Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), in the brain and plasma.
OBJECTIVE
Glioblastomas are amongst the most highly vascularised tumours, and the pursuit of anti-angiogenic approaches such as bevacizumab has provided short-term benefits. The purpose of this study was to determine whether the vascular-disrupting agent, dimethylxanthenone-4-acetic acid (DMXAA), could provide longer-lasting therapeutic benefits in a murine model of glioblastoma.


METHODS
Luciferase-expressing murine GL261 glioma cells were inoculated subcutaneously or intracranially into C57Bl/6 mice. Mice with tumours were administered DMXAA, and tumours measured using callipers or by optical imager. Concentrations of DMXAA in plasma and brain were measured by LC-MS/MS.


RESULTS
DMXAA (25 mg/kg) caused widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % of the mice with subcutaneous GL261 tumours. Co-administered lenalidomide (100 mg/kg) increased the growth delay to 20 days and the percentage of cures to 83 %. The same dose of DMXAA with or without lenalidomide had minimal effects on intracranial GL261 tumours. Concentrations of DMXAA extracted from brain tissue were approximately 25-fold lower than those measured in plasma 15 min to 4 h after DMXAA administration. The presence of intracranial GL261 tumours did not alter the concentrations of DMXAA entering the brain.


CONCLUSIONS
DMXAA does not appear to cross the blood-brain barrier efficiently. Thus, whilst excellent activity was obtained against subcutaneous GL261 gliomas, minimal effects were observed against intracranial GL261 tumours. These results emphasise the need to use appropriate orthotopic models for the evaluation of new approaches for the treatment of brain cancers.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Raymond
R
Yung
Vahid
V
Seyfoddin
Christopher
C
Guise
Sofian
S
Tijono
Ailsa
A
McGregor
Bronwen
B
Connor
Lai-Ming
LM
Ching
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000097:blood / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D055104:Infusions, Subcutaneous; D000077269:Lenalidomide; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011897:Random Allocation; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology; D044004:Xanthones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D044004:Xanthones; C066668:vadimezan; D013792:Thalidomide; D000077269:Lenalidomide