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Arizona Cancer Center [D. S. A., R. T. D., J. G. E., K. S., M. J. X., Y-M. P., R. G., J. A. F., S. S., D. J. R., G. T. B.], and Department of Surgery, College of Medicine [J. A. W.], University of Arizona, Tucson, Arizona 85724; and Kaiser Center for Health Research, Portland, Oregon 97227-1098 [M. A.]
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-2-(Difluoromethyl)-dl-ornithine
(DFMO), an irreversible inhibitor of ornithine decarboxylase,
has been shown to suppress skin carcinogenesis in murine models after
oral or topical administration. We designed a randomized,
placebo-controlled study using a topical hydrophilic ointment
formulation with or without 10% (w/w) DFMO. Forty-eight participants
with moderate-severe actinic keratoses (AKs) on their forearms
(i.e., at least 10 well-circumscribed lesions on the
lateral surface) completed a 1-month run-in on placebo ointment. Before
randomization, all lateral forearm AKs were circled, counted,
photographed, and skin biopsies were obtained for DFMO and polyamine
levels. Then participants were randomized to receive DFMO ointment on
the right versus the left forearm and placebo
hydrophilic ointment on the contralateral forearm twice daily for 6
months. DFMO was not detected in the blood of any subject, and there
were no systemic toxicities. None of a subsample of 17 placebo forearms
had measurable concentrations of DFMO, whereas 13 of the corresponding
DFMO-treated forearms had high DFMO skin levels. As compared with
placebo, the 6-month DFMO treatment caused a 23.5% reduction in the
number of AKs (P = 0.001) as well as significant
suppression of AK biopsy spermidine levels (26%; P = 0.04). Seven of the 48 (14.6%) participants experienced severe (2;
4.2%) or moderate (5; 10.4%) inflammatory reactions on their
DFMO-treated arms which required dosing modification. Topical DFMO for
6 months can reduce the number of AK lesions and skin spermidine
concentrations in high-risk participants and deserves additional study
as a skin cancer chemopreventive agent. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The most common treatments of AK continue to be a topical application of 5% fluorouracil cream (21) or liquid nitrogen (22) . Both of these methods result in severe inflammation, erythema, and superficial ulceration. There continues to be a need for the development of less toxic drugs which can be applied chronically as chemopreventive agents for patients with severely sun-damaged skin and AKs.
DFMO is an enzyme-activated irreversible inhibitor of ornithine
decarboxylase (Fig. 1)
, which is the
rate-limiting enzyme in polyamine synthesis, and decreases
intracellular levels of putrescine and spermidine in the skin and other
vital tissues (23
, 24)
. In conjunction with the
administration of model carcinogens, DFMO significantly reduced tumor
incidence in several mammalian in vivo tests for
chemopreventive activity (25
, 26)
. Additionally, DFMO
chemopreventive activity has been demonstrated in chemical and UV
models of mouse skin carcinogenesis (27, 28, 29)
. Gensler has
shown that p.o.-administered DFMO reduced UVB-induced skin cancers in
C3H/HeN mice from 38% in placebo-treated controls to 9% in treated
animals (30)
. Similarly, topically administered DFMO in an
acetone vehicle dramatically reduced UVBinduced skin cancers in
BALB/c
mice.4
In adult
participants with psoriasis, the application of 10% DFMO cream
resulted in a 66% reduction in spermine concentrations in the skin and
a marginal improvement in psoriatic lesions (31)
.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DFMO Formulation
DFMO was supplied as a white powder of the monohydrate,
monochloride (MW = 236.65) from Marrion-Merrell Dow
Pharmaceutical Company (Lot No. 71,782a; Kansas City, MO). The drug was
weighed and mixed by blender into a 10% w/w concentration in
hydrophilic ointment USP (Lot No. 0210; East Fougera & Company,
Melville, NY). Once mixed, the ointment was transferred to
polyethylene-lined, 30-g metal ointment tubes which were then
crimp-sealed to preclude exposure to light and air. A HPLC assay, as
described below, was used to determine the chemical stability of DFMO
in hydrophilic ointment over a 6-month period during storage at 4°C
in the sealed metal tubes. There was <1% loss of DFMO noted at the
6-month time point.
When applied to full thickness skin samples in vitro using a standard skin chamber apparatus, uptake after 24 h at 37°C was considerable in mouse skin (6.8 mg/g wet weight), but there was negligible transdermal penetration of human skin (32) .
On the basis of data from toxicological and pharmacological experiments, the Food and Drug Administration approved our Investigational New Drug application for a Phase IIB clinical study of DFMO in hydrophilic ointment (data not shown).
Study Design
To obtain baseline adherence data, a 1-month run-in was performed
during which participants used a placebo formulation (hydrophilic
ointment) twice daily on both right and left forearms. Participants who
signed University of Arizona Human Subjects Committee-approved informed
consents applied 
1 inch (in length) of the formulation to the
exposed area of the forearm from the elbow to the knuckles of the hand
in the morning and at night. Before randomization, participants were
stratified on the basis of gender and numbers of AKs on the forearms.
Participants were then randomly assigned, in a double-blind fashion, to
treatment with hydrophilic DFMO ointment on the right versus
the left forearm and placebo hydrophilic ointment on the contralateral
forearm twice daily for 6 months. The weighed tubes were color coded
and had large "left" and "right" labels. At the end of each
month, the tubes were returned to the clinic and reweighed to provide a
measure of adherence. Participants also maintained a daily diary of
ointment usage.
Before the first application of the placebo ointment, at randomization, and at each succeeding monthly visit, a clinical toxicity assessment was completed. Data were collected on the presence of any redness (erythema), dryness, burning, itching or pain that had been experienced on each forearm. Each toxicity measure was rated for frequency and severity. Severity of each symptom was assessed using a scale in which level "0" was indicative of no symptoms, "1" indicated mild symptoms (easily tolerated), "2" indicated moderate symptoms (caused some discomfort and inconvenience), and "3" indicated severe symptoms (caused considerable discomfort and interference with activities and required some degree of treatment modification). Symptoms were also rated in terms of perceived severity on a 3-point scale of mild, moderate, or severe. Moderate or severe symptoms were assessed by the study dermatologist and appropriate measures taken (dose reduction or the additional use of moisturizers).
During the placebo run-in and at the end of 6 months there was a clinical evaluation of AKs (individual AK lesions were circled and counted on each arm by a dermatologist and then photographed using a Nikon N5005 camera with a 60-mm Micor Nikkor lens, SB-21 Macro Speedlight, and Kodachrome ASA 64 film) and skin punch biopsies (3 mm) were obtained for polyamine levels. Additionally, serum samples were obtained from all participants who completed the study for measurement of DFMO levels, and skin punch biopsies were obtained on a subset of 17 participants for DFMO and ornithine concentrations at baseline and after 6 full months of treatment. Punch biopsies were taken from an area of clinically apparent AK located on the lateral surface of forearms before and after treatment with placebo or DFMO. Complete blood counts and serum chemistry panels (SMA20s) were performed during the run-in and at end of study.
Laboratory Methods
Tissue Preparation.
The area of skin to be biopsied was anesthetized with 1% lidocaine
HCL with epinephrine (Elkins-Sinn, Incorp. Cherry Hill, NJ). Two
3-mm punch biopsies were obtained for polyamines, DFMO, and ornithine
concentrations from AKs on the lateral surfaces of each of the two
forearms and transported on ice to the analytical chemistry laboratory.
HPLC Methods.
Polyamines were quantitated in skin biopsies by measurement of dansyl
derivatives (33)
. Skin biopsy samples were homogenized
with 0.2 M perchloric acid containing 10 µM
1,7-diaminoheptane as an internal standard. The homogenate was then
centrifuged, and 100 µl of the supernatant were transferred to a new
1.5-ml Eppendorf tube which contained 100 µl of 1 M
sodium carbonate. One hundred µl of 1% dansyl-chloride in acetone
was added to the sample tube, and the sample was placed at
60°C for 1 h to allow for derivatization to occur. Fifty µl of
10% glycine was then added to remove excess dansyl-chloride. After
incubation for an additional 30 min, dansyl-polyamines were extracted
with hexane. The extract was dried under nitrogen and redissolved with
250 µl of acetonitrile. A 50-µl aliquot of the resulting solution
was injected onto the HPLC column. An Ultrasphere ODC 5-µm
reversed-phase column (4.6 x 250 mm; Beckman Instruments, Inc.,
San Ramon, CA) was used for analysis at room temperature with a
gradient of acetonitrile-disodium phosphate (1.2 mM; pH
5.49), a flow rate of 2.5 ml/min, and a 7-min sample time. Detection
was provided by a Kratos Spectroflow 980 fluorescence detector (ABI
Analytical, Inc., Remsey, NJ) with excitation at 340 nm and emission at
550 nm. The detection limit was <1 pmol, with linearity of 
250 pmol
for each polyamine injected. Recoveries for putrescine,
spermidine, and spermine were 105%, 99%, and 81%, respectively.
