The rat subcutaneous air sac model: a new and simple method for in vivo screening of antiangiogenesis.
An experimental rat model, the Subcutaneous Air Sac (SAS) model, was developed to provide an animal model in which neo-vascularization can be easily assessed in situ and quantified using a radiolabelled plasma marker. The SAS model was designed to replace a previous model where neovascularization was induced by chemical injury of rat or rabbit cornea or by implantation of tumour cells intracorneally, a methodology which is believed to cause severe pain to the animals. In the SAS model the air sac replaces the cornea as a transparent avascular substratum in which vascularization can be observed. The air sac is induced by injection of air subcutaneously on the back of the animal. After 8 to 10 days a sufficient air sac has been established. The animal is anaesthesized and by a minor operation the cellulose sponge is implanted upon the air sac under the skin. The vasoproliferative effect of the cellulose sponge causes formation of new vessels which are macroscopically visible 10 days after implantation. The ability of the in vivo SAS model to show an antiangiogenic effect of a systemically applied test compound was investigated using the fumagillin analogue TNP-470 (ochloro-acetylcarbamoyl)-fumagillol) as a positive control at dose levels of 0, 1, 2.5, 5 and 10 mg/kg/day given subcutaneously for 10 days. The neo-angiogenesis was scored both in situ using a subjective point system and by measuring the 125I-activity of the implant and the membrane after an intravenous injection of 125I-labelled antibodies. The neo-angiogenesis was reduced by approximately 45-50% in animals treated with 5 or 10 mg/kg/day of TNP-470 compared to animals treated with the vehicle. The animals treated with 10 mg/kg/day TNP-470 showed signs of toxicity. The SAS model is considered highly relevant for in vivo testing of potential antiangiogenic drugs on humane grounds. The high reproducibility, the low cost and the technical simplicity of the method makes it attractive.
Lichtenberg
J
J
Leo Pharmaceutical Products, Research and Development Department, Ballerup, Denmark.
Hansen
C A
CA
Skak-Nielsen
T
T
Bay
C
C
Mortensen
J T
JT
Binderup
L
L
D000388:Air; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity; D003315:Cornea / Q000098:blood supply; D003510:Cyclohexanes; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000494:pharmacology / Q000633:toxicity; D015503:Surgical Sponges
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D007457:Iodine Radioisotopes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol