Botulinum toxin potentiates cancer radiotherapy and chemotherapy.
OBJECTIVE
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.


METHODS
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.


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.


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.
Ansiaux
Réginald
R
Laboratory of Biomedical Magnetic Resonance, Université Catholique de Louvain, Brussels, Belgium.
Baudelet
Christine
C
Cron
Greg O
GO
Segers
Jérôme
J
Dessy
Chantal
C
Martinive
Philippe
P
De Wever
Julie
J
Verrax
Julien
J
Wauthier
Valérie
V
Beghein
Nelson
N
Grégoire
Vincent
V
Buc Calderon
Pedro
P
Feron
Olivier
O
Gallez
Bernard
B
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015552:Injections, Intralesional; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000532:radiotherapy*; D009465:Neuromuscular Agents / Q000008:administration & dosage / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010477:Perfusion; D012501:Saphenous Vein / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects / Q000528:radiation effects
D018906:Antineoplastic Agents, Alkylating; D009465:Neuromuscular Agents; D003520:Cyclophosphamide; D019274:Botulinum Toxins, Type A; D010100:Oxygen