TY  - JOUR
A1  - Bähr, Oliver
A1  - Gross, Stefanie
A1  - Harter, Patrick Nikolaus
A1  - Kirches, Elmar
A1  - Mawrin, Christian
A1  - Steinbach, Joachim Peter
A1  - Mittelbronn, Michel Guy André
T1  - ASA404, a vascular disrupting agent, as an experimental treatment approach for brain tumors
T2  - Oncology letters
N2  - Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.
KW  - ASA404
KW  - DMXAA
KW  - vadimezan
KW  - brain tumor
KW  - glioblastoma
KW  - meningioma
KW  - brain metastases
KW  - STING
KW  - vascular disrupting agents
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45061
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-450614
SN  - 1792-1082
SN  - 1792-1074
N1  - Copyright: © Bähr et al. This is an open access article distributed under the terms of Creative Commons Attribution License. https://creativecommons.org/licenses/by-nc-nd/4.0/
VL  - 14
IS  - 5
SP  - 5443
EP  - 5451
PB  - Athens
CY  - Spandidos Publ.
ER  -