For Patients & Caregivers
How It Works
A specific form of perillyl alcohol may be helpful in palliative care patients with recurrent gliomas. However, oral forms were not effective in several cancers and were accompanied by adverse side effects.
Perillyl alcohol (POH) is a natural substance called a monoterpene, isolated from the essential oils of lavender, peppermint, spearmint, cherries, celery seeds, and several other plants. Laboratory evidence suggests that it interferes with the replication of dividing cells. POH has shown antitumor activity against a range of cancer types including pancreatic, lung, colon, and liver cancers in laboratory and animal studies, but these results have not yet translated into benefits in humans. Clinical trials of oral POH for various cancers including breast, prostate, and ovarian cancers did not find benefit and also noted adverse side effects, even after modifying dosing regimens to try to improve effectiveness and tolerability. However, an inhaled form of POH has shown preliminary evidence of safety and effectiveness in patients with recurrent gliomas. In addition, other purified forms are being studied as chemical modifiers of established drugs used to treat cancer in order to improve outcomes.
To prevent and treat cancer
POH developed as a nasal spray has shown initial evidence of safety and effectiveness in palliative care patients with recurrent gliomas. A study of topical POH applied to sun-damaged skin did not suggest it could prevent skin cancers. Oral POH has yet to suggest benefit in humans and was also associated with adverse side effects.
Oral POH: nausea, unpleasant taste, gastrointestinal distress, feeling full after eating a small amount of food, fatigue
Toxicity can develop at high doses including nausea, fatigue, diarrhea, low blood potassium levels, inflamed oral mucous membranes, and loss of appetite. There have also been cases of vomiting, low white blood cell counts, and inflammation of the pancreas.
Intranasal POH: Initial studies have shown good tolerability and no adverse effects.
For Healthcare Professionals
Perillyl alcohol (POH) is a naturally occurring monoterpene derived from the essential oils of various botanicals including lavender, peppermint, cherries, sage, and lemongrass. It has been used topically as a mosquito repellant and in toiletries, and may be touted as a constituent of natural products such as tart cherry juice.
In human studies, oral POH did not benefit patients with prostate (10), ovarian (7), or breast cancers (14). Another study attempting to achieve higher daily oral doses or better long-term tolerability in a variety of malignant tumors found no significant advantages with interrupted administration over continuous dosing schedules (22). Topical POH also did not show chemopreventive effects in subjects with skin damage (13). These delivery methods were consequently abandoned due to either dose-limiting side effects and/or lack of efficacy (23). More recent preliminary studies found intranasal POH delivery in patients with malignant gliomas to be well-tolerated and effective, with one study reporting tumor size regression (15), and another reporting increased overall survival and no side effects after long-term use (24). Confirmatory studies are needed.
POH is also in preclinical development as part of a novel drug to improve upon the effects of temozolomide (TMZ), which is used to treat a variety of cancers. TMZ conjugated to POH (TMZ-POH) increased anticancer activity in several breast cancer cell lines including those resistant to TMZ (25). Animal models also suggest its potential for brain-targeted breast cancer metastases (25), TMZ-resistant gliomas (26), O6-methyl-guanine DNA methyltransferase (MGMT) melanomas (27), and nasopharyngeal carcinomas (28) versus TMZ alone or simply a mixture of TMZ and POH. Amino-modified POH derivatives are also being evaluated and have shown anticancer activity in human lung cancer, melanoma, and fibrosarcoma cells (29).
The POH that may occur in natural products are different from their scientifically studied counterparts, which are extracted from plants or developed synthetically into highly purified forms and are being used for research and clinical trial purposes to determine safety and efficacy.
Mechanism of Action
Perillyl alcohol metabolites perillic acid and dihydroperillic acid may prevent tumor growth through inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway (1) (2). These metabolites also induce G1 cell cycle arrest, inhibit posttranslational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes (3). POH may also affect Ras signaling pathways (30) and Na/K-ATPase inhibition (31). In addition, some POH glycosides, most particularly POH 4’-azido-D-glucoside (PG9), are identified as having improved antiproliferative activity and inhibition of S6 ribosomal protein phosphorylation (32).
Intranasal POH may be more successful than dose-limiting oral POH because it crosses the blood-brain barrier to enter the central nervous system, eliminating the need for systemic delivery and reducing unwanted systemic side effects (30).
In breast cancer cell lines and animal models, the more efficient DNA damage and cell death that occurs with the novel compound TMZ-POH versus TMZ alone was due to the increased biologic half-life acquired with POH linkage, providing more opportunity for placement of cytotoxic DNA lesions (25). A combination of POH and lovastatin, which may also reduce glioma risk, impaired mevalonate- and Ras-Raf-MEK-ERK pathway regulation in glioblastoma cells (33).
Rare (oral): vomiting (22).
At 1200 mg/m2/day: one instance of hypokalemia (low potassium levels) (10).
At 1600 mg/m2/dose: gr 3 hypokalemia with course 2; acute pancreatitis in a patient with non-Hodgkin’s lymphoma during course 6 (22).
At 2000 mg/m2/dose: gr 2–3 hypokalemia over 2 courses (22).
At >2800 mg/m2/day: nausea, fatigue, diarrhea, hypokalemia, stomatitis, and anorexia (2) (8).
At high doses on a tid schedule: gr 3 neutropenia in 2 heavily treated ovarian cancer patients (3).