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PHARMACODYNAMICS

Cutaneous Pharmacodynamics of a Toll-Like Receptor 7 Agonist, 852A, in Humans

Calvin Astry, PhD, Woubalem Birmachu, PhD, Lester I. Harrison, PhD and Tze-Chiang Meng, MD

From the Department of Medical and Scientific Affairs (former employees Drs Astry and Meng), Department of Pharmacology (Dr Birmachu), and Department of Pharmacokinetics/Drug Metabolism (Dr Harrison), 3M Pharmaceuticals, St Paul, Minnesota.

Address for reprints: Lester I. Harrison, 3M Pharmaceuticals, Department of Pharmacokinetics/Drug Metabolism, 3M Center Bldg 260-3A-05, St. Paul, MN 55144; e-mail: liharrison{at}mmm.com.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
852A is a specific toll-like receptor 7 (TLR7) agonist. Thirty-two healthy adults (8 subjects per group) received two 1-g topical applications over 400 cm2, separated by ≥ 5 days, of 852A 0.01% followed by vehicle, vehicle followed by 852A 0.1%, 852A 0.3% followed by vehicle, or vehicle followed by 852A 1.0%. Systemic absorption was minimal as 852A was not quantifiable in any serum sample up to 24 hours postadministration and was only quantifiable at 24 hours in the urine of 4 of 8 subjects after application of 852A 1.0%. No systemic adverse events were associated with drug treatment. Gene expression analysis from application site biopsies showed a ≥2-fold increase in expression for 40 genes in at least 2 subjects. CXCL9/MIG (8/32 subjects), CCL2/MCP1 (7/32), and OAS3 (5/32) were most frequently increased, followed by other type I interferon-inducible genes. Cluster analysis of the genes with a ≥2-fold increase did not reveal a definitive pattern with respect to 852A concentration or time of biopsy. Overall, single topical application of 852A up to 1.0% was well tolerated. Data gathered from these subjects are suggestive that 852A can produce increases in local gene expression consistent with TLR7 stimulation.

Key Words: 852A • toll-like receptor 7 • cutaneous pharmacodynamics • innate immunity • gene expression

Toll-like receptors (TLRs) detect pathogen-associated molecular patterns and are one of the mechanisms by which innate immune cells recognize and respond to infectious agents.1 In humans, TLR7 and TLR8 appear to involved in recognition of single-stranded RNA viruses.2 852A (N-[4-(4-amino-2-ethyl-1H-imidazo [4,5-c]quinolin-1-yl) butyl]methanesulfonamide; see Harrison et al3 for structure) is a small synthetic molecule of the imidazoquinoline class that functions as a TLR7-selective agonist. 852A can activate innate immune cells and induce endogenous cytokine production, such as interferon-alpha (IFN-{alpha}) and a large number of IFN-inducible genes in plasmacytoid dendritic cells (pDCs), and can upregulate costimulatory molecule expression, enhance pDC survival, and activate natural killer cells.4-7

852A has been previously administered to humans by the intravenous, subcutaneous, and oral routes.3,4 To explore the safety, pharmacokinetics, and pharmacodynamics of the topical administration of 852A, we conducted a phase I, modified-blind, randomized, vehicle-controlled, crossover dose escalation cohort study of a single application of 852A cream in healthy adults.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects and Study Design
The study was conducted at PRACS Institute, Ltd (Fargo, North Dakota) in accordance with good clinical practice guidelines. The study protocol was approved by the PRACS Institute, Ltd institutional review board, and all subjects gave written informed consent. Male and female subjects were required to be healthy, be between 18 and 65 years of age, have a body mass index between 20 and 30 kg/m2, have no physical abnormalities at the target application sites, and have hemoglobin >12.0 g/dL, white blood cell count >3.0 x 108 cells/L, and platelet count >140 x 109 cells/L. Female subjects were required to be surgically sterile or at least 2 years postmenopausal. Subjects were excluded for a positive human immunodeficiency virus serology, active chemical dependency or alcoholism, a history of bleeding disorder or deep vein thrombosis, receipt of an investigational medication within 4 weeks, donation of blood within 8 weeks or plasma within 1 week, breastfeeding within 1 month, smoking within 6 months, or use of any medications (including herbal supplements) within 2 weeks of dosing.

