidence interval, 54.0%-65.4%), respectively. Receipt of allogeneic hematopoietic stem cell or solid-organ transplant, progression of underlying malignancy, prior respiratory disease, receipt of corticosteroid therapy, renal impairment, low monocyte counts, disseminated aspergillosis, diffuse pulmonary lesions, pleural effusion, and proven or probable (as opposed to possible) aspergillosis are predictors of increased overall mortality. Similar factors are also predictors of increased attributable mortality, with the following exceptions: pleural effusion and low monocyte counts have no impact, whereas neutropenia is associated with a higher attributable mortality.

Conclusions: Identification of predictors of death helps in the identification of patients who could benefit from more-aggressive therapeutic strategies. Initiation of therapy at the stage of possible infection improves outcome, and this finding calls for the development of efficient preemptive strategies to fill the gap between empirical and directed therapy.
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http://dx.doi.org/10.1086/592255DOI Listing
November 2008

Pleiotropic functional properties of androgen receptor mutants in prostate cancer.

Hum Mutat 2009 Feb;30(2):145-57

EA 3430-Signalisation et Cancer de la Prostate, Faculté de Médecine, Université Strasbourg, Strasbourg, France.

The androgen receptor (AR) signaling pathway plays an important role during the development of the normal prostate gland, but also during the progression of prostate cancer on androgen ablation therapy. Mutations in the AR gene emerge to keep active the AR signaling pathway and to support prostate cancer cells growth and survival despite the low levels of circulating androgens. Indeed, mutations affecting the ligand binding domain (LBD) of the AR have been shown to generate so-called "promiscuous" receptors that present widened ligand specificity and allow the stimulation of these receptors by a larger spectrum of endogenous hormones. Another class of mutations, arising in the amino-terminal domain (NTD) of the receptor, modulate AR interactions with coregulators involved in cell proliferation regulation. Besides characteristics of these well-known types of mutations, the properties of other classes of AR mutants recently described in prostate cancer are currently under investigation. Most interestingly, in addition to their potential role in the mechanisms which allow prostate cancer cells to escape androgen ablation therapy, data suggest that certain AR mutations are present early in the natural history of the disease and may play a role in many aspects of prostate cancer progression. Surprisingly, singular truncated AR devoid of their carboxy-terminal end (CTE) region seem to exert specific paracrine effects and to induce a clonal cooperation with neighboring prostate cancer cells, which may facilitate both the invasion and metastasis processes. In this article, we review the functional properties of different classes of AR mutants and their potential impact on the natural history of prostate cancer. Hum Mutat 0, 1-14, 2008. (c) 2008 Wiley-Liss, Inc.
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http://dx.doi.org/10.1002/humu.20848DOI Listing
February 2009

Clinical pharmacology of trastuzumab.

Curr Clin Pharmacol 2008 Jan;3(1):51-5

Department of Pharmacy and Pharmacology, Hôpitaux Universitaires de Strasbourg, Hôpital Hautepierre, avenue Molière, 67000 Strasbourg, France.

Trastuzumab is a monoclonal antibody that targets the extracellular domain of HER2, a member of the epidermal growth factor receptor (EGFR) family. Trastuzumab is currently approved for the treatment of breast cancer overexpressing HER2, given alone or in combination with paclitaxel or docetaxel. Trastuzumab pharmacokinetics are characterized by a low systemic clearance, a low volume of distribution (4l) and a very long half-life (28 days) comparable to that of endogenous immunoglobulins G. The elimination pathways are not yet defined and the clinical relevance of trastuzumab kinetic variability is unknown. Whether exposure might correlate with toxic effects or inadequate response has not been explored. No drug-drug interactions have been reported. This is not surprising because based on the current knowledge, no monoclonal antibody (including trastuzumab) has been found to interact with major molecular pharmacokinetic determinants such enzymes, drug transporters or orphan nuclear receptors. Dosage regimens of trastuzumab are similar either it is used in the adjuvant setting (postoperative) or in metastatic disease. According to the official labelling, trastuzumab is given by intravenous perfusion at a dose based on body weight, weekly (metastatic, adjuvant) or 3-weekly (adjuvant). The schedule also includes a loading dose at the initiation of the treatment. The recommended duration of treatment is currently one year (adjuvant) or until the progression of the disease (metastatic). Regarding the adjuvant setting, different dosage regimens have been tested (from 9 weeks to 2 years) but the optimal duration of treatment is unknown. The short course of trastuzumab (9 weeks) appears promising in terms of activity, tolerance and cost but should be compared to 1 or 2-years treatments. In addition, dosing regimens might be optimized by integrating pharmacokinetic elements. In the adjuvant setting, given the more favorable kinetic situation (absence of tumor penetration), a less intense dosage regimen might be appropriate when compared with that used in metastatic disease. Further body weight is weakly related to trastuzumab exposure and it is not proven that it significantly affects clinical activity. These pharmacokinetic considerations may support the use of fixed doses given monthly, on short periods, for the treatment of early breast cancer.
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http://dx.doi.org/10.2174/157488408783329931DOI Listing
January 2008

