The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers.

Perillyl alcohol (POH) is a naturally occurring monoterpenoid related to limonene that is present in the essential oils of various plants. It has diverse applications and can be found in household items, including foods, cosmetics, and cleaning supplies. Over the past three decades, it has also been investigated for its potential anticancer activity.

Phase I trial of intranasal NEO100, highly purified perillyl alcohol, in adult patients with recurrent glioblastoma.

Background: Better treatments for glioblastoma (GBM) patients, in particular in the recurrent setting, are urgently needed. Clinical trials performed in Brazil indicated that intranasal delivery of perillyl alcohol (POH) might be effective in this patient group. NEO100, a highly purified version of POH, was current good manufacturing practice (cGMP) manufactured to evaluate the safety and efficacy of this novel approach in a Phase I/IIa clinical trial in the United States.

Adjuvant effect of low-carbohydrate diet on outcomes of patients with recurrent glioblastoma under intranasal perillyl alcohol therapy.

Background: Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect.

Methods: To investigate LCD's effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients.

Intranasal administration of perillyl alcohol-loaded nanoemulsion and pharmacokinetic study of its metabolite perillic acid in plasma and brain of rats using ultra-performance liquid chromatography/tandem mass spectrometry.

Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical trials have shown their low tolerance through oral administration. We proposed the entrapment of POH into an oil-in-water chitosan nanoemulsion aiming its intranasal administration for brain targeting.

Intranasal perillyl alcohol therapy improves survival of patients with recurrent glioblastoma harboring mutant variant for MTHFR rs1801133 polymorphism.

Background: Polymorphisms in MTHFR gene influence risk and overall survival of patients with brain tumor. Global genomic DNA (gDNA) methylation profile from tumor tissues is replicated in peripheral leukocytes. This study aimed to draw a correlation between rs1801133 MTHFR variants, gDNA methylation and overall survival of patients with recurrent glioblastoma (rGBM) under perillyl alcohol (POH) treatment.

Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats.

The inhalational administration of drugs is a practical and non-invasive approach with the potential to reduce side effects and with a quick onset of therapeutic activity. Perillyl alcohol (POH) is a monoterpene with antitumor activity that currently is undergoing clinical evaluation as an inhalational anticancer agent. A detection method was developed that will be applicable to pharmacokinetic studies of not only POH, but also its longer-lived main metabolite, perillic acid (PA), in lung tissue and plasma after inhalational delivery.

Intranasal Perillyl Alcohol for Glioma Therapy: Molecular Mechanisms and Clinical Development.

Intracranial malignancies, such as primary brain cancers and brain-localized metastases derived from peripheral cancers, are particularly difficult to treat with therapeutic agents, because the blood-brain barrier (BBB) effectively minimizes brain entry of the vast majority of agents arriving from the systemic circulation. Intranasal administration of cancer drugs has the potential to reach the brain via direct nose-to-brain transport, thereby circumventing the obstacle posed by the BBB. However, in the field of cancer therapy, there is a paucity of studies reporting positive results with this type of approach.

Circulating Cell-Free DNA as a Prognostic and Molecular Marker for Patients with Brain Tumors under Perillyl Alcohol-Based Therapy.

Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors.

Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma.

It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6-methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma.

Perillyl alcohol, a pleiotropic natural compound suitable for brain tumor therapy, targets free radicals.

Monoterpenes such as limonene and perillyl alcohol (POH) are promising natural compounds with pro-oxidant properties partly due to endoplasmic reticulum (ER) stress-induced cytotoxicity, and antioxidant activity owing to their activity as free radical scavengers, inhibition of coenzyme Q synthesis, activation of antioxidant-responsive elements (inducing detoxification enzymes) and induction of apoptosis. Activation of ER-stress responses generates reactive oxygen species (ROS), which are highly reactive free radicals mainly produced during mitochondrial electron transfer for adenosine triphosphate (ATP) synthesis. When cells are subjected to oxidative stress conditions, there is an accumulation of ROS that can lead to irreversible cell injury caused primarily by lipid peroxidation, protein aggregation and/or DNA damage.

Patients' perspective on awake craniotomy for brain tumors-single center experience in Brazil.

Background: Awake craniotomy with brain mapping is the gold standard for eloquent tissue localization. Patients' tolerability and satisfaction have been shown to be high; however, it is a matter of debate whether these findings could be generalized, since patients across the globe have their own cultural backgrounds and may perceive and accept this procedure differently.

Methods: We conducted a prospective qualitative study about the perception and tolerability of awake craniotomy in a population of consecutive brain tumor patients in Brazil between January 2013 and April 2015.

Survival rate and perioperative data of patients who have undergone hemipelvectomy: a retrospective case series.

Background: Hemipelvectomy is a major orthopedic surgical procedure indicated in specific situations. Although many studies discuss surgical techniques for hemipelvectomy, few studies have presented survival data, especially in underdeveloped countries. Additionally, there is limited information on anesthesia for orthopedic oncologic surgeries.

Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases.

Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site.

A Time-Based and Intratumoral Proteomic Assessment of a Recurrent Glioblastoma Multiforme.

Tumors consist of cells in different stages of transformation with molecular and cellular heterogeneity. By far, heterogeneity is the hallmark of glioblastoma multiforme (GBM), the most malignant and aggressive type of glioma. Most proteomic studies aim in comparing tumors from different patients, but here we dive into exploring the intratumoral proteome diversity of a single GBM.