Additionally, all analytes were stable in skin stored at -80°C for
at least 2 months.
HPLC analysis of DFMO required precolumn derivitization with 6-aminoquinolyl-N-hydroxysuccinimidyl to produce highly stable derivatives (34) . Two-hundred µl of the plasma samples were mixed with 200 µl of 0.4 M perchloric acid containing 120 µM dl-2,4-diamino-n-butyric acid (as internal standard) to precipitate the proteins. A 3-mm skin punch biopsy sample was homogenized with 0.2 M perchloric acid (1.67%, w/v) in the presence of 60 µM dl-2,4-diamino-n-butyric acid. After centrifugation, 20 µl of the supernatant was transferred to a microcentrifuge tube containing 80 µl of saturated sodium tetraborate solution (pH 9.1). Derivatives were formed via the addition of 20 µl of 10 mM 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate in acetonitrile and then by vortexing for 5 s. A 5-µl volume of the derivatives was directly injected onto the HPLC column. A Nova-Pak C18 column (3.9 x 300 mm; Waters Chromatography Division, Millipore, Millford, MA) with a gradient elution of sodium acetate-acetonitrile, a flow rate of 1.2 ml/min, and detection with a Kratos Spectroflow 980 fluorescence detector (excitation at 245 nm and emission at 370 nm). The complete cycle/sample was 30 min with a retention time of 7.9 min for DFMO. The detection limit (signal:noise ratio = 3) was 90 fmol for DFMO. Two skin samples were used for reproducibility studies, where samples were homogenized and the aliquots of supernatant were stored at -80°C for the analysis of DFMO on 5 different days. The results indicated good precision with the coefficient of variation for each compound being <8%. For recovery studies, known amounts of mixed standards were added to plasma or tissue samples. Recovery was calculated by dividing the peak height of the standard in tissue sample to the peak height of the standard in aqueous solution. In the case of skin samples, recovery for DFMO was 94–99%.
Statistical Methods
The DFMO effects were assessed by fitting regression models
for change data. The outcome measure was the difference in the change
(of a factor) on the DFMO-treated arm minus the difference on the
untreated arm. The explanatory factor was the change on the untreated
arm, centered at its mean so that the regression intercept had the
interpretation as the (adjusted) DFMO effect (35)
. Initial
values were used to adjust for regression to the mean, whereas the
change on the untreated arm was used to adjust for person-specific
effects. Additionally, all models initially included dummy variables
for whether the right or left arm was treated.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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10)
clinically diagnosed AKs on their lateral forearms began the
1-month placebo cream run-in period. Two of these participants did not
complete the 1-month run-in period and were not randomized. Forty-eight
participants were randomized to apply DFMO cream to either their right
(24)
or left (24)
posterior forearms, with
the placebo cream to be used on the contralateral arm. Ultimately, 42
(87.5%) of 48 randomized participants completed the full 6 months of
treatment and underwent analysis. Six of 48 randomized participants did
not complete the study protocol before the 6-month completion date
because of the development of a rash (2 participants; see description
below) or for personal reasons (4 participants). As shown in Table 1
, there was an even distribution of age
and gender on the two treatment arms among the 42 participants who
completed 6 months of treatment. The majority of participants were male
(76%). Among the 42 participants included in this analysis, adherence
during the 1-month run-in was 99%. Overall adherence to the study
protocol was >95%.
