A series of ellipticinium derivatives with selective cytotoxicity towards brain tumor cell lines has been identified through in vitro screening against disease-oriented panels of human tumor cell lines. Unfortunately 9-methoxy-2-methylellipticinium, the lead compound of this series, has shown only very limited evidence for in vivo activity when examined in a variety of human tumor xenograft models. This lack of activity has been postulated to be due to metabolism. To address this issue, a derivative was synthesized which was blocked at the theoretically vulnerable 9-position and yet could be shown to retain brain tumor selectivity in vitro. In vivo xenograft testing was performed to assess the therapeutic potential of this second generation compound. To maintain continuity with the in vitro screening data, in vivo experimental therapeutic models were devised employing one of the in vitro sensitive cell lines, the U-251 glioblastoma. Cells were cultivated in vitro and injected into female athymic nude mice for therapeutic studies. The 9-chloro-derivative of the lead compound produced growth delay of subcutaneously implanted tumor cells when. administered by seven-day continuous infusion. Based on this evidence for activity in a systemic chemotherapy mode, further studies were conducted using an orthotopic brain cancer model. In three separate experiments, intracranial implantation of 1x10(7) tumor cells resulted in 100% mortality of control mice with median survival ranging from 15-18.5 days. In all experiments, mice treated by subcutaneous infusion with 9-chloro-2-methylellipticinium acetate showed increases in survival. Statistically significant effects and individual long-term survivors were observed in two experiments; These results provide support for the further preclinical development of 9-chloro-2-methylellipticinium acetate as a candidate for clinical trials against human brain cancer.

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