Papers by Vincent Favaudon
European Journal of Biochemistry, 1983
Substitution of Fe2+ for the Zn2+ ion in Hansenula anomala cytochrome c provides a luminescent de... more Substitution of Fe2+ for the Zn2+ ion in Hansenula anomala cytochrome c provides a luminescent derivative suitable as a probe for the determination of the interaction of cytochrome c with H. anomala flavocytochrome b2; its light absorption and fluorescence properties have been characterized. H. anomala Zn-cytochrome c appears to be in the form of a stable though non-covalent dimer from molecular weight determinations performed using gel filtration, polyacrylamide gel electrophoresis under denaturing conditions, and ultracentrifugation methods. By contrast, metal-free porphyrin-cytochrome c, the precursor of Zn-cytochrome c obtained upon removal of iron from cytochrome c in cold anhydrous fluorhydric acid, had the same partition coefficient as native cytochrome c through conventional gel filtration. Significant conformational perturbations of H. anomala cytochrome c should therefore follow from Zn2+ incorporation into the porphyrin c moiety. Titrations at low ionic strength with native, tetrameric H. anomala flavocytochrome b2 in the lactate-reduced state showed a simple binding equilibrium (Kd = 0.1 microM at I = 0.03 M, 10 degrees C) with a stoichiometry of one Zn-cytochrome c dimer per protomer of flavocytochrome b2. Quenching of the Zn-porphyrin c fluorescence within this complex was much larger (43%) than reported by other authors using cytochrome c and flavocytochrome b2 from different sources.
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BMC Pharmacology, Feb 6, 2002
Growth inhibition by RPR-130401, a non-peptidomimetic farnesyltransferase inhibitor, was investig... more Growth inhibition by RPR-130401, a non-peptidomimetic farnesyltransferase inhibitor, was investigated without or with combined exposure to ionizing radiation in three human tumor cell lines (HCT-116, MiAPaCa-2 and A-549) bearing a point mutation in the K-Ras gene. RPR-130401 inhibited cell growth with an IC50 of 50 nM (HCT-116), 120 nM (MiAPaCa-2) and 710 nM (A-549), with a poor incidence of apoptosis. The drug brought about G1 and S phase depletion together with arrest of cells in G2 phase and induced a significant accumulation of hyperploid cells showing active S phase DNA synthesis, with HCT-116 and A-549 cells being the most and least responsive, respectively. The drug also produced dramatic changes of the nuclear lamin B pattern, without lamin B cleavage and perturbation of the actin cytoskeleton. On the other hand, RPR-130401 elicited strictly additive interaction in combined treatment with ionizing radiation with regard to cell kill, altered cell cycle progression and induced...
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The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with gamma-ra... more The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with gamma-ray irradiation was investigated using Chinese hamster V-79 cells in culture. gamma-ray irradiation and drug treatment (1-h drug exposure) were applied at 1-h intervals for partial DNA damage recovery in growth medium. Isobologram analysis of the clonogenic potential gave evidence of supraadditive interaction in the radiation----drug sequence with 10% survival as an endpoint. No synergistic potentiation was observed at higher survival or as pazelliptine was applied first. Pazelliptine abolished the low-dose shoulder characteristic of asynchronous cell response to gamma-rays. Although rejoining of radiation-induced DNA strand breaks was completed at the time of drug exposure, pazelliptine brought about a larger amount of DNA strand breaks in preirradiated than in nonirradiated cells. The time and dose dependencies of DNA strand break formation and repair with radiation and/or pazelliptine w...
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Molecular cancer …, 2005
Enhanced cytotoxicity of etoposide by wortmannin, an inhibitor of enzymes holding a phosphatidyli... more Enhanced cytotoxicity of etoposide by wortmannin, an inhibitor of enzymes holding a phosphatidylinositol 3-kinase domain, was investigated in eight cell lines proficient or deficient for DNA double-strand break repair. Wortmannin stimulated the decatenating activity of topoisomerase II, ...
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Bioorganic & medicinal …, 1999
The crystal structures of CDK2 complexes with olomoucine and (R)-roscovitine have been solved at ... more The crystal structures of CDK2 complexes with olomoucine and (R)-roscovitine have been solved at 2.2–2.4 Å resolution.[9, 12] Interestingly, the position of the purine nucleus in the ATP binding pocket of CDK2 differs markedly from that for the natural substrate, ATP. In addition, ...
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Cancers
The development of innovative approaches that would reduce the sensitivity of healthy tissues to ... more The development of innovative approaches that would reduce the sensitivity of healthy tissues to irradiation while maintaining the efficacy of the treatment on the tumor is of crucial importance for the progress of the efficacy of radiotherapy. Recent methodological developments and innovations, such as scanned beams, ultra-high dose rates, and very high-energy electrons, which may be simultaneously available on new accelerators, would allow for possible radiobiological advantages of very short pulses of ultra-high dose rate (FLASH) therapy for radiation therapy to be considered. In particular, very high-energy electron (VHEE) radiotherapy, in the energy range of 100 to 250 MeV, first proposed in the 2000s, would be particularly interesting both from a ballistic and biological point of view for the establishment of this new type of irradiation technique. In this review, we examine and summarize the current knowledge on VHEE radiotherapy and provide a synthesis of the studies that ha...
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Medical Physics
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International journal of radiation oncology, biology, physics, Jan 11, 2018
Recent in vivo investigations have shown that short pulses (FLASH) of electrons are less harmful ... more Recent in vivo investigations have shown that short pulses (FLASH) of electrons are less harmful to healthy tissues, but just as efficient as conventional dose-rate radiation to inhibit tumor growth. In view of the potential clinical value of FLASH and the availability of modern proton therapy infrastructures to achieve this goal, we herein describe a series of technological developments required to investigate the biology of FLASH irradiation, using a commercially available clinical proton therapy system. Numerical simulations and experimental dosimetric characterization of a modified clinical proton beamline, upstream from the isocenter were performed with Monte Carlo toolkit and different detectors. A single scattering system was optimized together with a ridge filter and a high current monitoring system. In addition, a submillimetric set-up protocol based on image-guidance using a digital camera and an animal positioning system was also developed. The dosimetric properties of th...
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Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, Sep 1, 2017
This study shows for the first time that normal brain tissue toxicities after WBI can be reduced ... more This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100Gy/s, whereas 10Gy WBI at a conventional radiotherapy dose rate (0.1Gy/s) totally impairs spatial memory.
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Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 6, 2018
Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differenti... more Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals. Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at ultra-high dose rate called FLASH-RT and irradiation delivered at conventional dose rate called Conv-RT. A clinical-phase-I single-dose escalation trial (25-41 Gy) was performed in six cat-patients with locally-advanced T2/T3N0M0 squamous-cell-carcinoma of the nasal planum, to determine the maximal tolerated dose and progression-free survival of single-dose FLASH-RT. Using respectively depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥ 20% dose-equivalent difference vs Conv-RT). Three cats experienced no acute toxicity, whereas three exhibited moderate/mild transient mucositis and all cats ha...
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Bulletin du Cancer
In this review, we present the synthesis of the newly acquired knowledge concerning high dose-rat... more In this review, we present the synthesis of the newly acquired knowledge concerning high dose-rate irradiations and the hopes that these new radiotherapy modalities give rise to. The results were presented at a recent symposium on the subject.
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Biochemistry Usa, 1975
The dismutation reactions of flavines in dimethylformanide have been investigated using the stopp... more The dismutation reactions of flavines in dimethylformanide have been investigated using the stopped-flow technique under anaerobic conditions. The ionization constants of fully reduced and oxidized tetraacetylriboflavine were measured spectrophotometrically in buffered dimethylformanide. The dismutation equilibrium of the flavine as a function of pH in dimethylformanide was roughly comparable to that reported in water and allowed the estimation of the pKa value of the flavosemiquinone. The dismutation kinetics of tetraacetylriboflavine in unbuffered dimethylformanide were investigated using the fully oxidized and reduced flavines in their neutral form at constant produce of concentrations and varying the reduction degree. The kinetics at very low reduction ratios (less than3%) were triphasic. The kinetic analysis of the initial and simultaneous formation of the anionic and neutral radicals revealed a second-order reaction. The electron transfer between the oxidized and reduced flavines was not directly coupled with prton exchange. The multiphasic time course of the reaction proceeded primarily from differences in the intrinsic rates of the direct and mixed backward dismutation reactions of the two radical species, and finally from a change in the equilibrium conditions resulting from the accumulation of anionic flavohydroquinone. An acidic-basic negative catalytic effect from the neutral flavohydroquinone appeared progressively as the reduction degree was increased. It was complete at reduction ratios higher than 30%, i.e. under conditions where the radical anion could not be observed at any reaction time. Acids with a pKa value lower than the second one of the flavosemiquinone exhibited a similar catalytic effect. These acidic-basic catalytic effects are associated with changes in the ionic state of labile intermediate dimers formed in the forward as well as in the backward direactions of the dismutation reaction. Such a transient complex revealed by the kinetic analysis could be observed directly by absorption spectroscopy in alkaline-buffered dimethylformanide. Its spectral characteristics, as well as the kinetic effects induced by substitution of the benzenoid part of the flavine, can hardly be taken into account by a quinhydrone-like structure for the intermediate dimers at any pH value. The experimental results favored a more specific interaction, possibly of covalent character, involving the benzenoid part of the isoalloxazine ring.
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Bulletin Du Cancer, Dec 1, 2005
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Febs Lett, 1987
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Cancer Radiother, 1999
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Inorg Chem, 1979
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Cancer Radiother, 1997
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The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with f-ray ir... more The cytotoxic effect of the 9-azaellipticine derivative pazelliptine in combination with f-ray irradiation was investigated using Chinese ham ster Y-79 cells in culture. 7-ray irradiation and drug treatment (1-h drug exposure) were applied at 1-h intervals for partial DNA damage recovery in growth medium. Isobologram analysis of the clonogenic potential gave evidence of supraadditive interaction in the radiation â€"» drug
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Bulletin Du Cancer, Dec 1, 2005
... 6 Akimoto T, Hunter N, Buchmiller L, Mason K, Kian Ang K, Milas L. Inverse relationship betwe... more ... 6 Akimoto T, Hunter N, Buchmiller L, Mason K, Kian Ang K, Milas L. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. ... 46Abdollahi A, Lipson K, Han X, Krempien R, Trinh T, Weber K, et al. ...
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Targeted Oncology, 2015
Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent der... more Pancreatic adenocarcinoma is characterized by a high frequency of KRAS mutations and frequent deregulation of the epidermal growth factor receptor (EGFR) and other EGFR family members such as HER2/ErbB2. The EGFR inhibitor erlotinib is approved for treatment of pancreatic cancer, but has shown modest activity in most patients. Here we investigated the activity of afatinib, a second-generation irreversible pan-EGFR family kinase inhibitor, alone or in combination with ionizing radiation, toward pancreatic cancer cells. The influence of afatinib on cell proliferation, cell cycle distribution, clonogenic survival, nuclear fragmentation, ploidy, and centrosome amplification following irradiation was determined. Expression and phosphorylation of HER receptors, Akt, DNA-PKcs, and ERK1/2 was characterized by Western blot analysis. Afatinib was growth-inhibitory for all three cell lines but cytotoxic only toward BxPC3 (KRAS (wt)) and Capan-2 (KRAS (mut)) cells, both of which express high levels of EGFR, HER2, and HER3 receptors. Afatinib increased the radiosensitivity of BxPC3 and Capan-2 cells, prevented the radio-induced phosphorylation of Akt, and induced mitotic catastrophe following irradiation. In comparison, Panc-1 cells (KRAS (mut)) expressing low levels of EGFR family receptors were resistant to afatinib-induced radiosensitization. These results must be confirmed in vivo. Afatinib showed cytotoxic and radiosensitizing effects toward a subset of pancreatic cancer cells which was closely correlated with expression of EGFR, HER2, and HER3 receptors, but not with KRAS status.
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Papers by Vincent Favaudon