Diffuse primary angiosarcoma of the pleura: a case report and review of the literature.

Sarcoma 2004 ;8(4):103-6

Department of Hematology and Oncology Hôpitaux Universitaires de Strasbourg 1 Av Molière Strasbourg 67098 France.

Primary pleural angiosarcoma is an extremely rare tumor. We report the case of a patient who presented with recurrent massive bilateral hemothoraxes. Although thoracoscopy was performed, biopsy samples of the pleura were inconclusive. The delayed onset of skin metastases led to the diagnosis of angiosarcoma, however the patient died from pleuropulmonary progression before treatment could be started. We review the literature of primary pleuropulmonary angiosarcoma and discuss its treatment modalities.
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http://dx.doi.org/10.1080/1357-7140400003596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2395614PMC
July 2011

Specific properties of a C-terminal truncated androgen receptor detected in hormone refractory prostate cancer.

Adv Exp Med Biol 2008 ;617:529-34

Laboratoire de Cancerologie Experimentale et de Radiobiologie, Strasbourg, France.

Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFkappaB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.
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http://dx.doi.org/10.1007/978-0-387-69080-3_53DOI Listing
July 2008

Effect of pO2 on antitumor drug cytotoxicity on MDR and non-MDR variants selected from the LoVo metastatic colon carcinoma cell line.

Anticancer Res 2008 Jan-Feb;28(1A):55-68

EA/ULP 3430, Laboratoire de Cancérologie Expérimentale et de Radiobiologie, IRCAD/HUS, BP426, F-67091 Strasbourg cedex, France.

Two chemosensitive cell lines, LoVo-fusoid (LoVo-f) and LoVo-small cells (LoVo-sc) were derived from the original LoVo cell line. These two variants and the multidrug-resistant (MDR) cell line LoVo-Dox were screened for various properties. In non-permeabilized cells, only LoVo-sc showed mucin-2 staining whereas labelling was positive in all permeabilized cell lines. As shown by electron microscopy screening and by relative resistance to trypsin detachment, only LoVo-sc cells showed strong mucus secretion. All three cell lines displayed strong staining for P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and lung-resistance-related protein (LRP) in different locations according to the drug resistance state. The three cell lines showed intracellular labelling of LRP and MRP. The sensitive cells showed P-gp in a large perinuclear ring and in the cytoplasm, but little (LoVo-sc cells) or no staining (LoVo-f cells) was shown at the plasma membrane level. For the Lovo-Dox cells, P-gp was located in the plasma membrane, in cellular anchorages and in the cytoplasm as well. Cell resistance against antineoplastic agents often results from mobilization of various factors, the modulation of which is linked to the culture conditions. As most of the protocols utilize cells growing in (air + 5-10% CO2) atmosphere e.g. 20% O2, balance of the respective participants in the MDR multi-modal mechanism may not be representative of the in vivo situation and may lead to erratic pharmacological response. Indeed, cells within solid tumours were exposed to low pO2, most of them being under hypoxic condition (0.1-5% O2). In the absence of anticancer drugs, all LoVo cell lines grew notably faster at 20% O2 than at 5% O2. Moreover, respective sensitivities of both non-MDR variants to doxorubicin were altered according the pO2. Whatever the pO2 was, virtually none of the antioxidants tested affected the cytotoxic activity of doxorubicin for the three cell lines. By contrast, trolox showed a strong inhibitory effect on doxorubicin activity. These results underline the importance of evaluating the role of hypoxia on the cytotoxic effect of chemotherapeutic agents used either as single drugs or in combination therapy.
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April 2008

A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions.

Endocrinology 2007 Sep 31;148(9):4334-43. Epub 2007 May 31.

Faculté de Médecine/Signalisation et Cancer de la Prostate/Equipe d'Accueil 3430, Université Strasbourg, Strasbourg, France.

The androgen receptor (AR) is a ligand-activated transcription factor that displays genomic actions characterized by binding to androgen-response elements in the promoter of target genes as well as nongenomic actions that do not require nuclear translocation and DNA binding. In this study, we report exclusive cytoplasmic actions of a splicing variant of the AR detected in a metastatic prostate cancer. This AR variant, named AR23, results from an aberrant splicing of intron 2, wherein the last 69 nucleotides of the intronic sequence are retained, leading to the insertion of 23 amino acids between the two zinc fingers in the DNA-binding domain. We show that the nuclear entry of AR23 upon dihydrotestosterone (DHT) stimulation is impaired. Alternatively, DHT-activated AR23 forms cytoplasmic and perinuclear aggregates that partially colocalize with the endoplasmic reticulum and are devoid of genomic actions. However, in LNCaP cells, this cytoplasmic DHT-activated AR23 remains partially active as evidenced by the activation of transcription from androgen-responsive promoters, the stimulation of NF-kappaB transcriptional activity and by the decrease of AP-1 transcriptional activity. Our data reveal novel cytoplasmic actions for this splicing AR variant, suggesting a contribution in prostate cancer progression.
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http://dx.doi.org/10.1210/en.2007-0446DOI Listing
September 2007

Unexpected paracrine action of prostate cancer cells harboring a new class of androgen receptor mutation--a new paradigm for cooperation among prostate tumor cells.

Int J Cancer 2007 Sep;121(6):1238-44

Université Strasbourg-Fac de Médecine, EA 3430-Signalisation et Cancer de la Prostate, Strasbourg, France.

The emergence of mutations in the androgen receptor (AR) gene is a recurrent event during progression of prostate cancer (PCa) on androgen ablation therapy. In this study, we show that nonsense mutations that lead to carboxyl-terminal end truncated ARs are found at high frequency in metastatic PCas. Transcriptional activities of the Q640X mutant AR in the androgen-sensitive LNCaP cell line differ to those of the wild-type AR. Indeed, this mutant AR exhibits strong and ligand-independent transcriptional activities from an artificial promoter construct containing two repeats of androgen-responsive elements, but is inactive on the human PSA gene promoter. Nevertheless, the expression of the Q640X mutant AR in LNCaP cells is accompanied by an increase in the level of PSA protein, and by an increase in the expression of the endogenous AR gene. This enhanced expression of the endogenous AR gene is not limited to the sole transfected cells, but is observed in non-transfected neighboring cells. Additionally, in co-cultures of transfected and non-transfected LNCaP cells, the Q640X mutant AR leads to an unpredicted nuclear localization of the endogenous AR protein in the two cellular populations and this, in the absence of androgen. These data indicate that cells expressing the Q640X mutant AR acquire the property to emit a signal that activates the AR in neighboring cells by a paracrine mechanism and in a ligand-independent manner. Our data strongly support the notion of cooperation among tumor cells in PCa and could be of relevance for the understanding of progression on androgen ablation therapy.
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http://dx.doi.org/10.1002/ijc.22830DOI Listing
September 2007

The cytotoxicity of high-linear energy transfer radiation is reinforced by oxaliplatin in human glioblastoma cells.

Cancer Lett 2007 Aug 26;254(1):54-62. Epub 2007 Mar 26.

Laboratoire de Cancérologie Expérimentale et de Radiobiologie, EA-3430, IRCAD, Hôpitaux Universitaires, 1 Place de l'Hôpital, Strasbourg, France.

The combination of high-linear energy transfer (LET) radiation with chemotherapeutic agents may offer new perspectives in cancer treatment. We therefore assessed the consequences of a treatment in which U-87 human glioblastoma cells were irradiated with p(65)+Be neutrons in the presence of oxaliplatin, a third generation platinum anticancer drug having higher apoptosis-inducing activity than cisplatin. Cell survival, apoptosis, cell cycle progression as well as p21 and p53 protein expressions were analyzed. Results show that an enhanced cytotoxic effect was obtained when the two treatments were combined and that, unlike what we previously observed with cisplatin, this was not due to a reinforcement of apoptosis. Altogether, our results also indicate the potential of oxaliplatin for use in association with high-LET radiation against tumors refractory to conventional photon radiotherapy.
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http://dx.doi.org/10.1016/j.canlet.2007.02.001DOI Listing
August 2007