Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

Murren, John R.; Pizzorno, Giuseppe; DiStasio, Susan A.; McKeon, Anne; Peccerillo, Kathleen; Gollerkari, Ashwin; McMurray, Walter J.; Burtness, Barbara; Rutherford, Thomas J.; Li, Xin; Ho, Peter; Sartorelli, Alan C.

doi:10.4161/cbt.57

Cited by 18 publications

(4 citation statements)

References 32 publications

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“…Nausea, which was a limiting side effect in other trials using novobiocin, was well controlled by the administration of serotonergic antiemetics. Diarrhea was common but mild in most patients [142]. In summary, most pharmacological studies involve mainly coumarin itself as an anti-neoplastic drug.…”

Section: Defining the Clinical Course Of Cou-marin Compoundsmentioning

confidence: 99%

Coumarins: Old Compounds with Novel Promising Therapeutic Perspectives

Riveiro

Kimpe²,

Moglioni³

et al. 2010

CMC

400

202

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Natural as well as synthetic coumarins have recently drawn much attention due to its broad pharmacological activities. Many coumarins and their derivatives exert anti-coagulant, anti-tumor, anti-viral, anti-inflammatory and anti-oxidant effects, as well as anti-microbial and enzyme inhibition properties. The recognition of key structural features within coumarin family is crucial for the design and development of new analogues with improved activity and for the characterization of their mechanism of action and potential side effects. The different substituents in the coumarin nucleus strongly influence the biological activity of the resulting derivatives. Although some coumarins have been already characterized to evoke a particular biological activity, the challenge would be the design and synthesis of new derivatives with high specific activity for other pharmacological targets and define their mechanism of action to achieve new therapeutic drugs. The present review highlights the current progress in the development of coumarin scaffolds for drug discovery as novel anti-cancer agents. The major challenges about coumarins include the translation of current knowledge into new potential lead compounds and the repositioning of known compounds for the treatment of cancer.

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Section: Defining the Clinical Course Of Cou-marin Compoundsmentioning

confidence: 99%

Coumarins: Old Compounds with Novel Promising Therapeutic Perspectives

Riveiro

Kimpe²,

Moglioni³

et al. 2010

CMC

400

202

View full text Add to dashboard Cite

show abstract

“…Based on the collective outcome of the above-mentioned animal studies, POH was formulated in soft gelatin capsules and tested in a number of phase I and II cancer trials, where it was given orally three to four times each day for several months [ 99 , 100 , 101 , 102 , 103 , 104 , 105 ]. However, the results were disappointing.…”

Section: Intranasal Drug Deliverymentioning

confidence: 99%

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

Chen

Fonseca

Schönthal

2016

IJMS

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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. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here.

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“…POH was formulated in gelatin capsules and, due to its short biological half-life, was administered 3–4 times daily on a continuous basis over several months. Initial phase 1 trials used 2.1 to 2.4 g/m 2 POH delivered in 3 doses [110,111], or 4.8 g/m 2 delivered in 4 doses [59], and eventually the MTD (maximum tolerated dose) was established at 8.4 g/m 2 per day, delivered in four equal doses distributed over the day [112]. For most subsequent phase 2 trials, 4.8 g/m 2 , distributed over 4 doses, was used [113,114,115,116,117], although in some of these trials POH was dose-escalated to 6.0 and 6.4 g/m 2 , respectively, for patients who tolerated the initial dose [113,114,116] (Table 1).…”

Section: Perillyl Alcoholmentioning

confidence: 99%

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

Chen

Fonseca

Schönthal

2018

IJMS

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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. A remarkable exception is the natural compound perillyl alcohol (POH). Its potent anticancer activity was convincingly established in preclinical studies, but it nonetheless failed in subsequent clinical trials, where it was given orally and displayed hard-to-tolerate gastrointestinal side effects. Intriguingly, when switched to intranasal delivery, POH yielded highly promising activity in recurrent glioma patients and was well tolerated. As of 2018, POH is the only intranasally delivered compound in the field of cancer therapy (outside of cancer pain) that has advanced to active clinical trials. In the following, we will introduce this compound, summarize its molecular mechanisms of action, and present the latest data on its clinical evaluation as an intranasally administered agent for glioma.

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Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies

Cited by 18 publications

References 32 publications

Coumarins: Old Compounds with Novel Promising Therapeutic Perspectives

Coumarins: Old Compounds with Novel Promising Therapeutic Perspectives

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

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

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