title: A phase 2a study of topical perillyl alcohol cream for chemoprevention of skin cancer.
abstract: The chemopreventive and antitumor properties of perillyl alcohol (POH) that were studied preclinically indicate that topical POH inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene-induced murine melanoma (transgenic models involving tyrosinase-driven Ras). A previous phase 1 clinical trial in participants with normal-appearing skin showed that topical POH cream was well tolerated at a dose of 0.76% (w/w). Here, we performed a 3-month, double-blind, randomized, placebo-controlled phase 2a trial of two different doses of topical POH in individuals with sun-damaged skin. Participants applied POH cream twice daily to each dorsal forearm. Baseline and end-of-study biopsies were taken from each participant to evaluate whether the topical application of POH was effective in reversing actinic damage as evidenced by normalization of quantitative skin histopathologic scores and change in nuclear chromatin pattern as measured by karyometric analysis. There was a borderline reduction in the histopathologic score of the lower-dose POH group compared with the placebo (P = 0.1), but this was not observed in the high-dose group. However, in the high-dose group, a statistically significant reduction in the proportion of nuclei deviating from normal was observed by the use of karyometric analysis (P < 0.01). There was no statistical significance shown in the lower-dose group. No changes were observed in p53 expression, cellular proliferation (by proliferating cell nuclear antigen expression), or apoptosis in either treatment group compared with the placebo group. These results suggest that whereas our karyometric analyses can detect a modest effect of POH in sun-damaged skin, improved delivery into the epidermis may be necessary.
authors.affiliation: Department of Medicine, University of Arizona, Tucson, 85724, USA. sstratton@azcc.arizona.edu
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.forename: Janine G
authors.initials: JG
authors.lastname: Einspahr
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sagerman
authors.forename: James A
authors.initials: JA
authors.lastname: Warneke
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.forename: Paul B
authors.initials: PB
authors.lastname: Myrdal
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Karlage
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Nickoloff
authors.forename: Chris
authors.initials: C
authors.lastname: Brooks
authors.forename: Kathylynn
authors.initials: K
authors.lastname: Saboda
authors.forename: Michael L
authors.initials: ML
authors.lastname: Yozwiak
authors.forename: Mary F
authors.initials: MF
authors.lastname: Krutzsch
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Hu
authors.forename: Maria
authors.initials: M
authors.lastname: Lluria-Prevatt
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: G Timothy
authors.initials: GT
authors.lastname: Bowden
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bartels
mesh_terms: D000287:Administration, Topical; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D002843:Chromatin / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D039821:Monoterpenes / Q000008:administration & dosage*; D012878:Skin Neoplasms / Q000517:prevention & control*
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D039821:Monoterpenes; C032208:perillyl alcohol