Treatment Of Hyperproliferative Skin Disorders Research Articles

Cold atmospheric plasma in combination with laser therapy provides a window for the treatment of hyperproliferative skin disease

Modern medical understanding suggests that hyperproliferative skin diseases (HSDs) are complex syndromes characterized by localized hypertrophy or hyperplasia and infiltration of inflammatory cells. Various treatments, including systemic and topical pharmacotherapy, laser interventions, photodynamic therapy, and surgery, have been proposed for managing HSDs. However, challenges such as wound healing and recurrence after laser treatment have hindered the effectiveness of laser therapy. To overcome these challenges, we conducted a study combining laser therapy with cold atmospheric plasma (CAP) for the treatment of HSDs. Seven patients with different forms of HSDs, who had not responded well to conventional treatments, were enrolled in the study. These HSDs included cases of erythroplasia of Queyrat, pyoderma gangrenosum, keloids and hypertrophic scars, cellulitis, cutaneous lichen planus, and verruca vulgaris. Laser therapy was performed to remove the hyperplastic skin lesions, followed immediately by daily CAP treatment. The results were promising, with all patients successfully treated and no recurrence observed during the follow-up periods. The combined application of CAP and laser therapy proved to be an effective and complementary strategy for managing HSDs. This innovative approach provide evidence for addressing the limitation of laser therapy by utilizing CAP to promote wound healing and mitigate inflammatory responses.Chinese Clinical Trial Registry (ChiCTR2300069993).

Lipid Nanocarriers for Hyperproliferative Skin Diseases.

Simple SummaryDifferent drugs, including antiproliferative and corticosteroids in general, are recommended for the treatment of hyperproliferative skin diseases (HSD). The effectiveness of many of these drugs is limited due to their low solubility in water and low penetration in the skin. The loading of these drugs in lipid nanocarriers, such as lipid nanoparticles and liposomes, has been considered as a successful solution to improve the drug bioavailability through the skin, to control their release kinetics and thus reduce the risk of potential side effects. In this work, we discuss the use of lipid nanocarriers loading drugs against HSD.Hyperproliferative skin diseases (HSD) are a group of diseases that include cancers, pre-cancerous lesions and diseases of unknown etiology that present different skin manifestations in terms of the degree and distribution of the injuries. Anti-proliferative agents used to treat these diseases are so diverse, including 5-aminolevulinic acid, 5-fluorouracil, imiquimod, methotrexate, paclitaxel, podophyllotoxin, realgar, and corticosteroids in general. These drugs usually have low aqueous solubility, which consequently decreases skin permeation. Thus, their incorporation in lipid nanocarriers has been proposed with the main objective to increase the effectiveness of topical treatment and reduce side effects. This manuscript aims to describe the advantages of using lipid nanoparticles and liposomes that can be used to load diversity of chemically different drugs for the treatment of HSD.

The RATIOnal Role of Polyamines in Epidermal Differentiation

Polyamines have been implicated in skin tumorigenesis; however, their role in epidermal homeostasis remains obscure. In a new article in the Journal of Investigative Dermatology, Rahim etal. (2021) report that keratinocyte differentiation requires a shift in polyamine ratios that is mediated by AMD1. Results suggest that targeting polyamine availability might be useful in the treatment of hyperproliferative skin disorders.

The Polyamine Regulator AMD1 Upregulates Spermine Levels to Drive Epidermal Differentiation

Maintaining tissue homeostasis depends on a balance between cell proliferation, differentiation, and apoptosis. Within the epidermis, the levels of the polyamines putrescine, spermidine, and spermine are altered in many different skin conditions, yet their role in epidermal tissue homeostasis is poorly understood. We identify the polyamine regulator, Adenosylmethionine decarboxylase 1 (AMD1), as a crucial regulator of keratinocyte (KC) differentiation. AMD1 protein is upregulated on differentiation and is highly expressed in the suprabasal layers of the human epidermis. During KC differentiation, elevated AMD1 promotes decreased putrescine and increased spermine levels. Knockdown or inhibition of AMD1 results in reduced spermine levels and inhibition of KC differentiation. Supplementing AMD1-knockdown KCs with exogenous spermidine or spermine rescued aberrant differentiation. We show that the polyamine shift is critical for the regulation of key transcription factors and signaling proteins that drive KC differentiation, including KLF4 and ZNF750. These findings show that human KCs use controlled changes in polyamine levels to modulate gene expression to drive cellular behavior changes. Modulation of polyamine levels during epidermal differentiation could impact skin barrier formation or can be used in the treatment of hyperproliferative skin disorders.

Aliskiren: Preclinical evidence for the treatment of hyperproliferative skin disorders

Psoriasis is a complex inflammatory and hyperproliferative skin disease. The pathogenesis and mechanisms involved are not completely understood, which makes treatment a difficult issue. Angiotensin II, the most active peptide of the renin-angiotensin system, seems to be involved in processes related to psoriasis pathogenesis, such as inflammation and cell proliferation. The aim of this study was to investigate the influence of renin inhibition on inflammation parameters and keratinocyte proliferation in a mouse model of chronic skin inflammation induced by croton oil. Aliskiren had anti-inflammatory effects by reducing levels of tumor necrosis factor-α and interleukin -6, and by inhibiting myeloperoxidase activity. Aliskiren also showed antiproliferative activity by reducing epidermal hyperplasia and proliferating cell nuclear antigen levels. Aliskiren treatment did not induce alterations in the cardiovascular system, normal skin thickness, and organ weight. These results suggest that aliskiren could be a valuable tool to be incorporated in the treatment of hyperproliferative and inflammatory skin disorders such as psoriasis.

B1 and B2 kinin receptor participation in hyperproliferative and inflammatory skin processes in mice

Kinins are released during dermal injury and inflammation and seem to contribute to the pathogenesis of cutaneous diseases. Participation of kinins in skin inflammatory process was evaluated using knockout mice and non-peptide kinin receptor antagonists. Chronic skin inflammation was induced by multiple applications of TPA in mice ear. The B(2) knockout mice (B(2)(-/-)) showed a significant increase of ear weight (23 ± 10%) and epidermal cellular hyperproliferation and acanthosis formation upon histological analysis when compared with wildtype mice. Also, evaluation of PCNA levels by Western blot and immunohistochemistry confirmed the increase in the epidermis hyperproliferation in the ear skin of B(2)(-/-) mice. In contrast, no modification in these parameters was detected in B(1) knockout mice (B(1)(-/-)). However, mice lacking both kinin receptors (B(1)B(2)(-/-)) presented a considerable reduction of epidermis thickness and in PCNA levels. Following the establishment of skin inflammation (5th day of TPA application) treatment with the non-peptide antagonists SSR 240612 (B(1) receptor antagonist), FR 173657 (B(2) receptor antagonist), or SSR 240612 plus FR 173657 topically applied, caused a significant inhibition of ear weight (20 ± 5%, 34 ± 4% and 32 ± 6%, respectively). In the histological analysis, the antagonists produced a reduction in epidermal hyperplasia and acanthosis formation; but the treatment with a combination of the two antagonists did not increase efficacy. Kinin receptors seem to be involved in the control of the keratinocyte hyperproliferative process, and non-peptide kinin receptor antagonists may be useful tools in the treatment of hyperproliferative skin disorders.

Optimization of the comet assay for the sensitive detection of PUVA-induced DNA interstrand cross-links

Psoralen plus ultraviolet A (PUVA), commonly used for the treatment of hyperproliferative skin disorders, has been found to be associated with an increased risk of squamous cell cancer. Interstrand cross-link (ICL) formation by PUVA treatment is considered the major factor contributing to the carcinogenesis. However, it remains unclear how PUVA causes, or promotes cancers, in humans. As an initial step in understanding the mechanisms of mutagenesis and carcinogenesis of PUVA photochemotherapy, we have optimized and subsequently utilized a modified alkaline comet assay involving a post-lysis gamma-irradiation at 9 Gy to sensitively measure the formation and repair of PUVA-induced ICLs in the immortalized human keratinocyte cell line HaCaT. A clear dose-dependent response of HaCaT cells to PUVA exposure was observed with a combination of a fixed UVA dose at 0.05 J/cm(2) and a dose of 8-methoxypsoralen ranging from 10 to 100 microM. Results also indicated that the ICL repair was concentration dependent. We have also demonstrated that PUVA-induced monoadduct formation, at an estimated ratio of 3:1 to ICLs in the present experimental conditions, does not interfere with the detection of the ICLs in the modified alkaline comet assay. Furthermore, comparison of the amount of ICL formation between the single-dose UVA treatment and a split-dose protocol was performed. The split-dose protocol was believed to generate more ICLs than the single-dose treatment, thus more effective in PUVA photochemotherapy. Our results demonstrate that comparable amounts of ICLs were formed in HaCaT cells for each dose of UVA, using either the split-dose or single-dose protocols.

Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPARalpha and PPARgamma is decreased. This observation suggests the possibility that PPARalpha and PPARgamma activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPARgamma, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPARalpha immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARdelta appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARdelta. PPARdelta has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARalpha and PPARgamma activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARgamma activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPARalpha activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARalpha ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.

Calcipotriol Affects Keratinocyte Proliferation by Decreasing Expression of Early Growth Response-1 and Polo-like Kinase-2

Calcipotriol is a potent drug for topical treatment of psoriasis because it manages to inhibit keratinocyte proliferation. In the present study we investigated the effects of calcipotriol on gene expression in human keratinocytes in terms of mechanism of how calcipotriol decreases proliferation. Cell proliferation was analyzed by MTT assay. The differential display approach together with qPCR was used to assess the gene expression after treatment. In addition, Western immunoblotting revealed differences on the protein level. Finally, transfection of the KCs with specific small interfering RNA determined the genes necessary to inhibit proliferation. KCs proliferation was decreased in a concentration-dependent manner. Moreover, calcipotriol dowregulated the expression of two proliferation factors: early growth response-1 (EGR1) and polo-like kinase-2 (PLK2). The protein levels of EGR1 and PLK2 were also decreased. Specific siRNA against EGR1 and PLK2 in KCs resulted in marked reduction of EGR1 and PLK2 expression. In both cases, the reduction resolved in the decreased proliferation of KCs. This study provides a new insight into how calcipotriol affects proliferation of keratinocytes by decreasing the expression of EGR1 and PLK2. Furthermore, the results offer groundwork for developing novel compounds for the treatment of hyperproliferative skin disorders like psoriasis.

Modulation of growth factor/cytokine synthesis and signaling by 1alpha,25-dihydroxyvitamin D(3): implications in cell growth and differentiation.

Distinct from its classic functions in the regulation of calcium and phosphorus metabolism as a systemic hormone, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] is involved in the local control and regulation of cellular growth and differentiation in various tissues, including epidermis (keratinocytes) and bone (osteoblasts and osteoclasts). In this review, the impact of 1alpha,25(OH)(2)D(3) on growth factor/cytokine synthesis and signaling is discussed, particularly as it pertains to bone cells and keratinocytes. 1alpha,25(OH)(2)D(3) not only regulates growth factor/cytokine synthesis but may also alter growth factor signaling. Recently discovered examples for such interactions are the interactions between the vitamin D receptor and the mothers against decapentaplegic-related proteins that function downstream of TGFbeta receptors. Inhibitory effects of 1alpha,25(OH)(2)D(3) on keratinocytes through TGFbeta activation and IL-1alpha, IL-6, and IL-8 suppression may provide a rationale for its beneficial effects in the treatment of hyperproliferative skin disorders, whereas stimulatory effects through the epidermal growth factor-related family members and platelet-derived growth factor may be operative in its beneficial effects in skin atrophy and wound healing. Modulation of cytokines and growth factors by 1alpha,25(OH)(2)D(3) during bone remodeling plays an important role in the coupling of osteoblastic bone formation with osteoclastic resorption to maintain bone mass.

Nonpsoriatic Uses of Calcipotriol

Background:Calcipotriol is a synthetic vitamin D3analog that binds to vitamin D receptors in epidermal cells. In vitro studies have shown that calcipotriol stimulates terminal cell differentiation and has antiproliferative effects. In vivo, calcipotriol has been shown to reduce the number of cycling epidermal cells. Calcipotriol also has less effect on calcium metabolism than calcitriol, which is the natural, bioactive, 1,25-dihydroxyvitamin D3.Objective:These properties make calcipotriol an ideal candidate for the topical treatment of hyperproliferative skin disorders. While it has been approved for topical use in psoriasis, its potential for use in other dermatological disorders has not yet been fully investigated.Conclusion:This survey of the literature suggests that calcipotriol may show promise in the treatment of other conditions involving abnormal keratinization and hyperproliferation of epidermal cells. While some of these disorders are rare, and therefore difficult to study, further study into the nonpsoriatic uses of calcipotriol may be rewarding.

Nonpsoriatic uses of calcipotriol.