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Five (10.4%) additional participants, who were included in the efficacy analysis, experienced moderate, localized skin toxicities and were managed as follows. One of these participants experienced symptoms after 145 days, was taken off study for one week, rechallenged with treatment, experienced rash after 2 days of rechallenge, and discontinued treatment. A second participant experienced erythema, redness, and scaling after 54 days of treatment. Treatment was discontinued for 43 days, and the subject was rechallenged. Symptoms returned after 22 days and treatment was discontinued. The three other participants experienced localized skin toxicities of moderate severity and discontinued topical treatment within 2 days of completing the study. These three participants were not rechallenged before final biopsies were taken.
The skin DFMO and ornithine concentrations after 6 months of DFMO and
placebo topical administration are shown in Table 2
for the subsample of 17 participants
who underwent skin punch biopsies. As shown in the table, none of the
punch biopsies obtained from the forearms assigned to the placebo
topical treatment contained DFMO, whereas, 13 of the 17 forearms
assigned to DFMO topical treatment contained high DFMO concentrations
with a mean of 962.7 nmol/g wet skin. The mean ornithine concentrations
were 390.1 nmol/g wet skin in the AKs on the DFMO-treated arm and 479.0
nmol/g wet skin in the AKs in the placebo-treated arm
(P = 0.28; t test). Additionally, there was
no evidence of DFMO found in plasma samples obtained after 6 months of
DFMO administration in any of the 42 randomized participants who
completed treatment.
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are the primary study
end point results concerning the number of AKs and individual polyamine
concentrations in skin biopsies. Statistical comparisons are not
possible in this table because of the associations between paired
outcomes and matched participant arms. However, the data in Table 3
demonstrate that there was a magnitude of change in the primary end
point, the number of AKs per arm, with a decrease of 6.6 on the treated
posterior forearm (compared with the placebo forearm). This represents
a 23.5% decrease from the baseline mean of 28.1 AKs. Shown in Fig. 2
are the baseline (upper
panel) and post-topical DFMO (lower panel) photographs
of the right lateral forearm of one of the DFMO-treated study
participants. As demonstrated by inked circles, there was substantial
clearing of the AKs after 6 months of DFMO treatment.
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. The
change in number of AKs is negatively related to the initial number,
which presumably represents the regression to the mean effect. The
change on the treated arm is negatively related to the change on the
matched placebo arm, suggesting that those participants who had the
largest improvement on the treated arm tended to have the least
improvement on the placebo arm. The DFMO effect was estimated to be a
reduction of 6.1 AK lesions on the treated arm (P =
0.001).
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and 4)
. The relative percent of reduction in skin spermidine
concentrations was 26%, which was similar to the 23.5% reduction
observed for AK number.
In the process of examining other potential effects, it was discovered
that the DFMO effect on AKs was essentially restricted to the case in
which the right arm was treated. In Table 5
, a simplification of the regression
analysis is presented for all study end points. There was a
10.8 AK reduction on treated right arms (P for
the difference = <0.001) with no effect on treated left arms. A
similar effect was observed for the polyamine measurements, with
spermidine concentrations being significantly reduced
(P = 0.034) and a nonsignificant reduction in
putrescine concentrations (P = 0.098) on the right arm
only; however, there were no statistically significant differences in
participant age, compliance, number of AKs, or in polyamine
concentrations at baseline between the right and left arms.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We formulated DFMO in a hydrophilic ointment at a 10% (w/w) concentration for studies of stability, tolerance, and penetration through human and mouse skin in supplied tubes. We documented that the topical administration of this formulation to human skin in vitro was associated with substantial uptake after 24 h at 37°C, with little evidence of transdermal penetration.
Participants in this Phase IIb study were randomly assigned to topical DFMO treatment of the right versus left forearm and placebo treatment of the contralateral arm. A subset of 17 participants was randomly selected to undergo biopsies of AK lesions on the forearms for measurement of DFMO and ornithine levels. Thirteen of 17 biopsies from DFMO-treated forearms had high levels of DFMO, whereas none of the biopsies from placebo-treated forearms showed evidence of DFMO uptake into skin, documenting reasonably good adherence to the randomized right- versus left-arm topical DFMO and placebo daily treatments.