Subjects were enrolled in 2 sequential cohorts of 16 subjects each. In cohort 1, subjects were randomly assigned (8 subjects each) to receive either 852A 0.01% in treatment period 1, followed by vehicle in treatment period 2, or vehicle in treatment period 1, followed by 852A 0.1% in treatment period 2. In cohort 2, subjects were randomly assigned to receive either 852A 0.3% in treatment period 1, followed by vehicle in treatment period 2, or vehicle in treatment period 1, followed by 852A 1.0% in treatment period 2. Each subject received 852A once. The subjects, the investigator, and study center personnel performing assessments were blinded with respect to treatment assignment but not the staff preparing the dose or study monitors. A safety review of the treatment period was performed upon completion prior to beginning the next treatment period with a higher 852A concentration.

Study center personnel applied separate 500-mg (weighed) doses of assigned study cream (852A or vehicle; 3M Pharmaceuticals, St Paul, Minnesota) to each of two 200-cm2 areas (left upper back and left upper arm during treatment period 1; right upper back and right upper arm during treatment period 2) on each subject, for a total of 1 g and 400 cm2 per treatment period. Subjects remained domiciled at the study center for 24 hours after study cream application. Study cream remained on the skin (covered with loose clothing) for 8 hours before study center personnel washed the treatment site with soap and water. There was a 5-day minimum washout period between the dose applications.

Safety assessments included physical examinations; vital sign measurements; 12-lead electrocardiograms; HIV, hepatitis B, and hepatitis C virus antibody and drugs of abuse panel at screening; routine laboratory tests, including complete blood count with differential and platelet count, serum chemistry panel, coagulation tests, urinalysis, and serum and urine pregnancy tests (if applicable); investigator assessment of local skin reactions (erythema, edema, weep/exudates, erosion/ulceration); photographs of the application site; and monitoring of concomitant medication use and adverse events.

Blood samples were collected at predose and 3, 6, 9, 12, 18, and 24 hours after application of each dose to measure systemic drug exposure. A 24-hour urine collection was performed after each dose application to measure urine drug levels. At 2, 4, 6, or 8 hours (1 per subject) after application of a dose, an area on the inner aspect of the arm application site was cleaned with isopropyl alcohol and a 3-mm diameter punch skin biopsy obtained for gene expression profiling.

852A Quantification
Serum and urine 852A concentrations were quantified by reversed-phase isocratic liquid chromatography coupled to a tandem mass spectrometry system operated with turbo-ion spray in the positive ion mode.3 An internal standard with similar mass and structure and an elution profile that did not interfere with 852A were included in the solid-phase extraction step. The bioanalytical method was validated with respect to linearity, specificity, intraday and interday precision, accuracy, and recovery. The lower limits of quantitation were 0.100 ng/mL in serum and 0.200 ng/mL in urine.

mRNA Quantitation
A total of 64 biopsy samples were obtained, a vehicle and an 852A pair for each subject. Punch biopsies were immediately placed in RNALater (Ambion, Austin, Texas), incubated overnight at 4°C, and then stored at –70°C until processing. Each biopsy sample had some genes run in triplicate, as well as some run in quadruplicate, as described below.

Total RNA was extracted and purified using the Qiagen RNeasy Mini Kit (Qiagen, Inc, Valencia, California) per the manufacturer's instructions. RNA was quantified by measuring the absorbance at 260 nm and RNA purity by determining the 260/280-nm absorbance ratio. The average ratio (SD) across all samples was 2 ± 0.09, indicating high purity.

Purified RNA was reverse transcribed using the SuperScript Single Stranded cDNA Synthesis Kit (Invitrogen Corp, Gaithersburg, Massachusetts) per the manufacturer's instructions. Then, 1 µg of RNA was used per reaction with the exception of 4 samples with a low RNA yield. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) was performed using custom TaqMan low-density arrays (LDAs) (Applied Biosystems, Foster City, California). One LDA containing reagents for 23 different genes and a glyceraldehyde 3-phosphate dehydrogenase (GAPDH) control (24-gene LDA, duplicate wells) and 2 LDAs containing 47 different genes and GAPDH (48-gene LDA, single wells) were used (see Supplemental Tables I, II, and III, available in an online appendix at http://jcp.sagepub.com/supplemental/). Samples were run in duplicate arrays for 24-gene LDAs or in triplicate on 48-gene LDAs, providing quadruplicate or triplicate data sets per gene, respectively. Some genes were assayed on more than 1 array for a total of 110 genes not including GAPDH.

PCR was performed using 1 ng cDNA, with the exception of 4 samples with low RNA yield, which were run at 0.24 to 0.92 ng cDNA, per PCR reaction. PCR was performed for 35 cycles of 30 seconds at 97°C and 1 minute at 59.7°C, preceded by incubation for 2 minutes at 50°C and 10 minutes at 94.5°C, using an ABI PRISM 7900HT Sequence Detection System (Applied Biosystems). Amplification cycle threshold values (Ct) were analyzed using SDS 2.01 software according to the ABI PRISM 7900HT operating manual.

Data Analyses
Pharmacokinetic parameters were to be estimated as previously described.3

For skin biopsy gene expression analyses, Ct values were normalized within each subject using the average GAPDH value for that subject only. For each gene examined, a t test was performed on replicate normalized Ct values for each vehicle- and 852A-treated sample pair using Excel 2003 (Microsoft Corp, Redmond, Washington). Sample pairs with statistically significant differences at the 95% confidence level were used for calculation of fold change of expression. The fold change of expression after 852A treatment for each gene was calculated relative to the vehicle-treated sample for each subject using the "relative quantitation of gene expression" method ({Delta}{Delta}Ct method) as described in User Bulletin #2 (Applied Biosystems). The data were further filtered by requiring a ≥2-fold change for significance. Because there were only 2 subjects for each time point, further statistical analysis was not warranted.

A 2-way hierarchical cluster analysis of the gene expression data was performed with Spotfire DecisionSite-8.1 for Functional Genomics (Spotfire, Inc, Somerville, Massachusetts) using the unweighted pair-group method with arithmetic mean (UPGMA) and the Euclidean similarity measure.

For safety assessments, all vehicle treatments were pooled into 1 combined vehicle group.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subject Population
Of the 32 subjects screened, all were enrolled and all completed the study. The population was predominantly male (72%) and white (97%), with a median age of 28 years (range, 19-60 years) (Table I).


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  		Table I Baseline Demographic Characteristics

 

Pharmacokinetics
852A was not quantifiable (<0.100 ng/mL) in any serum sample from all groups or from any of the 24-hour urine collections following dosing with 852A 0.01%, 0.1%, or 0.3%. 852A was quantifiable in the urine of 4 of 8 subjects after the 852A 1.0% dose; 24-hour urinary recoveries of unchanged drug ranged from 193 to 432 ng (mean ± SD: 282 ± 104 ng, n = 4). The percentage of dose excreted unchanged in these 4 subjects was <0.005%.

Pharmacodynamic Measures
Of the 110 genes analyzed, a ≥2-fold increase in expression at any of the time points was observed in at least 1 subject for 55 transcripts representing 52 unique genes (Figure 1). There were 9, 53, 25, and 57 gene transcripts with a ≥2-fold increase for the 852A 0.01%, 0.1%, 0.3%, and 1.0% groups, respectively. There did not appear to be a definitive pattern with respect to 852A concentration, although the 0.01% group appeared to have the least changes in expression. There also did not appear to be a definitive pattern when samples were analyzed with respect to timing of biopsy following 852A application with the exception of the 852A 1.0% group, in which clearly a lower number of genes were increased in expression for the 2- and 4-hour time points as compared with the 6- and 8-hour time points. In each of the 0.1%, 0.3%, and 1% dose groups, the highest number of genes was increased in expression at either 4 or 6 hours postdose.


Figure 1
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  		Figure 1. Hierarchical clusters for 852A 0.01%, 0.1%, 0.3%, and 1.0% samples. The x-axis for each column designates time postdose (hours), 2 subjects per time point. The y-axis displays the 55 transcripts that showed ≥2-fold increases in expression in at least 1 subject. The insert bar shows the grayscale gradient in the cluster, ranging from white, designating a less than 1 log2-fold change (fold change <2), to black, designating a 4 log2-fold change (fold change of 16 or greater).

 
A 2-fold increase was observed in at least 2 subjects for each of 41 transcripts representing 40 unique genes and at least 3 subjects for each of 24 transcripts representing 22 genes (Table II). The genes with ≥2-fold increase in the most subjects were CXCL9/MIG (8 subjects), CCL2/MCP1 (7 subjects), and OAS3 (5 subjects). Seven genes (MX1, OAS2, PRKAR2B, CCL5, FOS, INHBA, and LAMP3) had a ≥2-fold increase in 4 subjects. An increase in IFN-{alpha}2 expression, a type I IFN, was not observed with any of the 852A doses.


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  		Table II Summary of Gene Expression for the Transcripts with ≥2-Fold Increase in ≥3 Subjects

 

Per the protocol, serum samples were collected for possible cytokine analyses. However, serum cytokine analyses were not performed as serum drug levels were not measurable.

Safety
Median exposures were 0.10, 1.00, 3.00, and 10.00 mg of 852A for the 0.01%, 0.1%, 0.3%, and 1% groups, respectively. Postprocedural hemorrhage (1/8 [13%] for 852A 0.3% and 2/32 [6%] for combined vehicle) secondary to biopsy was the most commonly reported adverse event.

There were 6 (19%), 1 (13%), 1 (13%), 1 (13%), and 2 (25%) subjects reporting adverse events for the combined vehicle and the four 852A rising dose groups, respectively. The number of subjects reporting adverse events that were considered by the investigator to be possibly or probably related to study drug were 1 (3%), 0, 0, 1 (13%), and 2 (25%) for the combined vehicle and the four 852A rising dose groups, respectively. Only application site reactions and a postprocedural reaction were considered by the investigator to be possibly or probably related to study drug. The distribution of the adverse events by system organ class is given in Table III; all adverse events were mild in intensity. No meaningful changes from baseline, by subject, were observed with respect to clinical laboratory values or vital signs.


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  		Table III Incidence of Adverse Events During Treatment, All Adverse Events

 

Local skin reactions, which were assessed by the investigator separately from other adverse events, were reported for 5 (16%), 0, 2 (25%), 3 (38%), and 4 (50%) of the subjects for the vehicle and 852A 0.01%, 0.1%, 0.3%, and 1% groups, respectively. Erythema was most common, followed by edema; no subject had erosion/ulceration or weeping/exudates. Maximal intensity was mild except for moderate erythema reported by 1 subject each in the 1.0% group and in the combined vehicle group. Of the subjects with a local skin reaction reported, more had a reaction when the study drug was applied to the back (8 subjects) than to the arm (2 subjects), and the moderate erythema and edema (2 subjects) occurred after application to the back.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
A single topical administration of up to 1 g of 852A 1.0% cream to 400 cm2 of normal skin was well tolerated in this study and was not associated with any systemic adverse events. Erythema was the most common investigator-assessed local skin reaction; slightly more subjects in the 1.0% group had local skin reactions noted than in the other 852A groups or in the combined vehicle group.

It appeared that minimal amounts of 852A were systemically absorbed as serum levels never reached a quantifiable level with any dose. In another pharmacokinetic study with 852A, 40% of an intravenous dose was excreted unchanged in the urine.3 Assuming that this relationship holds for topical administration, the highest 852A absorption measured in this study was estimated to be 0.01% of the applied dose.

Despite the minimal systemic bioavailability, a suggestion of an association between the applied dose of 852A and gene expression was observed in some subjects because the lowest dose applied (0.01%) showed very little gene expression response, whereas the higher doses showed increased gene expression response. This suggests a minimum dose range at which gene expression response is observed. Limitations of study design did not permit statistically significant correlations between dose and gene response. Therefore, our findings must be considered preliminary evidence for a local innate immune response with topical 852A.

Most genes with increased expression observed in this study were those inducible by type I IFNs, including MX1, OAS2, OAS3, IFI27, IFI44, IFIT2, IFITM1, SN, TRIM22, LAMP3, and BST2.8 IFN-inducible genes regulate cellular processes, such as cell growth and differentiation, cell death, and T cell costimulation, activation, and migration, and are part of the innate antiviral response.9,10 Many of these genes also have direct antiviral activity, including MX1 and IFI27.11-13 The chemokines CCL2 (MCP1), CCL5 (Rantes), and CXCL9 (MIG) are chemotactic for T cells and were also increased by 852A.

An increased expression of the IFN-{alpha}2 gene was not seen with 852A in this study. However, the observed increases in expression of type I IFN-inducible genes suggest that there was induction of significant levels of type I IFN by 852A. It may be that other types of type I IFN, including other species of IFN-{alpha}, were induced. It is also possible that pDCs, which are believed to be predominantly responsible for systemic IFN-{alpha} production, were only transiently increased in the treated tissue after single dosing.

This study reports the first comprehensive gene expression analysis for the cutaneous application of 852A using highly sensitive real-time RT-PCR. Conclusions are limited by the small number of subjects (2) per time point per dose and high subject-to-subject variability. This may have precluded the observation of a clear time dependence and dose dependence as well as the expression of many of the genes that have been observed to be induced by 852A in peripheral blood mononuclear cells or in isolated pDC. Although gene responses were observed in some subjects in the 852A 0.1% group, topical concentrations of 852A 1.0% or higher may be required to obtain more consistent cutaneous pharmacodynamic responses in all subjects.

A comparison of topical 852A with topical imiquimod, another small molecule of the imidazoquinoline class, is of value. Imiquimod has been approved in a 5% topical formulation for the treatment of external genital warts, superficial basal cell carcinoma, and actinic keratosis.14 852A is structurally similar to imiquimod but is more potent than imiquimod in activating TLR7 in the human HEK293 TLR7-NF{kappa}B-luciferase cotransfection assay.4 Based on a comparison of the percentage of the dose recovered in the urine, topical imiquimod 5% appears to be absorbed 10 times greater than 852A 1%.15,16 It is significant that all of the genes observed to be increased in expression by 852A in this study have also been observed to be induced by imiquimod 5% cream.17-19 The apparent lower systemic bioavailability of the topical 852A formulations, therefore, may allow selection of 852A concentrations that are as effective in inducing a cutaneous pharmacologic response as imiquimod yet still result in safer serum drug levels that are not pharmacologically active. This possibility supports the continued development of topical 852A.

In summary, this is the first report of the dermal administration of 852A, and the results are encouraging. Topical application of a single dose of 852A induced local gene expression in some subjects, consistent with its activity as a TLR7 agonist and, up to the maximum concentration studied of 1%, was well tolerated and not associated with detectable systemic drug levels. Multidose studies of topical 852A in patients with dermatologic conditions appear to be warranted.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
The authors gratefully acknowledge the many valuable contributions of Barrie March, MD, and the staff of PRACS Institute (Fargo, North Dakota) for study conduct and Raymond Gleason, Patti Stampone, Cathryn Lloyd, Sarala Kurup, and Sandeep Kumar, MD, of 3M Pharmaceuticals (St Paul, Minnesota).

Supplementary data for this article are available at http://jcp.sagepub.com/supplemental/.

DOI: 10.1177/0091270008314466

Financial disclosure: This study was sponsored by 3M Pharmaceuticals. Drs Astry, Birmachu, Harrison, and Meng were employees of 3M Pharmaceuticals when the study was conducted.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Medzhitov R, Janeway C. The toll receptor family and microbial recognition. Trends Microbiol. 2000;8: 452-456.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

2. Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science. 2004;303: 1526-1531.[Abstract/Free Full Text]

3. Harrison LI, Astry C, Kumar S, Yunis C. Pharmacokinetics of 852A, an imidazoquinoline toll-like receptor 7-specific agonist, following intravenous, subcutaneous, and oral administrations in humans. J Clin Pharmacol. 2007;47: 962-969.[Abstract/Free Full Text]

4. Dudek AZ, Yunis C, Harrison LI, et al. First in human phase I trial of a novel TLR7 agonist to activate immune responses in patients with advanced cancer. Clin Canc Res. In press.

5. Gorden KB, Gorski KS, Gibson SJ, et al. Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. J Immunol. 2005;174: 1259-1268.[Abstract/Free Full Text]

6. Gorski KS, Waller EL, Bjornton-Severson J, et al. Distinct indirect pathways govern human NK cell activation by TLR-7 and TLR-8 agonists. Int Immunol. 2006;18: 1115-1126.[Abstract/Free Full Text]

7. Birmachu W, Gleason RM, Bulbulian BL, et al. Transcriptional networks in plasmscytoid dendritic cells stimulated with synthetic TLR7 agonists. BMC Immunol. 2007;8: 26 [Epub].[CrossRef][Medline] [Order article via Infotrieve]

8. Stroncek DF, Basil C, Nagorsen D, et al. Delayed polarization of mononuclear phagocyte transcriptional program by type I interferon isoforms. J Transl Med. 2005;3: 24.[CrossRef][Medline] [Order article via Infotrieve]

9. de Veer MJ, Holko M, Frevel MJ, et al. Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69: 912-920.[Abstract/Free Full Text]

10. Khabar KS, Al-Haj L, Al-Zoghaibi F, et al. Expressed gene clusters associated with cellular sensitivity and resistance towards anti-viral and anti-proliferative actions of interferon. J Mol Biol. 2004;342: 833-846.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Gordien E, Rosmorduc O, Peltekian C, Garreau F, Brechot C, Kremsdorf D. Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein. J Virol. 2001;75: 2684-2691.[Abstract/Free Full Text]

12. Austin BA, James C, Silverman RH, Carr DJ. Critical role for the oligoadenylate synthetase/RNase L pathway in response to IFN-beta during acute ocular herpes simplex virus type 1 infection. J Immunol. 2005;175: 1100-1106.[Abstract/Free Full Text]

13. Noyce RS, Collins SE, Mossman KL. Identification of a novel pathway essential for the immediate-early, interferon-independent antiviral response to enveloped virions. J Virol. 2006;80: 226-235.[Abstract/Free Full Text]

14. Gupta AK, Cherman AM, Tyring SK. Viral and nonviral uses of imiquimod: a review. J Cutan Med Surg. 2004;8: 338-352.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Owens ML, Bridson WE, Smith SL, Myers JA, Fox TL, Wells TM. Percutaneous penetration of Aldara cream, 5% during the topical treatment of genital and perianal warts. Prim Care Update Ob Gyn. 1998;5: 151.

16. Harrison LI, Skinner SL, Marbury TC, et al. Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms. Arch Dermatol Res. 2004;296: 6-11.[Web of Science][Medline] [Order article via Infotrieve]

17. Urosevic M, Dummer R, Conrad C, et al. Disease-independent skin recruitment and activation of plasmacytoid predendritic cells following imiquimod treatment. J Natl Cancer Inst. 2005;97: 1143-1153.[Abstract/Free Full Text]

18. Torres A, Storey L, Anders M, et al. Immune-mediated changes in actinic keratosis following topical treatment with imiquimod 5% cream. J Transl Med. 2007;5: 7.[CrossRef][Medline] [Order article via Infotrieve]

19. Panelli MC, Stashower ME, Slade HB, et al. Sequential gene profiling of basal cell carcinomas treated with imiquimod in a placebo-controlled study defines the requirements for tissue rejection. Genome Biol. 2007;8: R8.[CrossRef][Medline] [Order article via Infotrieve]
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