Angiostatin prolongs the survival of mice with leptomeningeal metastases.
BACKGROUND
As a result of the more effective treatment of primary tumours, the incidence of leptomeningeal metastases (LM) is increasing. Current treatment modalities have little effect on the survival of patients with LM. We investigated whether antiangiogenic treatment inhibits the progression of leptomeningeal tumours.


METHODS
To assess the role of angiogenesis in leptomeningeal tumours, we inoculated melanoma cells in the subarachnoid space in balb/c mice. At different stages, the mice were sacrificed and the microvessel density was determined. Human specimens of LM were compared with the mouse model. For the intervention studies, the mice were treated with the angiogenesis inhibitor angiostatin. Survival was the endpoint in these studies.


RESULTS
Tumour seeding in the early disease stages was concentrated around the pre-existent arachnoid vasculature. In the more advanced stages, the tumour masses covered larger areas of the leptomeninges. Arachnoidal microvessel density in this advanced stage was increased compared with control mice. Systemic treatment of the mice with LM with angiostatin (100 mg kg-1 day-1) resulted in prolonged survival compared with mice treated with vehicle and with approximately one-fifth of the long-term survivors of the angiostatin-treated group.


CONCLUSIONS
This study shows that neovascularization is important in the growth of LM in mice. Systemic targeting of the vascular compartment may be a useful approach in novel therapeutic strategies for patients with LM.
Reijneveld
J C
JC
Department of Neurology, University Medical Center, 3508 GA Utrecht, the Netherlands.
Taphoorn
M J B
MJ
Kerckhaert
O A J
OA
Drixler
T A
TA
Boogerd
W
W
Voest
E E
EE
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008577:Meningeal Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use*; D010958:Plasminogen / Q000627:therapeutic use*; D015996:Survival Rate
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen