THERAPEUTIC ACTIVITY OF 9-CHLORO-2-METHYLELLIPTICINIUM ACETATE IN AN ORTHOTOPIC MODEL OF HUMAN BRAIN CANCER

A series of ellipticinium derivatives with selective cytotoxicity towa rds brain tumor cell lines has been identified through in vitro screen ing against disease-oriented panels of human tumor cell lines. Unfortu nately 9-methoxy-2-methylellipticinium, the lead compound of this seri es, has shown only very limited evidence for in vivo activity when exa mined in a variety of human tumor xenograft models. This lack of activ ity 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 sel ectivity in vitro. In vivo xenograft testing was performed to assess t he therapeutic potential of this second generation compound. To mainta in continuity with the in vitro screening data, in vivo experimental t herapeutic models were devised employing one of the in vitro sensitive cell lines, the U-251 glioblastoma. Cells were cultivated in vitro an d injected into female athymic nude mice for therapeutic studies. The 9-chloro-derivative of the lead compound produced growth delay of subc utaneously implanted tumor cells when. administered by seven-day conti nuous infusion. Based on this evidence for activity in a systemic chem otherapy mode, further studies were conducted using an orthotopic brai n cancer model. In three separate experiments, intracranial implantati on of 1x10(7) tumor cells resulted in 100% mortality of control mice w ith median survival ranging from 15-18.5 days. In all experiments, mic e treated by subcutaneous infusion with 9-chloro-2-methylellipticinium acetate showed increases in survival. Statistically significant effec ts and individual long-term survivors were observed in two experiments ; These results provide support for the further preclinical developmen t of 9-chloro-2-methylellipticinium acetate as a candidate for clinica l trials against human brain cancer.