Relationship between tumour endothelial cell apoptosis and tumour blood flow shutdown following treatment with the antivascular agent DMXAA in mice

• Published in: British journal of cancer 2004-02, Vol.90 (4), p.906-910
• Main Authors: Ching, L-M, Zwain, S, Baguley, B C
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Chemotherapy; Colonic Neoplasms - blood supply; Colonic Neoplasms - pathology; Colonic Neoplasms - veterinary; Drug Resistance; Endothelial Cells - physiology; Endothelium; Epidemiology; Experimental Therapeutics; In Situ Nick-End Labeling; Labeling; Medical research; Medical sciences; Mice; Mice, Knockout; Molecular Medicine; Neoplasms, Experimental; Oncology; Pharmacology. Drug treatments; Regional Blood Flow; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumors; Xanthones - pharmacology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6601606

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is currently undergoing clinical evaluation as an antivascular agent for the treatment of cancer. We have previously demonstrated that DMXAA induces apoptosis of vascular endothelial cells in murine tumour sections and in a breast carcinoma biopsy from one patient in a Phase I trial. We wished to determine the tissue selectivity of this effect and its relationship to induced blood flow changes. Mice with Colon 38 tumours were treated with DMXAA and tissues were examined for apoptosis by TdT-mediated dUTP nick-end labelling (TUNEL). Hoechst 33342 was used to stain functional vessels, with the loss of stained vessels used as a measure of tumour vascular collapse. Treatment with DMXAA at 25 mg kg −1 , its maximum tolerated dose (MTD), showed, after 3 h, a 12-fold increase in TUNEL staining of tumour vascular endothelial cells. In contrast, tissue from the heart, brain, liver and spleen showed no increase. Induction of apoptosis in tumour tissue was both dose-dependent, observable at doses as low as 5 mg kg −1 , and time-dependent. Apoptosis was significantly lower in Colon 38 tumours of mice, with a targeted disruption in the TNF gene (TNF −/− ), or in the TNF receptor 1 gene (TNFR −/− ), as compared with that in wild-type mice. Increasing the DMXAA dose to 50 mg kg −1 in these knockout mice raised tumour apoptosis to a level comparable to that induced in wild-type mice given DMXAA at the MTD. For all the data, a significant correlation ( r =0.94; P