A phase I trial of perillyl alcohol in patients with advanced solid tumors Journal Article

Authors: Azzoli, C. G.; Miller, V. A.; Ng, K. K.; Krug, L. M.; Spriggs, D. R.; Tong, W. P.; Riedel, E. R.; Kris, M. G.
Article Title: A phase I trial of perillyl alcohol in patients with advanced solid tumors
Abstract: Purpose: Perillyl alcohol is a plant-derived lipid with preclinical antitumor activity. Its proposed mechanism of action involves inhibition of post-translational isoprenylation of small G proteins, including the proto-oncogene p21-ras, thereby blocking signal transduction. This phase I trial was conducted to determine the optimal dose of perillyl alcohol. Methods: The study group comprised 21 adults with advanced solid tumors who were treated with perillyl alcohol, delivered orally, four times daily, without interruption. Doses ranged from 4,800 to 11,200 mg/m2 per day. Results: The maximum tolerated dose (MTD) for this schedule was determined to be 8400 mg/m2 per day. The dose-limiting toxicities in this trial were nausea and vomiting, encountered in all patients at the highest dose level. No antitumor activity was observed. Pharmacokinetic data suggest dose-dependent increases in Cmax of perillic acid, a metabolite of perillyl alcohol, but with high inter- and intrapatient variability. Conclusions: The MTD of perillyl alcohol for this schedule was determined to be 8400 mg/m2 per day. This is higher than the MTDs determined in other similar phase I trials. This may have been due to the fact that the gastrointestinal symptoms caused by perillyl alcohol are highly subjective, with high interpatient variability. Phase II trials of perillyl alcohol in hormone-refractory prostate, breast, ovarian and colorectal cancer using doses in the range 4800-6400 mg/m2 per day are underway.
Keywords: signal transduction; adult; clinical article; middle aged; clinical trial; fatigue; advanced cancer; area under the curve; solid tumor; antineoplastic agents; neoplasms; proto oncogene; quality of life; gastrointestinal symptom; nausea; vomiting; antineoplastic activity; questionnaires; drug mechanism; drug response; ondansetron; optimal drug dose; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; drug metabolite; guanine nucleotide binding protein; metoclopramide; prochlorperazine; humans; human; male; female; priority journal; article; perillyl alcohol; limonene; g proteins; isoprenylation; monoterpenes; p21-ras; perillic acid; terpene derivative; belching; early satiety; plant product; proto oncogene p21 ras
Journal Title: Cancer Chemotherapy and Pharmacology
Volume: 51
Issue: 6
ISSN: 0344-5704
Publisher: Springer  
Date Published: 2003-06-01
Start Page: 493
End Page: 498
Language: English
PUBMED: 12695855
PROVIDER: scopus
DOI: 10.1007/s00280-003-0599-7
Notes: Export Date: 12 September 2014 -- Source: Scopus
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MSK Authors
  1. William Ping-Yiu Tong
    141 Tong
  2. Kenneth K Ng
    36 Ng
  3. Lee M Krug
    211 Krug
  4. Christopher G Azzoli
    105 Azzoli
  5. Vincent Miller
    266 Miller
  6. David R Spriggs
    319 Spriggs
  7. Mark Kris
    639 Kris