GeneticsPreliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas
Introduction
Understanding the molecular features of glioma will eventually allow for targeted intervention and more promising approaches for treating gliomas. Aberrations in a number of signal transduction pathways have been identified as playing a key role in the molecular pathogenesis of astrocytomas and their progression to high-grade GBM. Glioblastoma multiformes are characterized by overexpression of the PDGF and its receptor (PDGF-R), as well as the EGF and its receptor (EGF-R). These receptors activate the Ras pathway, a key cellular signal transduction pathway, leading to the activation of a wide range of Ras-dependent cellular events [12]. Recent experiments show that ERK, a MAP kinase, may have a critical role in cell proliferation. Results indicate higher p-ERK1/2 in GBM [6]. Although ERK/MAPK activation was not restricted to neoplastic glia, consistent patterns of selective activation in tumor cells suggest that sustained activation may contribute to the neoplastic glial phenotype [12]. Indeed, POH, a novel Ras inhibitor that produces apoptosis in GBM cell lines [9], [17], also seems to induce inhibition of the regulated kinase (ERK) in A549 cell line [10].
Perillyl alcohol (Fig. 1), also known as p-metha,1,7-diene-6-ol or as 4-isopropenyl-cyclohexenecarbinol, is composed of 2 isoprene units produced by the mevalonate pathway. It has been found to be active in tumor cells with no impact on normal cells and also to have the ability to change tumor cells to a differentiated state [5]. Although the mechanism by which POH exerts its anticancer activity is not clear, a number of potentially important drug-related activities have been observed in preclinical studies. Such activities range from cellular effects (early G1 arrest and the induction of apoptosis) [20], biochemical effects (decrease in the levels of isoprenylated Ras and Ras-related proteins) [11], and differential gene regulation with overexpression of M6P/IGF-II and TGF-β type II receptor genes [1].
Our experiments [8] showed that treatment with POH in vitro consistently inhibited proliferation and caused significant alteration in the cytoarchitecture of both human and murine GBM cells. Using the chick embryo model with the murine C6 cell line, we showed that POH also inhibited cell migration and antimetastatic activity [22]. These results indicated a chemotherapeutic action of POH by promoting cytotoxicity and arresting the migration of glioblastoma cell lines. Another study from our group [9] demonstrated that treatment of both human primary cultures and established cell lines of GBM with POH led to a decrease in cell viability and death by apoptosis.
Preclinical activity of the monoterpene POH was observed in a number of different tumor types, including mammary [1], [19], pancreatic [20], colonic [18], prostatic [13], gliomatous [17], and hepatic tumors [14]. Phase I and II clinical trial protocols in patients with advanced solid tumors are underway, and the maximum tolerated dose was determined to be 8.4 g/M2 per day delivered orally in 4 doses [2], [3]. Toxicities consisted of nausea, early satiety, eructation, and unpleasant taste as well as fatigue. The chronic nature of the toxicities led to problems with patient tolerance and compliance. The life quality data suggest that oral consumption of POH is an unpleasant experience for most patients. Modest clinical responses were attained in trials. Efforts are now directed toward building high-dose formulations of POH free of gastrointestinal toxicity. Based on the favorable therapeutic ratio observed in in vitro and in vivo treatment, commercial availability, low cost, and low toxicity, we are developing clinical trial phase I/II that delivers POH by inhalation in patients with relapsed GBM. This trial was approved by the Brazilian Committee of Ethics and Research (CONEP 9681 no. 25000.009267/2004-25, July 12, 2004).
Therapeutic efficacy in humans, particularly with regard to the CNS, is frequently diminished or nullified by the inability of the drugs to reach and maintain effective concentrations in the brain for an appropriate length of time. Frequently, the molecule is too large or has polar functional groups, and the BBB limits its access to the CNS. The role of olfactory epithelium as a gateway for substances entering the CNS and peripheral circulation is well known. Recently, it has been shown that intranasal delivery provides a practical, noninvasive, rapid, and simple method to deliver the therapeutic agents to the CNS [4]. It was proposed that this is due to the unique connection that the olfactory and trigeminal nerves (involved in sensing odors and chemicals) provide between the brain and external environments [4].
Our phase I/II study, conducted to further define the clinical activity of POH among patients with recurrent malignant gliomas, provides the first report of an intranasal delivery of a signal transduction inhibitor with a cytotoxic agent for these patients. Furthermore, we demonstrate that this regimen has antitumor activity and is well tolerated among these patients [7].
Section snippets
Patients and methods
This study was approved by the Ethics Council of Hospital Universitario Antonio Pedro–Universidade Federal Fluminense (UFF). Informed consent was obtained from either the patient or next-of-kin.
Patient characteristics
Thirty-seven patients with recurrent malignant gliomas were enrolled, including 29 patients with GBM, 5 patients with anaplastic astrocytoma, and 3 patients with AO. Age of patients with GBM ranged from 38 to 62 years (median, 50 years); for those with AA, 41 to 64 years (median, 52.5 years); and for those with AO, 35 to 69 years (median, 52) years. Before entering the clinical trial, all patients received prior conventional therapy (surgery, chemotherapy, and radiotherapy), were out of
Discussion
Malignant gliomas, including the most common subtype, GBM, are among the most devastating of neoplasms. Their aggressive infiltration in the CNS typically produces progressive and profound disability, ultimately leading to death in nearly all cases. Improvement in outcome has been elusive despite decades of intensive clinical and laboratory research. Surgery and radiotherapy, the traditional therapy, provide palliative benefit [21], whereas the value of chemotherapy with classic cytotoxic
Conclusion
Malignant gliomas remain essentially resistant to traditional cancer therapy. Current targeted therapies largely focus on the disruption of oncogenic cellular pathways—either growth-factor receptors or intracellular effectors. Here, we are investigating a novel therapeutic strategy using intranasal delivery of POH, an inhibitor of Ras. The treatment was well tolerated and suggests improvement in tumor response rates.
Acknowledgments
The authors would like to thank Paulo Costa Carvalho, PhD student in bioinformatics from UFRJ/COPPE, for the helpful discussions. We gratefully acknowledge the financial support of CNPq, FAPERJ, AMIL Assistencia Médica Internacional, and Hospital Universitário Antonio Pedro-UFF.
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