Immune-modulating and anti-vascular activities of two xanthenone acetic acid analogues: A comparative study to DMXAA.
In order to proliferate, solid tumours require the development and continuous expansion of an organised host-derived vascular network. The anti-vascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) emerged as derivative of the flavone-8-acetic acid (FAA) and xanthenone-4-acetic acid (XAA). Its anti-vascular activity is not based on direct cytotoxic effects, but is characterized by an immune-mediated component, through the activation of NF-kappaB pathway, and a direct anti-vascular action, involving the induction of endothelial cell apoptosis and changes in tumour vessel permeability. Despite promising pre-clinical results, DMXAA showed moderate anti-tumour activity in clinical trials. In this study, we compared to DMXAA the in vitro immune-modulating and the anti-vascular properties of two XAA analogues, AP/1649 and AP/1897. Their immune-stimulating activities were evaluated on a human monocyte cell line and their anti-vascular activities were studied by measuring the induction of HUVECs apoptosis and using DCE-MRI to determine tumour perfusion following drug treatment. Although the two molecules exerted an immune stimulation comparable to that produced by DMXAA, they showed reduced (AP/1649) or minimal (AP/1897) anti-vascular activity in vitro, and no anti-vascular effects in vivo. These results endorse the current theories concerning two independent actions exerted by DMXAA.
Barbera
Mariagnese
M
Department of Pharmacology and Anaesthesiology, University of Padova, 35131 Padova, Italy. mb584@hutchison-mrc.cam.ac.uk
Kettunen
Mikko I
MI
Caputo
Anna
A
Hu
De-En
DE
Gobbi
Silvia
S
Brindle
Kevin M
KM
Carrara
Maria
M
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase; D007111:Immunity, Cellular / Q000187:drug effects*; D007938:Leukemia / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008808:Mice, Inbred CBA; D008833:Microcirculation / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D012513:Sarcoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha; D014471:Umbilical Veins / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones; C066668:vadimezan; D051550:I-kappa B Kinase