Perillyl alcohol: Dynamic interactions with the lipid bilayer and implications for long-term inhalational chemotherapy for gliomas.

Background: Gliomas display a high degree of intratumor heterogeneity, including changes in physiological parameters and lipid composition of the plasma membrane, which may contribute to the development of drug resistance. Biophysical interactions between therapeutic agents and the lipid components at the outer plasma membrane interface are critical for effective drug uptake. Amphipathic molecules such as perillyl alcohol (POH) have a high partition coefficient and generally lead to altered lipid acyl tail dynamics near the lipid-water interface, impacting the lipid bilayer structure and transport dynamics.

Morphometric analysis of the medial opticocarotid recess and its anatomical relations relevant to the transsphenoidal endoscopic endonasal approaches.

Background: The medial opticocarotid recess (MOCR) is located in the posterior wall of the sphenoid sinus, medial to the junction of the optic canal (OC) and the carotid prominence (CP). There is controversy in the literature in relation to the presence of the MOCR and its constancy, which is relevant when approaching the skull base through an endoscopic route.

Methods: The morphometric relations of the MOCR with the surrounding structures were studied in 18 cadaveric specimens after endoscopic endonasal approach (EEA).

Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation.

Aim: This retrospective study aimed to evaluate the long-term response and toxicity of recurrent malignant glioma patients to inhalation chemotherapy with perillyl alcohol (POH).

Patients And Methods: The cohort included 117 men and 81 women with primary glioblastoma multiforme (GBM; n=154), grade III astrocytoma (AA; n=26) and anaplastic oligodendroglioma (AO; n=5). POH inhalation schedule 4-times daily started with 66.

Intranasal administration of perillyl alcohol activates peripheral and bronchus-associated immune system in vivo.

Perillyl alcohol (POH) presents antitumoral activity but clinical application is hampered by adverse effects following oral administration. This work aimed to verify the cytotoxic effect of intranasal POH administration in the histology of lung, liver, brain; the cellularity and function of peripheral and bronchoalveolar-associated immune system. C57 adult mice received 1-min inhalation with POH, vehicle 70 % ethanol or saline buffer, once (84 μg/day) or twice (164 μg/day) during five consecutive days, and were killed 72 h after treatment.

Chemo-resistant protein expression pattern of glioblastoma cells (A172) to perillyl alcohol.

Glioblastoma multiform (GBM) is by far the most malignant glioma. We have introduced a new treatment for GBMs that comprises the inhalation of a naturally occurring terpene with chemotherapeutic properties known as perillyl alcohol (POH). Clinical trial results on recurrent GBM patients showed that POH extends the average life by more than eight months, temporarily slows tumor growth, and in some cases even decreases tumor size.

The anticancer drug perillyl alcohol is a Na/K-ATPase inhibitor.

The monoterpene perillyl alcohol (POH) is a drug used in the treatment of several malignant tumors, including gliomas. The present study defines a POH inhibitory effect on Na/K-ATPase activity from kidney and brain guinea pig extracts and from a human glioblastoma cell line. This inhibition showed a high degree of selectivity toward the kidney enzyme expressing, as do glioblastoma cells, the α(1) subunit.

Efficacy of monoterpene perillyl alcohol upon survival rate of patients with recurrent glioblastoma.

Purpose: The monoterpene perillyl alcohol (POH) a Ras inhibitor with potential capacity to arrest gliomagenesis is being used in a phase I/II clinical trial in adults with recurrent malignant glioma. The present study aimed to investigate the efficacy of intranasal administration of monoterpene POH upon survival rate of patients with recurrent glioblastoma (GBM) in comparison with historical control group of GBM patients.

Patients And Methods: It was included 89 adults with recurrent GBM receiving daily intranasal administration of 440 mg POH and 52 matched GBM patients as historical control untreated group only with supportive treatment.

Anti-thrombin as a prognostic biomarker candidate for patients with recurrent glioblastoma multiform under treatment with perillyl alcohol.

Perillyl alcohol (POH) is a naturally occurring monoterpene with antiangiogenic and anti-tumoral properties. This chemotherapeutic agent has proven effectiveness in several clinical trials, including an ongoing phase I, comprising patients with recurrent glioblastoma multiform (GBM) under treatment with POH by intranasal administration. Proteomics offers tools to distinguish states of biological systems according to protein expression differences and therefore, can be used to gain pathological insights and to search for disease follow-up biomarkers.

Correlation of tumor topography and peritumoral edema of recurrent malignant gliomas with therapeutic response to intranasal administration of perillyl alcohol.

Background: The aim of this study was to establish a correlation of tumor topography and peritumoral brain edema with the therapeutic response to intranasal administration of perillyl alcohol (POH) in a cohort of patients with recurrent malignant gliomas.

Methods: The retrospective study reviewed clinical and neuroradiological data from patients with recurrent malignant gliomas who received intranasal daily administration of POH 440 mg. The following parameters were assessed: demographic characteristics, initial symptoms, overall survival, tumor topography and tumor size, presence of midline shift and extent of peritumoral edema.

Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol.

Introduction: Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Malignant gliomas commonly overexpress the oncogenes EGFR and PDGFR and contain mutations and deletions of the tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy.