Preliminary studies of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas

Abstract

This work discusses intranasal delivery of peril-lyl alcohol (POH) as a potential adjuvant therapeu-tic strategy for patients with relapsing malignant gli-omas. POH is a monoterpene with preclinical antitu-mor activity in several types of tumor in rodent mod-els and is currently under phase I and phase II clinical trials. The proposed mechanism of action involves in-hibition of post-translational isoprenylation of small G proteins, including p21-Ras, thereby blocking sig-nal transduction. Deregulated p21-Ras function, as a result of mutation, overexpression or growth factor-induced overactivation, contributes to growth of ma-lignant gliomas. Intranasal delivery is a practical and non-invasive approach that allows therapeutic agents which do not cross the blood-brain barrier (BBB) to enter the Central Nervous System (CNS), reducing un-wanted systemic side effects. Applying this method we performed a phase I / II study of POH in patients with relapsed malignant gliomas after standard treat-ment: surgery, radiotherapy and chemotherapy. POH was administrated in concentration 0.3% volume/vol-ume (55 mg) 4 times daily. The objective of this study was to evaluate the toxicity and progression-free survival after 6 months of treatment. The cohort consisted of thirty-seven patients including 29 with glioblastoma multiform (GBM), 5 with grade III astrocytoma (AA) and 3 with anaplastic oligodendroglioma (AO). Neurological ex-amination and suitable image analysis (tomography - CT, magnetic resonance – MRI) established disease progression.