1: Clin Cancer Res. 2006 Feb 15;12(4):1276-83. 

Botulinum toxin potentiates cancer radiotherapy and chemotherapy.

Ansiaux R, Baudelet C, Cron GO, Segers J, Dessy C, Martinive P, De Wever J,
Verrax J, Wauthier V, Beghein N, Gregoire V, Buc Calderon P, Feron O, Gallez B.

Laboratory of Biomedical Magnetic Resonance, Universite Catholique de Louvain,
Brussels, Belgium.

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.
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. 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.

PMID: 16489084 [PubMed - in process]