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Clermont-Ferrand, France

Bayet-Robert M.,University of Auvergne | Morvan D.,University of Auvergne | Morvan D.,Comprehensive Cancer Center Jean Perrin
PLoS ONE | Year: 2013

Background: Curcumin (CUR) has deserved extensive research due to its anti-inflammatory properties, of interest in human diseases including cancer. However, pleiotropic even paradoxical responses of tumor cells have been reported, and the mechanisms of action of CUR remain uncompletely elucidated. Methodology/Principal Findings: 1H-NMR spectroscopy-based metabolomics was applied to get novel insight into responses of MCF7 and MDA-MB-231 breast cancer cells to CUR alone, and MCF7 cells to CUR in cotreatment with docetaxel (DTX). In both cell types, a major target of CUR was glutathione metabolism. Total glutathione (GSx) increased at low dose CUR (≤ 10 mg.l-1-28 μM-) (up to +121% in MCF7 cells, P<0.01, and +138% in MDA-MB-231 cells, P<0.01), but decreased at high dose (≥ 25 mg.l-1 -70 μM-) (-49%, in MCF7 cells, P<0.02, and -56% in MDA-MB-231 cells, P<0.025). At high dose, in both cell types, GSx-related metabolites decreased, including homocystein, creatine and taurine (-60 to -80%, all, P<0.05). Together with glutathione-S-transferase actvity, data established that GSx biosynthesis was upregulated at low dose, and GSx consumption activated at high dose. Another major target, in both cell types, was lipid metabolism involving, at high doses, accumulation of polyunsaturated and total free fatty acids (between ×4.5 and ×11, P<0.025), and decrease of glycerophospho-ethanolamine and -choline (about -60%, P<0.025). Multivariate statistical analyses showed a metabolic transition, even a biphasic behavior of some metabolites including GSx, between low and high doses. In addition, CUR at 10 mg.l-1 in cotreatment with DTX induced modifications in glutathione metabolism, lipid metabolism, and glucose utilization. Some of these changes were biphasic depending on the duration of exposure to CUR. Conclusions/Significance: Metabolomics reveals major metabolic targets of CUR in breast cancer cells, and biphasic responses that challenge the widely accepted beneficial effects of the phytochemical. © 2013 Bayet-Robert, Morvan.

Cachin F.,Comprehensive Cancer Center Jean Perrin | Cachin F.,French Institute of Health and Medical Research | Cachin F.,Clermont University | Miot-Noirault E.,French Institute of Health and Medical Research | And 26 more authors.
Journal of Nuclear Medicine | Year: 2014

Our group has developed a new radiopharmaceutical, 123I-N-(2- diethylaminoethyl)-2-iodobenzamide (123I-BZA2), a benzamide derivative able to bind to melanin pigment in melanoma cells. In a prospective and multicentric phase III clinical study, the value of 18F-FDG PET/CT and 123I-BZA2 scintigraphy was compared for melanoma staging. Methods: Patients with a past history of cutaneous or ocular melanoma were included from 8 hospitals. 18F-FDG imaging was performed according to a standard PET protocol. Whole-body, static planar, and SPECT/CT (if available) images were acquired 4 h after injection of a - MBq/kg dose of 123I-BZA2. 18F-FDG and 123I-BZA2 sensitivity and specificity for the diagnosis of melanoma metastasis were calculated and compared on both a lesion basis and a patient basis. True-positive and true-negative lesion status was determined after ± mo of clinical follow-up or according to lesion biopsies (if available). Melanin content in biopsies was evaluated with the standard Fontana-Masson silver method and was correlated with 123IBZA2 uptake. Based on statistical analysis, the number of inclusions was estimated at 186. Results: In all, 87 patients were enrolled from 2008 to 2010. Of these, 45 (52%) had metastases. A total of 338 imaging abnormalities were analyzed; 86 lesions were considered metastases, and 20 of 25 lesion biopsies found melanoma metastases. In a patient-based analysis, the sensitivity of 18F-FDG for diagnosis of melanoma metastases was higher than that of 123I-BZA2, at 87% and 39%, respectively (P < 0.05). For specificity, 18F-FDG and 123I-BZA2 were not statistically different, at 78% and 94%, respectively. In a lesion-based analysis, the sensitivity of 18F-FDG was statistically higher than that of 123I-BZA2 (80% vs. 23%, P < 0.05). The specificity of 18F-FDG was lower than that of 123I-BZA2 (54% vs. 86%, P < 0.05). According to biopsy analysis, only 9 of 20 metastatic lesions (45%) were pigmented with high melanin content. 123I-BZA2 imaging was positive for ± of 8 melanin-positive lesions, fairly positive for 3 of 10 melanin-negative lesions, and negative for 7 of 10 melaninnegative lesions. The sensitivity and specificity of 123I-BZA2 for the diagnosis of melanin-positive lesions were 75% and 70%, respectively. Because of a low 123I-BZA2 sensitivity, this clinical trial was prematurely closed after 87 patients had been included. Conclusion: This study confirms the value of 18F-FDG PET/CT for melanoma staging and strengthens the high accuracy of 123I-BZA2 for diagnosis of melanin-positive metastatic melanoma. Moreover, benzamide derivatives radiolabeled with therapeutic radionuclide may offer a new strategy for the treatment of metastatic melanoma patients harboring melanin-positive metastases. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Kwiatkowski F.,Comprehensive Cancer Center Jean Perrin | Dessenne P.,Comprehensive Cancer Center Jean Perrin | Laquet C.,Comprehensive Cancer Center Jean Perrin | Petit M.-F.,Comprehensive Cancer Center Jean Perrin | Bignon Y.-J.,Comprehensive Cancer Center Jean Perrin
European Journal of Human Genetics | Year: 2012

How long counselees retain the information given during their genetic consultation is of major importance. To address this issue, we conducted a survey among the 3500 families that have been offered genetic counseling at our Center since 1988. In August 2007, we mailed a questionnaire to a representative subset of 579 persons belonging to breast/ovarian or colon cancer families seen in the last 10 years, either carrying an identified mutation or not. Targeted topics included the meaning of hereditary predisposition, the medical prevention related to the familial risk, the steps to undertake for a new family member to enter the genetic testing program and general knowledge of hereditary predisposition to cancer. A total of 91 randomized non-respondents were sent a second, more inciting letter, in order to assess any non-response bias. Overall, 337 questionnaires were collected: response rate was 58%. Standardized average knowledge was 7.28±1.52 of 10. Scores were lowest concerning medical prevention. The level of knowledge decreased with age (P<10-6), but increased with educational level (P<10-5) and mutation status (P=0.01). Surprisingly, no erosion of patients knowledge over the time was observed (P=0.41). Among persons at hereditary risk of colon cancer, the level of knowledge tended to improve with time, in contrast to the breast/ovarian group (P=0.017). Among persons with a familial risk of breast/ovarian or colon cancer, a renewal of oncogenetic counseling does not seem necessary to maintain the level of specific knowledge. Measures to help patients follow their medical prevention, as organizing or checking their medical examinations, seem indicated. © 2012 Macmillan Publishers Limited All rights reserved.

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