L’énigme de l’interprétation biologique du modèle linéaire-quadratique enfin résolue ? Une synthèse pour les non-mathématiciens

Published on Jun 1, 2016in Cancer Radiotherapie1.014
· DOI :10.1016/J.CANRAD.2016.02.014
Larry Bodgi8
Estimated H-index: 8
(French Institute of Health and Medical Research),
Aurélien Canet3
Estimated H-index: 3
(French Institute of Health and Medical Research)
+ 4 AuthorsNicolas Foray30
Estimated H-index: 30
(French Institute of Health and Medical Research)
Resume Le modele lineaire-quadratique (LQ) est aujourd’hui la seule relation mathematique liant la survie cellulaire et la dose de radiation qui soit suffisamment consensuelle pour que radiotherapeutes et radiobiologistes l’utilisent regulierement dans leurs interpretations des phenomenes radioinduits. Pourtant, cette formule proposee dans les annees 1970 et les parametres α et β sur lesquels elle est basee sont restes sans signification biologique coherente. A partir d’une collection de fibroblastes cutanes de radiosensibilite differente constituee pendant 12 ans par plus de 50 radiotherapeutes francais, nous avons mis recemment en evidence que la proteine ATM, acteur majeur de la reponse aux radiations ionisantes, diffuse du cytoplasme au noyau apres irradiation. La mise en evidence de ce transit cytonucleaire de la proteine ATM nous a permis de fournir une interpretation biologique coherente du modele lineaire-quadratique dans ses aspects les plus mathematiques, validee par une centaine de cas. Une explication mecanistique de la radiosensibilite des syndromes causes par des mutations de proteines cytoplasmiques et du phenomene d’hypersensibilite aux faibles doses a pu etre aussi avancee. Dans cette revue, nous avons aborde la resolution de ce modele lineaire-quadratique de facon didactique, en se limitant strictement aux aspects mathematiques les plus essentiels.
#1Adeline GranzottoH-Index: 9
Last. Nicolas Foray (French Institute of Health and Medical Research)H-Index: 30
view all 68 authors...
PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistan...
62 CitationsSource
#1Larry Bodgi (French Institute of Health and Medical Research)H-Index: 8
#2Nicolas Foray (French Institute of Health and Medical Research)H-Index: 30
AbstractPurpose For 50 years, cellular radiosensitivity has been defined in vitro as the lack of clonogenic capacity of irradiated cells and its mathematical link with dose has been described by the target theory. Among the numerous formulas provided from the target theory, the linear-quadratic (LQ) model empirically describes cell survival as a negative exponential of a second degree polynomial dose-function in which αD is the linear component and βD2 is the quadratic one. The LQ model is exten...
51 CitationsSource
#1Mélanie L. Ferlazzo (French Institute of Health and Medical Research)H-Index: 7
#2Laurène Sonzogni (French Institute of Health and Medical Research)H-Index: 3
Last. Nicolas Foray (French Institute of Health and Medical Research)H-Index: 30
view all 9 authors...
Huntington’s disease (HD) is a neurodegenerative syndrome caused by mutations of the IT15 gene encoding for the huntingtin protein. Some research groups have previously shown that HD is associated with cellular radiosensitivity in quiescent cells. However, there is still no mechanistic model explaining such specific clinical feature. Here, we examined the ATM-dependent signaling and repair pathways of the DNA double-strand breaks (DSB), the key damage induced by ionizing radiation, in human HD s...
46 CitationsSource
#1Larry Bodgi (French Institute of Health and Medical Research)H-Index: 8
#2Adeline Granzotto (French Institute of Health and Medical Research)H-Index: 9
Last. Nicolas Foray (French Institute of Health and Medical Research)H-Index: 30
view all 10 authors...
Immunofluorescence with antibodies against DNA damage repair and signaling protein is revolutionar- ising the estimation of the genotoxic risk. Indeed, a number of stress response proteins relocalize in nucleus as identifiable foci whose number, pattern and appearance/disappearance rate depend on several parameters such as the stress nature, dose, time and individual factor. Few authors proposed biomathematical tools to describe them in a unified formula that would be relevant for all the reloca...
