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

THESES

Preliminary studies of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. (Abstract)^*. Thesis. Rio de Janeiro, 2007

Clovis Orlando Pereira da Fonseca^**

This work discusses intranasal delivery of perillyl alcohol (POH) as a potential adjuvant therapeutic strategy for patients with relapsing malignant gliomas. POH is a monoterpene with preclinical antitumor activity in several types of tumor in rodent models and is currently under phase I and phase II clinical trials. The proposed mechanism of action involves inhibition of post-translational isoprenylation of small G proteins, including p21-Ras, thereby blocking signal transduction. Deregulated p21-Ras function, as a result of mutation, overexpression or growth factor-induced overactivation, contributes to growth of malignant 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 unwanted systemic side effects. Applying this method we performed a phase I / II study of POH in patients with relapsed malignant gliomas after standard treatment: surgery, radiotherapy and chemotherapy. POH was administrated in concentration 0.3% volume/volume (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 examination and suitable image analysis (tomography - CT, magnetic resonance – MRI) established disease progression. Complete Response was defined as neurological stability or improvement conditions, disappearance of CT/MRI tumor image and corticosteroid withdraw; Partial Response defined as >50% reduction of CT/MRI tumor image, neurological stability or improvement conditions and corticosteroid requirement; Progressive Course was defined as >25% increase CT/MRI tumor image or appearance of a new lesion; Stable Disease was defined as lack of any changes in the CT/MRI tumor image or neurological status.

After 6 months of treatment it was observed the following: Partial Response: 3.4% (n=1) with GBM and 33,3% (n=1) with AO; Stable Disease: 44.8% (n=13) with GBM, 60% (n=3) with AA and 33.3% (n=1) with AO; Progressive Course: 51.7% (n=15) with GBM, 40% (n=2) with AA and 33.3% (n=1) AO. The progression free survival (sum of partial responses and stable disease) was 48.2% for patients with GBM, 60%, 66.6% for AA patients and 66.6% for AO patients.

The present work indicate for the first time, that intranasal administration of the signal transduction inhibitor, perillyl alcohol, is a safe, non invasive, low cost and regression of tumor size in some patients is suggestive of antitumor activity.

Key words: perillyl alcohol, gliomas, intranasal administration.

*

Estudos preliminares da administração intranasal do álcool perílico em pacientes com gliomas malignos recidivos.(Resumo). Tese de Doutorado, Pós Graduação em Clínica Médica Universidade Federal do Rio de Janeiro (Área: Neurologia). Orientadores: Maurice Vincent e Thereza Quirico dos Santos.

Publication Dates

• Publication in this collection
  11 Apr 2008
• Date of issue
  Sept 2007