THE EFFICACY OF TAMOXIFEN AS AN ANTIPROLIFERATIVE AGENT IN-VITRO FOR BENIGN AND MALIGNANT PEDIATRIC GLIAL TUMORS

Recent studies have suggested that the triphenylethylene antiestrogen tamoxifen inhibits the proliferation in vitro of a substantial percentage of cell lines derived from adult high-grade gliomas, potentially acting through inhibition of the second messenger protein kinase C. These findings have formed the impetus for clinical trials of this agent in adults with malignant gliomas. However, it has previously remained uncertain whether tamoxifen has a similar inhibitory effect on the proliferation of pediatric high-grade gliomas, and whether low-grade gliomas, which constitute the majority of glial neoplasms in children, are also inhibited by this agent. To address these issues, the present study examined the effect of tamoxifen on proliferation and viability in a series of low-passage cell lines derived both from low-grade and high-grade pediatric gliomas. This agent was tested in three malignant gliomas, two pilocytic astrocytomas, two non-pilocytic low-grade astrocytomas, 1 mixed glioma, and 1 oligodendroglioma. Tamoxifen produced a dose-dependent inhibition of proliferation in two of the three malignant glioma cell lines and in each of the low-grade glioma cell lines with a 50% effective dose of approximately 3 mu g/ml (5.4 mu M), which is comparable to the IC50 for inhibition of PKC activity by this agent. No significant cytotoxicity was encountered at this concentration. However, complete elimination of proliferation was achieved with a dose of 10 mu g/ml(17.8 mu M), which produced a direct cytotoxic effect. We conclude that tamoxifen inhibits proliferation of cell lines derived from both low-grade and high-grade pediatric glial tumors in vitro at concentrations that may be achievable clinically with high-dose oral therapy. Accordingly, clinical trials using this agent have been initiated for children with high-grade glial tumors that have progressed after standard therapy to determine the safety and efficacy of tamoxifen for these patients.