Calcipotriol is a synthetic vitamin D3 analog that binds to vitamin D receptors in epidermal cells. In vitro studies have shown that calcipotriol stimulates terminal cell differentiation and has antiproliferative effects. In vivo, calcipotriol has been shown to reduce the number of cycling epidermal cells. Calcipotriol also has less effect on calcium metabolism than calcitriol, which is the natural, bioactive, 1,25-dihydroxyvitamin D3. These properties make calcipotriol an ideal candidate for the topical treatment of hyperproliferative skin disorders. While it has been approved for topical use in psoriasis, its potential for use in other dermatological disorders has not yet been fully investigated. This survey of the literature suggests that calcipotriol may show promise in the treatment of other conditions involving abnormal keratinization and hyperproliferation of epidermal cells. While some of these disorders are rare, and therefore difficult to study, further study into the nonpsoriatic uses of calcipotriol may be rewarding.

1α,25-Dihydroxyvitamin D3 Protects Human Keratinocytes from Apoptosis by the Formation of Sphingosine-1-Phosphate

Owing to its ability to induce growth arrest and differentiation of keratinocytes, 1alpha,25-dihydroxyvitamin D3 and its analogs are useful for the treatment of hyperproliferative skin diseases, such as psoriasis vulgaris. It has been implicated that the 1alpha,25-dihydroxyvitamin D3-induced differentiation of keratinocytes is mediated, at least in part, by the formation of ceramides; however, ceramides have also been identified to induce apoptosis in many cells, including keratinocytes. Therefore, it was of interest to investigate the influence of 1alpha,25-dihydroxyvitamin D3 on apoptosis in keratinocytes. Most interestingly, physiological concentrations of 1alpha,25-dihydroxyvitamin D3 did not induce apoptosis in keratinocytes, despite the formation of ceramides. Moreover, 1alpha,25-dihydroxyvitamin D3 appeared cytoprotective and made keratinocytes resistant to apoptosis induced by ceramides, ultraviolet irradiation, or tumor necrosis factor-alpha. The cytoprotective effect was accompanied by the formation of the sphingolipid breakdown product sphingosine-1-phosphate, which prevented apoptosis in analogy to 1alpha,25-dihydroxyvitamin D3. The effect of 1alpha,25-dihydroxyvitamin D3 was specific as the almost inactive precursor cholecalciferol neither induced sphingosine-1-phosphate formation nor prevented cells from apoptosis. Besides this, the cytoprotective aptitude of 1alpha,25-dihydroxyvitamin D3 was completely abolished by the sphingosine kinase inhibitor N,N-dimethylsphingosine, which blocked sphingosine-1-phosphate formation. Moreover, sphingosine-1-phosphate was able to restore the cytoprotective effect of 1alpha,25-dihydroxyvitamin D3 in the presence of N,N-dimethylsphingosine. Taken together, here we report for the first time that 1alpha,25-dihydroxyvitamin D3 protects keratinocytes from apoptosis and additionally this cytoprotection is mediated via the formation of sphingosine-1-phosphate.

Microemulsions for topical delivery of 8-methoxsalen

8-Methoxsalen (8-MOP) and related furocumarins have been extensively used for the treatment of hyperproliferative skin diseases in association with long-wavelength UVA light. In order to develop alternative formulations for the topical administration of 8-MOP, microemulsions were evaluated as delivery vehicles. Six microemulsion formulations were prepared using water, isopropyl myristate (IPM) and Tween ® 80: Span ® 80: 1,2-Octanediol (3:1:1.2 w/w). The microemulsions were characterized using conductimetric and dynamic light scattering analyses. The ability of the systems to deliver 8-MOP into and through the skin was evaluated in vitro using newborn pig-skin. The in vitro permeation data showed that the novel microemulsions increased the 8-MOP total penetration through the skin by order of 1.9–4.5, as compared with IPM. In general, the accumulation of 8-MOP into the skin was increased by a factor of 1.5–4.5 by the microemulsion systems with respect to their total amount of drug delivered across the skin. These results suggest that the studied microemulsion systems may be appropriate vehicles for the topical delivery of 8-MOP.

