Blood-brain barrier disruption and methotrexate in the treatment of a readily transplantable intracerebral osteogenic sarcoma of rats.

An animal model of intracerebral osteogenic sarcoma has been developed to evaluate blood-brain barrier disruption as an adjunct to chemotherapy of intracerebral tumors. Adult Sprague-Dawley rats (n = 225) were inoculated intracerebrally with transplantable, methotrexate sensitive, osteogenic sarcoma cells and 3 days later randomized to receive either no treatment or methotrexate with or without blood-brain barrier disruption using intracarotid mannitol. Methotrexate was administered i.v., i.p., or directly into the carotid artery (i.c.) in doses of 2.5, 10, 20, 50, or 100 mg/kg. Survival was the study's end point. Surgery, anaesthesia, or blood-brain barrier disruption with mannitol did not affect survival. However, there was a significant effect of dose and route of administration of methotrexate on survival. The shortest survival was in rats receiving no treatment in which death occurred reproducibly at 7.6 +/- 0.2 days (n = 29) and the longest survival was 12.7 +/- 0.3 day (p less than 0.001) in those given methotrexate 50 mg/kg i.c. (n = 6). The i.c. route was most effective in prolonging survival followed by i.v. and the least effective was the i.p. route of methotrexate administration. Blood-brain barrier disruption followed by methotrexate (i.v. or i.c.) was deleterious to survival (two-way analysis of variance, p less than 0.003 and p less than 0.011, respectively) and the reduced survival was in part related to early complications such as intratumor hemorrhage or possibly a methotrexate induced encephalopathy. It is concluded that this is a useful model for the study of the chemotherapy of cerebral tumors, that blood-brain barrier disruption did not appear to improve the dose-response curve but resulted in reduced survival. We caution against the use of this procedure in the treatment of cerebral tumor in humans.