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Pasquier E.,University of New South Wales | Street J.,University of New South Wales | Pouchy C.,University of New South Wales | Pouchy C.,University Pierre and Marie Curie | And 9 more authors.
British Journal of Cancer | Year: 2013

Background: The use of b-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether b-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma. Methods: Seven b-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma. Results: Three b-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. b-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, b-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, b-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01). Conclusion: b-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers. © 2013 Cancer Research UK. All rights reserved. Source

Pasquier E.,University of New South Wales | Tuset M.-P.,University of New South Wales | Street J.,University of New South Wales | Sinnappan S.,University of New South Wales | And 7 more authors.
Angiogenesis | Year: 2013

The anti-angiogenic activity of chemotherapy is both dose- and schedule-dependent. While conventional maximum tolerated dose (MTD) chemotherapy exerts only mild and reversible anti-angiogenic effects, low-dose metronomic (LDM) chemotherapy was developed to specifically target tumour angiogenesis. However, the long-term effects of either MTD or LDM chemotherapy on vascular endothelial cells have never been investigated. Here, we demonstrated that repeated exposure to MTD and LDM chemotherapy differentially impact on the angiogenic potential and chemosensitivity of immortalized endothelial cells. Repeated MTD vinblastine treatment of vascular endothelial cells led to an increased proliferation rate and resistance to paclitaxel. In contrast, repeated LDM treatment with vinblastine or etoposide impaired the angiogenic potential of endothelial cells and increased their chemosensitivity. This effect was associated with a significant decrease in βII- and βIII-tubulin expression. Functional analysis using siRNA showed that silencing the expression of βIII-tubulin in endothelial cells significantly decreased their capacity to form vascular structures and increased their sensitivity to the anti-angiogenic and vascular-disrupting effects of chemotherapy, whereas silencing βII-tubulin expression had no effect. Collectively our results show that LDM chemotherapy impairs the angiogenic potential of endothelial cells while increasing their chemosensitivity - an effect at least in part mediated by the down-regulation of βIII-tubulin expression. Furthermore, our study suggests that βIII-tubulin represents an attractive therapeutic target to increase the anti-angiogenic effects of chemotherapy and overall anti-tumour efficacy. © 2012 The Author(s). Source

Zapletalova D.,University Hospital Brno | Andr N.,Metronomics Global Health Initiative | Deak L.,University Hospital Koice | Kyr M.,University Hospital Brno | And 18 more authors.
Oncology (Switzerland) | Year: 2012

Background: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. Methods: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. Results: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. Conclusion: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile. © 2012 S. Karger AG, Basel. Source

Andre N.,Service dHematologie et Oncologie Pediatrique | Abed S.,Service dHematologie et Oncologie Pediatrique | Orbach D.,University Pierre and Marie Curie | Alla C.A.,Service dOncologie Pediatrique | And 5 more authors.
Oncotarget | Year: 2011

Background: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. MC is gaining interest as an alternative strategy to fight resistant cancer. Objective: to assess the safety of 4 drug MC regimen in pediatric patients with refractory or relapsing various tumors types. Setting: From November 2008 to December 2010, in three academic pediatric oncology centers, 16 children (median age 12 years old; range 5.5-20) were included in this pilot study. This treatment was proposed to children with refractory disease for whom no further effective treatments were available. Most frequent diagnosis were medulloblastoma/cerebral PNET (5) osteosarcoma (5), and one case each of nephroblastoma, high grade glioma, Hodgkin lymphoma, rhabdomyosarcoma, neuroblastoma and kidney rhabdoid tumour. The MC regimen consisted in cycles of 56 days (8 weeks) with weekly vinblastine 3 mg/mï¿1/2 (week 1-7), daily cyclophosphamide 30 mg/mï¿1/2 (days 1-21), and twice weekly methotrexate 10 mg/mï¿1/2 (days 21-42), and daily celecoxib 100 mg to 400 mg twice daily (days1-56) followed by a 2-weeks chemotherapy break. Adverse events were determined through laboratory analysis and investigator observations. Results: One objective response was observed in a patient with Hodgkin lymphoma, and 4 patients experienced disease stabilization and continued their treatment for 3 cycles (24 weeks) or more. At last follow-up, 7 patients (43%) are alive including 1 still undergoing treatment. During the overall 36 cycles of treatments received by patients, 4 grade IV toxicities and 24 grade III toxicities were observed in 11 cycles in only 10 different patients. Conclusion: The metronomic regimen we report here was well tolerated and associated with disease stabilization. This regimen is currently being evaluated in a national multicenter phase II study. © André et al. Source

Traore F.,Hospital Gabriel Toure | Togo B.,Hospital Gabriel Toure | Pasquier E.,Metronomics Global Health Initiative | Pasquier E.,University of New South Wales | And 2 more authors.
Indian Journal of Cancer | Year: 2013

Background: Metronomics is defined by the combination of metronomic chemotherapy and drug repositioning. Since off-patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, metronomics appears to be an invaluable alternative to bring affordable targeted therapies in low-income countries. Objective: The aim of this study was to report on the preliminary efficacy and safety of a metronomic vincristine/cyclophosphamide/ methotrexate/valproic acid regimen given to children with refractory cancer of various tumor types or with a very advanced disease. Materials and Methods: This prospective, single-center study evaluated the use of a metronomics protocol, consisting of a first cycle of weekly vincristine 1.5 mg/m 2 (days: 1, 8, 15 and 22), daily cyclophosphamide 25 mg/m 2 (days: 1-21), twice weekly methotrexate 15 mg/m (days: 21-42) and daily valproic acid (30 mg/kg/d) followed by a 1-week break. For the following cycles, vincristine was administrated only at week 1 and 5 of the cycle. This treatment was proposed to children with refractory disease and patients who were not eligible for the protocols available in the hospital. Adverse events were determined through laboratory analyses and investigator observations. Results: From January 2010 to January 2011, 7 children (mean age: 5.4 ± 3 years old) were treated. Most frequent diagnosis was retinoblastoma. Two partial responses were observed in patients with neuroblastoma and retinoblastoma. These two patients are alive with stable disease at last follow-up (6 and 26 months, respectively) after stopping treatment. Conclusion: Metronomics allows treating patients with advanced or refractory or relapsing disease and the introduction of targeted treatments in low-income countries. The potential of metronomics in children and young adults living in middle-and low-income countries warrants further larger studies. Source

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