The most clinically relevant DFMO effect with respect to study end points involved a significant 23.5% reduction in the number of discrete AK lesions from baseline to the 6-month follow-up evaluation. Of importance mechanistically, there also was a 26% reduction in spermidine concentrations in skin biopsies obtained from the DFMO-treated arms. Suppression of polyamines by DFMO can down-regulate the expression of genes demonstrated to play a role in transformation (i.e., c-myc) and in non-melanoma skin cancer (i.e., c-fos and c-jun) in vitro (38) . The ability of the topical DFMO formulation used in the present study to cause alterations in the expression of these genes or other genes important in skin epithelial cell transformation in vivo is currently under study in our research program.
Although our clinical study model, which uses a
within-participant randomization of chemoprevention agent and placebo
topical applications to opposite arms appears efficient and effective,
it was discovered that the topical DFMO effect on AKs was essentially
restricted to the treated right arm. There was a reduction of 10.8
AKs on the DFMO-treated right arms, but no reduction on the
DFMO-treated left arms. This right-arm efficacy effect of topical DFMO
correlated well with right-sided suppression of skin punch biopsy
spermidine concentrations. There is no obvious reason for this
disparity in DFMO effect. It is possible that the left arm tends to get
considerably more Arizona sun exposure than the right (related to the
amount of time spent driving automobiles) and thus, was less likely to
respond to topical DFMO. Also, the small participant sample size may
have contributed to a disproportionate chance for a DFMO effect on the
right forearm. Similarly, there were no significant differences in the
number of AKs or polyamine levels at baseline between left and right
arms that could explain this finding.
Although the DFMO topical treatment was associated with both a large and a significant reduction in the mean skin spermidine concentration, it is possible that the effect of topically administered DFMO on polyamines was washed out by our insistence on biopsying AK lesions that persisted through 6 months of DFMO treatment. In other words, these were AKs that survived the DFMO treatment and could be considered DFMO-resistant.
There was a 4.2% rate of severe and a 10.4% rate of moderate local skin toxicity requiring treatment modification associated with long-term administration of topical 10% DFMO. On the basis of this rate of local inflammatory reactions, we suggest that future topical DFMO clinical trials in participants with forearm AKs evaluate both lower topical concentrations (e.g., 5%) and/or the addition of topical steroids.
The present study results suggest efficacy for topically administered DFMO in the treatment of participants with severe AK. We believe that future randomized studies of topical DFMO, using standard trial designs, perhaps in participants with less severe AKs, are indicated in an attempt to reproduce and extend the results of the present clinical trial.
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Acknowledgments |
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Footnotes |
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1 Supported by USPHS Grant PO1 CA27502. 
2 To whom requests for reprints should be
addressed, at Arizona Cancer Center, University of Arizona, 1515 North
Campbell Avenue, P. O. Box 245024, Tucson, AZ 85724. Phone:
(520) 626-7685, Fax: (520) 626-2445; E-mail: dalberts{at}azcc.arizona.edu
3 The abbreviations used are: NMSC,non-melanoma
skin cancer; AK, actinic keratosis; DFMO,
-2-(difluoromethyl)-dl-ornithine; HPLC, high performance liquid
chromatography.
4 H. L. Gensler, personal communication.
Received 2/ 8/99; revised 8/ 4/00; accepted 9/25/00.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-difluoromethylornithine. Anticancer Res., 10: 67-72, 1990.[Medline]
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-difluoromethylornithine. J. Natl. Cancer. Inst., 85: 732-737, 1993.This article has been cited by other articles:
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 L. M. Petros, G. F. Graminski, S. Robinson, M. R. Burns, N. Kisiel, R. F. Gesteland, J. F. Atkins, D. L. Kramer, M. T. Howard, and R. S. Weeks Polyamine Analogs with Xylene Rings Induce Antizyme Frameshifting, Reduce ODC Activity, and Deplete Cellular Polyamines J. Biochem., November 1, 2006; 140(5): 657 - 666. [Abstract] [Full Text] [PDF]
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J. G. Einspahr, M. A. Nelson, K. Saboda, J. Warneke, G. T. Bowden, and D. S. Alberts Modulation of Biologic Endpoints by Topical Difluoromethylornithine (DFMO), in Subjects at High-Risk for Nonmelanoma Skin Cancer Clin. Cancer Res., January 1, 2002; 8(1): 149 - 155. [Abstract] [Full Text] [PDF]
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