Continuous intracranial administration of suberoylanilide hydroxamic acid (SAHA) inhibits tumor growth in an orthotopic glioma model

Abstract

OBJECT: Current treatments for malignant gliomas produce only a modest increase in survival time. New therapeutic approaches are desperately needed. Suberoylanilide hydroxamic acid (SAHA) is an effective inhibitor of the growth of many solid and hematological malignancies. Nevertheless, very few studies have investigated the effects of SAHA on glial tumors. The present study was designed to investigate the therapeutic effects of the intracranial local delivery of SAHA in an orthotopic glioma model. METHODS: The antiproliferative effect of SAHA was examined in six glioblastoma and one endothelial cell lines in vitro. In addition, one glioblastoma cell line (U87MG) used in in vivo short term (14 days) and survival studies in an orthotopic human glioma athymic mice model. Tumor volume, apoptosis rate, microvessel density, and proliferation index were determined by immunohistochemistry. RESULTS: SAHA treatment inhibited the growth of all cell lines in concentrations ranging from 1 microM to 30 microM. For short-term studies, histological analysis showed an 80% reduction of tumor volume in the treatment group (P < 0.001). This reduction in tumor volume was associated with a significant increase in the apoptosis rate (31.9%, P < 0.001), a significant decrease in the proliferation (36.8%, P < 0.001) and angiogenesis rates (30%, P < 0.05). For survival studies, the mean survival time was 22 days in the control group, whereas it was 42 days in the treatment group. CONCLUSIONS: These results suggest that local delivery with SAHA inhibits intracranial glioma growth in vitro and in vivo. SAHA is a promising candidate for further preclinical and clinical studies on glial tumors.