Chemotherapy of Experimental Metastatic Brain Tumors in Female Wistar Rats1

. â€M̃etastatic' †̃ brain tumors were produced in female Wistan rats by intracarotid inoculation of Walker 256 carcinoma cells and subsequent treatment with small doses of cycbophospha mide (CTX) which eradicated extnacnanial tumors, giving time for intracranial tumors to grow. Seven drugs currently in use for brain tumor chemotherapy were tested using this model. After toxicity for each drug was determined, symptomatic ani mals were treated with each drug 28 to 39 days after tumor inoculation, and their survival was compared to untreated or vehicle-treated controls. 1-(2-Chbonoethyl)-3-cycbohexyb-i -ni tnosourea, i -(2-chboroethyl)-3-(4-methylcycbohexyl)-i -nitro sourea and a new water-soluble nitrosounea, 1-(4-amino-2methyl-5-pynimidinyl)methyl-3-(2-chbonoethyl)-3-nitnosounea, along with CTX were very effective therapy and increased median survival time 135 to 213% of control. Methotrexate was minimally effective if given in a single i.v. dose, and procanbazine was ineffective. Dexamethasone was also inef fective at prolonging survival. The value of i.v. methotnexate and also of CTX in the therapy of this disease suggests that once metastatic brain tumors have developed, blood-brain barrier phenomena do not impede the entry of such agents into the tumor. Nevertheless, despite therapy, all animals eventually died of massive multiple intracranial metastatic tumors. Similar results were obtained in rats directly inoculated i.c. with tumor and in rats inoculated s.c. The facts that the metastatic brain tumor-bearing animals were not cured and that systemic then apy alone could not prevent the development of the metastatic tumor may mean that the blood-brain barrier is important along the edge of growing tumors and in the intact brain where metastases develop.