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Potential Antiglioma Activity of 9-Hydroxy-2-N-methylellipticine as Determined by Pharmacological and Human Tumor Clonogenic Cell Studies¹

Brain Tumor Research Center, Department of Neurological Surgery, School of Medicine, University of California, San Francisco, California 94143

The antiglioma activity of elliptinium (HME) was investigated in a human glioma clonogenic cell assay. Early passage cells of three human glioma cell lines (SF126, SF375, and SF407) were exposed to HME at the clinically achievable dose of 3 µM for 3 h. At this HME concentration, clonogenic cell survival was reduced by more than 3 logs in SF126 and SF375, and by 0.8 logs in SF407. A study of the kinetics of cell kill showed that whereas at moderate (1.5 µM) HME doses cell kill increased with treatment time up to a maximum at approximately 3 h, cytotoxicity was more dose than time dependent at higher doses. Flash treatment of SF375 cells with 3 µM HME resulted in more than 2 logs clonogenic cell kill. Using high-pressure liquid chromatography, we investigated the in vitro decay kinetics of HME under our in vitro drug treatment conditions and observed a very rapid, protein nondependent 40% drop in HME concentration which was dose dependent and was probably due to HME adsorption on the surface of tissue culture plasticware. Subsequent decay of the drug was very slow, with a decay rate constant of 0.022/h and a half-life of 298 h. In order to determine whether HME crosses the blood-brain barrier, we measured the rat brain capillary permeability coefficient, P, of [³H]HME and [¹⁴C]HME. The mean P value of 2.2 x 10^-6 cm/s ± 16% (SD) suggests that HME crosses the blood-brain barrier (t = 46 min) consistent with its molecular size and octanol-water partition coefficient.

¹ Supported in part by NIH Program Project Grant CA-13525, NIH Grants CA-31882 and CA-28529, and the Andres Soriano Cancer Research Fund.

² Present address: Hipple Cancer Research Center, Wright State University School of Medicine, 4100 South Kettering Boulevard, Dayton, OH 45439. To whom requests for reprints should be addressed.

Received 6/29/84. Revised 3/25/85. Accepted 3/27/85.