[fr] OBJECTIF: Des anomalies structurales et fonctionnelles dans le réseau vasculaire tumoral sont considérés comme des facteurs de résistance des tumeurs solides et à des traitements cytotoxiques. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. Pour augmenter l'efficacité des traitements anticancéreux, les efforts doivent être déployés pour trouver de nouvelles stratégies pour l'ouverture transitoire de la tumeur vasculaire à atténuer l'hypoxie tumorale (source de résistance à la radiothérapie) et améliorer la prestation des agents chimiothérapeutiques. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation. Nous avons supposé que neurotoxine botulique de type A (BoNT-A) pourrait interférer avec la libération des neurotransmetteurs à la bienveillance varicosités périvasculaire, conduisant à une inhibition des contractions neurogène des vaisseaux de la tumeur et donc d'améliorer la perfusion et l'oxygénation tumorale.
<br />
<br />EXPERIMENTAL DESIGN: To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO(2) in vivo repeatedly for 4 days. CONCEPTION EXPERIMENTALE: Pour tester cette hypothèse, la BoNT-A ont été injectés localement dans les tumeurs de souris (fibrosarcome FSaII, tumeur du foie hépatocarcinome transplantable), et la résonance paramagnétique électronique oxymétrie a été utilisé pour surveiller pO (2) in vivo de façon répétée pendant 4 jours. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. En outre, de contraste d'imagerie par résonance magnétique a été utilisée pour mesurer la perfusion tumorale in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells. Enfin, les artères isolées ont été montés dans myographe fil pour suivre spécifiquement le ton neurogène développée par artérioles qui ont été cooptés par la croissance des cellules tumorales environnantes.
<br />
<br />RESULTS: Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). RÉSULTATS: L'utilisation de ces modèles de tumeurs, nous avons montré que l'administration locale de la BoNT-A (deux sites; dose, 29 unités / kg) augmente considérablement l'oxygénation tumorale et de la perfusion, conduisant à une amélioration substantielle de la réponse tumorale à la radiothérapie (20 Gy de 250 kV rayonnement) et la chimiothérapie (cyclophosphamide, 50 mg / kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature. Cette thérapeutique résultats gain observé à partir d'une ouverture de la tumeur vasculaire par BoNT-A, car nous avons montré que la BoNT-A pourrait empêcher ton neurogène dans la vascularisation des tumeurs.
<br />
<br />CONCLUSIONS: The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy. CONCLUSIONS: L'ouverture du lit vasculaire induite par la BoNT-A offre un moyen d'augmenter significativement la réponse des tumeurs à la radiothérapie et la chimiothérapie. [en] PURPOSE: Structural and functional abnormalities in the tumor vascular network are considered factors of resistance of solid tumors to cytotoxic treatments. To increase the efficacy of anticancer treatments, efforts must be made to find new strategies for transiently opening the tumor vascular bed to alleviate tumor hypoxia (source of resistance to radiotherapy) and improve the delivery of chemotherapeutic agents. We hypothesized that Botulinum neurotoxin type A (BoNT-A) could interfere with neurotransmitter release at the perivascular sympathetic varicosities, leading to inhibition of the neurogenic contractions of tumor vessels and therefore improving tumor perfusion and oxygenation.
<br />
<br />EXPERIMENTAL DESIGN: To test this hypothesis, BoNT-A was injected locally into mouse tumors (fibrosarcoma FSaII, hepatocarcinoma transplantable liver tumor), and electron paramagnetic resonance oximetry was used to monitor pO(2) in vivo repeatedly for 4 days. Additionally, contrast-enhanced magnetic resonance imaging was used to measure tumor perfusion in vivo. Finally, isolated arteries were mounted in wire myograph to monitor specifically the neurogenic tone developed by arterioles that were co-opted by the surrounding growing tumor cells.
<br />
<br />RESULTS: Using these tumor models, we showed that local administration of BoNT-A (two sites; dose, 29 units/kg) substantially increases tumor oxygenation and perfusion, leading to a substantial improvement in the tumor response to radiotherapy (20 Gy of 250-kV radiation) and chemotherapy (cyclophosphamide, 50 mg/kg). This observed therapeutic gain results from an opening of the tumor vascular bed by BoNT-A because we showed that BoNT-A could inhibit neurogenic tone in the tumor vasculature.
<br />
<br />CONCLUSIONS: The opening of the vascular bed induced by BoNT-A offers a way to significantly increase the response of tumors to radiotherapy and chemotherapy.
Disciplines :
Oncology Radiology, nuclear medicine & imaging
Author, co-author :
ANSIAUX, Reginald; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance
BAUDELET, Christine; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance
CRON, Greg; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance
SEGERS, Jerome; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance ; Laboratory of Medicinal Chemistry and Radiopharmacy
DESSY, Chantal; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
Martinive, Philippe ; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
DE WEVER, Julie; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
VERRAX, Julien; Université Catholique de Louvain - UCL > Metabolism, Nutrition and Toxicology Unit > Pharmacokinetic,
WAUTHIER, Valérie; Université Catholique de Louvain - UCL > Nutrition and Toxicology Unit > Metabolism,
BEGHEIN, Nelson; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance ; Laboratory of Medicinal Chemistry and Radiopharmacy
GREGOIRE, Vincent; Université Catholique de Louvain - UCL > Metabolism, Nutrition and Toxicology Unit > Pharmacokinetic,
BUC CALDERON, Pedro; Université Catholique de Louvain - UCL > Pharmacokinetic, > Metabolism, Nutrition and Toxicology Unit
FERON, Olivier; Université Catholique de Louvain - UCL > Laboratory of Pharmacology and Therapeutics
GALLEZ, Bernard; Université Catholique de Louvain - UCL > Laboratory of Biomedical Magnetic Resonance ; Laboratory of Medicinal Chemistry and Radiopharmacy
Feron O. Targeting the tumor vascular compartment to improve conventional cancer therapy. Trends Pharmacol Sci 2004;25:536-42.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-57.
Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res 2004;10:415-27.
Fayette J, Soria JC, Armand JP. Use of angiogenesis inhibitors in tumour treatment. Eur J Cancer 2005;41: 1109-16.
Kaanders JH, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol 2002;3:728-37.
Padera TP, Stoll BR, Tooredman JB, Capen D, Di Tomaso E, Jain RK. Cancer cells compress intratumor vessels. Nature 2004;427:695.
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62.
Ansiaux R, Baudelet C, Jordan BF, et al. Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin Cancer Res 2005;11: 743-50.
Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004;6:553-63.
Brin MF, Hallett M, Jankovic J. Scientific and therapeutic aspects of Botulinum toxin. New York (USA): Lippincott Williams and Wilkins: 2002. p. 507.
Morris JL, Jobling P, Gibbins IL. Differential inhibition by botulinum neurotoxin A of cotransmitters released from autonomic vasodilator neurons. Am J Physiol Heart Circ Physiol 2001;281:H2124-32.
Morris JL, Jobling P, Gibbins IL. Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons. Am J Physiol Heart Circ Physiol 2002;283:H2627-35.
Gallez B, Jordan B, Baudelet C, Misson PD. Pharmacological modifications of the partial pressure of oxygen in tumors. Evaluation using in vivo EPR oximetry. Magn Reson Med 1999;42:627-30.
Gallez B, Baudelet C, Jordan BF. Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications. NMR Biomed 2004;17: 240-62.
Volpe JP, Hunter N, Basic I, Milas L. Metastatic properties of murine sarcomas and carcinomas. I. Positive correlation with lung colonization and lack of correlation with s.c. tumor take. Clin Exp Metastasis 1985;3: 281-94.
Taper HS, Woolley GW, Teller MN, Lardis MP. A new transplantable mouse liver tumor of spontaneous origin. Cancer Res 1966;26:143-8.
Jordan BF, Grégoire V, Demeure RJ, et al. Insulin increases the sensitivity of tumors to irradiation: involvement of an increase in tumor oxygenation mediated by a nitric oxide dependent decrease of the tumor cells oxygen consumption. Cancer Res 2002;62: 3555-61.
Baudelet C, Ansiaux R, Jordan BF, Havaux X, Macq B, Gallez B. Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia? Phys Med Biol 2004;49:3389-411.
Galbraith SM, Maxwell RJ, Lodge MA, et al. Combretastatin A4 phosphate has tumor antivascular activity in rat and man as demonstrated by dynamic magnetic resonance imaging. J Clin Oncol 2003;21: 2831-42.
Rogers DF, Boschetto P, Barnes PJ. Plasma exudation. Correlation between Evans blue dye and radiolabeled albumine in guinea pig airways in vivo. J Pharmacol Methods 1989;21:309-15.
Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of dye-binding. Anal Biochem 1976; 72:248-54.
Graff BA, Bjornaes I, Rofstad EK. Macromolecule uptake in human melanoma xenografts: relationships to blood supply, vascular density, microvessel permeability and extracellular volume fraction. Eur J Cancer 2000;36:1433-40.
Morris JL, Jobling P, Gibbins IL. Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons. Am J Physiol Heart Circ Physiol 2002;283:H2627-35.
Whall CW, Jr., Havlik RJ, Halpern W, Bohr DF. Potassium depolarization of adrenergic varicosities in resistance arteries from SHR and WKY rats. Blood Vessels 1983;20:23-33.
Sonveaux P, Dessy C, Martinive P, et al. Endothelin-1 is a critical mediator of myogenic tone in tumor arterioles: implications for cancer treatment. Cancer Res 2004;64:3209-14.
Sonveaux P, Dessy C, Brouet A, et al. Modulation of the tumor vasculature functionality by ionizing radiation accounts for tumor radio-sensitization and promotes gene delivery. FASEB J 2002;16: 1979-81.
Tang-Liu DDS, Aoki KR, Dolly JO, et al. Intramuscular injection of 125I-botulinum neurotoxin-complex versus 125I-botulinum- free neurotoxin: time course of tissue distribution. Toxicon 2003;42:461-9.
Hsu TSJ, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of Botulinum exotoxin A. Arch Dermatol 2004;140:1351-4.
Jordan BF, Sonveaux P, Feron O, et al. Nitric oxide as a radiosensitizer: evidence for an intrinsic role in addition to its oxygen effect on oxygen delivery and consumption. Int J Cancer 2004;109:768-73.
Klein AW. Complications, adverse reactions, and insights with the use of botulinum toxin. Dermatol Surg 2003;29:549-56.