Consequences of increased vascular permeability induced by treatment of mice with 5,6-dimethylxanthenone-4-acetic acid (DMXAA) and thalidomide.
OBJECTIVE
5,6-Dimethylxanthenone-4-acetic acid (DMXAA) (AS1404), a small-molecule vascular disrupting agent currently in clinical trial, increases vascular permeability and decreases blood flow in both murine and human tumours. DMXAA induces tumour necrosis factor (TNF) in mice and the effects on vascular permeability are hypothesised to result from both direct (DMXAA) and indirect (TNF) effects. Skin temperature decreases in mice treated with high doses of DMXAA, raising the question of whether host toxicity is mediated by the induction of increased vascular permeability in normal tissue. Thalidomide is an anti-inflammatory agent that potentiates the anti-tumour activity of DMXAA but decreases induction of TNF in plasma. We wished to determine how it potentiated the effects of DMXAA.


METHODS
Vascular permeability was measured in Colon 38 tumour and liver tissue by uptake of Evans Blue dye. Blood haematocrit and body temperature were also measured.


RESULTS
Tumour vascular permeability was increased following administration of DMXAA (25 mg/kg i.p.), minimally affected following thalidomide (100 mg/kg i.p.) but strongly increased following co-administration of both drugs. In contrast, dye uptake into liver tissue was decreased following administration of DMXAA, thalidomide or both drugs. Administration of DMXAA at a potentially toxic dose (35 mg/kg i.p. or 50 mg/kg orally) was found to decrease body temperature and to increase the blood haematocrit, while administration of thalidomide alone (100 mg/kg i.p.) had no effect. Co-administration of thalidomide potentiated the effects of DMXAA on both body temperature and haematocrit but surprisingly did not increase toxicity.


CONCLUSIONS
The results are consistent with the hypothesis that the host toxicity of high-dose DMXAA is mediated by effects on host vasculature. Co-administration of thalidomide increases the effective dose of DMXAA by reducing clearance but also, by inhibiting production of circulating TNF, reduces the host toxicity of DMXAA.
Chung
Francisco
F
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
Liu
Jenny
J
Ching
Lai-Ming
LM
Baguley
Bruce C
BC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000098:blood supply; D004396:Coloring Agents; D004357:Drug Synergism; D005070:Evans Blue; D006400:Hematocrit; D008102:Liver Circulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D013792:Thalidomide / Q000494:pharmacology*; D044004:Xanthones / Q000494:pharmacology*
D000970:Antineoplastic Agents; D004396:Coloring Agents; D044004:Xanthones; C066668:vadimezan; D005070:Evans Blue; D013792:Thalidomide