Blood-brain barrier and chemotherapy of experimental brain tumors (author's transl)

Abstract

Using an experimental model of meningeal carcinomatosis in rats, studies of how the blood-CSF barrier was affected by tumor growth in the subarachnoid space were conducted. The state of the blood-CSF barrier was estimated by drug delivery to the tumor. Cyclophosphamide which crosses the blood-brain barrier poorly and 1-(4-amino-2-methyl-5-pyrimidinyl)-methy 1-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) which crosses it easily had an equivalent cytostatic effect on the subcutaneously transplanted Walker 256 carcinosarcoma in SD rats at a dose of 30 mg/kg and 15 mg/kg, respectively. SD rats inoculated intracisternally with 1×104 Walker 256 carcinosarcoma cells were treated by either a single i. v. dose of cyclophosphamide 30 mg/kg or ACNU 15 mg/kg at 1, 2, 4 or 5 days after tumor inoculation. Effects of these two types of agents were compared by the survival time of animals. At 1 day after tumor inoculation, intravenously administered cyclophosphamide failed to prevent tumor growth in the subarachnoid space and survival time of tumor-bearing animals was prolonged only 10 to 14% compared to control. On the other hand, ACNU was effective and produced a maximum increased survival time of 180%. At 2 days after inoculation both cyclophosphamide and ACNU were effective and increased median survival time by 109% and 127%, respectively. At 4 days after inoculation, cyclophosphamide increased survival time 90% and ACNU 240%. At 5 days, cyclophosphamide increased survival time 52% and ACNU 74%. The results indicated that the subarachnoid tumor growth in its early stage was protected from the water-soluble chemotherapeutic agent by the intact blood-CSF barrier. In the advanced stage of tumor growth, the barrier was mostly circumvented, however there were still some areas where infiltrating neoplastic cells were protected by the intact barrier. These findings suggest that systemic chemotherapy of metastatic tumors of the central nervous system should include an agent which crosses the blood-brain (CSF) barrier, although the first choice is an agent to which the original tumor is most sensitive.