26 CitationsSource
Resume Etudier les mecanismes de la reparation des radiolesions de l’ADN conduit a deux applications medicales majeures : (1) l’identification des patients radiosensibles par des tests biologiques adaptes afin d’eviter une toxicite redhibitoire de la radiotherapie et parfois de la chimiotherapie ; (2) la diminution de la radioresistance des cellules tumorales pour obtenir un meilleur controle locoregional. La transposition a la clinique des connaissances fondamentales issues d’experimentation in...
7 CitationsSource
#1Zhi Guo (University of Texas at Austin)H-Index: 5
#2Sergei Kozlov (UQ: University of Queensland)H-Index: 23
Last. Tanya T. PaullH-Index: 56
view all 5 authors...
The ataxia-telangiectasia mutated (ATM) protein kinase is activated by DNA double-strand breaks (DSBs) through the Mre11-Rad50-Nbs1 (MRN) DNA repair complex and orchestrates signaling cascades that initiate the DNA damage response. Cells lacking ATM are also hypersensitive to insults other than DSBs, particularly oxidative stress. We show that oxidation of ATM directly induces ATM activation in the absence of DNA DSBs and the MRN complex. The oxidized form of ATM is a disulfide–cross-linked dime...
794 CitationsSource
Ataxia-telangiectasia is an autosomal recessive disorder caused by mutation in the ATM gene. Hallmarks of the disease comprise progressive cerebellar ataxia, oculocutaneous telangiectasiae, cancer susceptibility, and variable humoral and cellular immunodeficiency. We report a patient who, because of the pattern of her immunodeficiency, was primarily diagnosed as an autosomal recessive hyper-IgM syndrome. Only a mild cerebellar ataxia was present at the age of 7 years then she developed a Wilms t...
21 CitationsSource
#1Brian Marples (Beaumont Hospital)H-Index: 20
#2Spencer J. Collis (University of Cambridge)H-Index: 21
This review article discusses the biology of low-dose hyper-radiosensitivity (HRS) with reference to the molecular regulation of DNA repair and cell cycle control processes. Particular attention is paid to the significance of G2-phase cell cycle checkpoints in overcoming low-dose hyper-radiosensitivity and the impact of HRS on low-dose rate radiobiology. The history of HRS from the original in vivo discovery to the most recent in vitro and clinical data are examined to present a unifying hypothe...
152 CitationsSource
#1Andy Trotti (USF: University of South Florida)H-Index: 56
Last. Philip Rubin (URMC: University of Rochester Medical Center)H-Index: 28
view all 11 authors...
Multiple systems have been developed for grading the adverse effects (AEs) of cancer treatment. The National Cancer Institute Common Toxicity Criteria (CTC) system has substantially evolved since its inception in 1983. The most recent version, CTCAE v3.0 (Common Terminology Criteria for Adverse Events version 3.0) represents the first comprehensive, multimodality grading system for reporting the acute and late effects of cancer treatment. The new CTC requires changes in the application of AE cri...
1,979 CitationsSource
#1Marco Zaider (Columbia University)H-Index: 22
35 CitationsSource
Cited By2
#1Abdulhamid Chaikh (UNICAEN: University of Caen Lower Normandy)H-Index: 6
#1Abdulhamid Chaikh (UNICAEN: University of Caen Lower Normandy)H-Index: 2
Last. J.M. Fontbonne (UNICAEN: University of Caen Lower Normandy)H-Index: 1
view all 9 authors...
Resume La prescription de la dose en radiotherapie est actuellement basee sur des abaques qui ne prennent pas en compte la complexite de la relation patient/dose/effet. Leurs performances predictives tant sur l’efficacite anti-tumorale que sur la toxicite peuvent etre ameliorees par l’utilisation de modeles radiobiologiques. C’est dans cette optique qu’ont ete developpes les modeles de calculs TCP (Tumor Control Probability) et NTCP (Normal Tissue Complication Probability). Leur construction com...
3 CitationsSource
#1Alan U. Sabino (USP: University of São Paulo)H-Index: 2
#2Miguel F. S. Vasconcelos (USP: University of São Paulo)H-Index: 1
Last. Alexandre F. Ramos (USP: University of São Paulo)H-Index: 9
view all 7 authors...
Randomness is an unavoidable feature of inner cellular environment and its effects propagate to higher levels of living matter organization such as cells, tissues, and organisms. Approaching those systems experimentally to understand their dynamics is a complex task because of the plethora of compounds interacting in a web that combines intra and inter level elements such that a coordinate behavior come up. Such a characteristic points to the necessity of establishing principles that help on the...