Angular Furoquinolinones, Psoralen Analogs: Novel Antiproliferative Agents for Skin Diseases. Synthesis, Biological Activity, Mechanism of Action, and Computer-Aided Studies

With the aim of obtaining new potential photochemotherapeutic agents, having increased antiproliferative activity and decreased undesired effects, we have prepared some new furoquinolinones. Two of them have been studied in detail: 1,4,6,8-tetramethyl-2H-furo[2,3-h]-quinolin-2-one (8), and 4,6,8,9-tetramethyl-2H-furo[2,3-h]quinolin-2-one (10). These compounds form a molecular complex with DNA, undergoing intercalation inside the duplex macromolecule, as shown by linear flow dichroism. The complexed ligands, by subsequent irradiation with UV-A light, photobind with the macromolecule forming only monocycloadducts with thymine with cis-syn configuration. In order to evaluate the electronic effects induced by the nitrogen atom in position 1 of 8, semiempirical calculations have been performed on both 4,6,4'-trimethylangelicin (TMA) and 8. The results obtained do not clearly differentiate between the two molecules which, at this level of approximation, show the possibility of photoreaction with both the 3,4- and 8,9-olefinic bonds for 8 and the 3,4- and 4',5'-bonds for TMA. In the lower energy conformation of intercalated 8, the furan ring is turned toward the minor groove of the polynucleotide, in such a way that photoreaction of this ring with thymine is favored. These compounds unexpectedly inhibit DNA and RNA synthesis in Ehrlich cells, in the dark. They also show a strong photoantiproliferative activity, 2 orders of magnitude higher than 8-methoxypsoralen (8-MOP), the most used drug for photochemotherapy. Their mutagenic activity on Escherichia coli is similar to that of TMA and 8-MOP. On the basis of these results, the compounds should deserve evaluation of their activity in the treatment of hyperproliferative skin diseases.

Calcipotriol: a new drug for topical psoriasis treatment.

Vitamin D is best known for its role in the regulation of calcium and bone metabolism. The effects of the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25 (OH)2D3), are mediated by binding to a specific intracellular vitamin D receptor, which is present in most tissues including the skin where it regulates the growth of epidermal cells. Calcipotriol is a synthetic analogue of 1,25(OH)2D3. In vitro the activity of calcipotriol is comparable to that of 1,25(OH)2D3. In vivo, however, the risk of calcipotriol changing calcium metabolism is greatly reduced. Animal studies have established that calcipotriol is 100-200 times less calcaemic than 1,25(OH)2-D3. This low calcaemic activity is mainly due to the rapid metabolism of calcipotriol. This pharmacological profile makes calcipotriol an ideal candidate for topical treatment of hyperproliferative skin disorders, such as psoriasis. This paper reviews the clinical experience with calcipotriol in psoriasis patients.

A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice.

The biologic action of parathyroid hormone (PTH)-related peptide (PTHrP) in normal skin was investigated in cultured human keratinocytes and in SKH-1 hairless mice. The results indicate that the PTHrP agonists human PTHrP-(1-34) and PTH(1-34) are potent inhibitors of epidermal cell proliferation. [Nle8,18,Tyr34]bovine PTH-(7-34)-amide, an antagonist of the PTH/PTHrP receptor, blocked the inhibitory effect of PTH-(1-34) in cultured keratinocytes. In the SKH-1 mice, PTH-(7-34) caused a 244% increase of [3H]thymidine incorporation into isolated epidermal DNA and 246% and 180% increases in the number and length of hair shafts, respectively. Thus, PTH and PTHrP may play an important role in the normal physiology of skin, and their agonists and antagonists have potentially wide therapeutic applications in the treatment of hyperproliferative skin disorders and aging skin and could also be effective in stimulating and maintaining hair growth.

Ciclosporin inhibits phorbol-ester-induced hyperplastic transformation and tumor promotion in mouse skin probably by suppression of Ca2+/calmodulin-dependent processes such as phosphorylation of elongation factor 2.

This study deals with the mechanism of the inhibitory effect exerted by the immunosuppressant ciclosporin (CsA) on phorbol-ester-induced inflammation, epidermal hyperplasia and tumor promotion in mouse skin in vivo. This effect coincides with an inhibition of the phosphorylation of a 100-kilodalton protein (p100) in epidermal cytosol in vitro, which has been identified as elongation factor 2 (EF-2) of protein biosynthesis. Phosphorylation of EF-2 is dependent on Ca2+ and calmodulin, and inhibition of EF-2 phosphorylation by CsA is due to an interaction of CsA with calmodulin. The EF-2 phosphorylation system has a metabolic half-life of 1.5 h probably due to a rather rapid turnover rate of the EF-2 kinase. Since CsA inhibits specifically 12-O-tetradecanoylphorbol-13-acetate (TAP)-stimulated but not basal protein synthesis in epidermis, it is proposed that Ca2+/calmodulin-dependent phosphorylation of EF-2 is involved in the induction of the hyperplastic response by TPA and that CsA suppresses TPA effects by inhibition of EF-2-phosphorylation and perhaps other calmodulin-dependent processes. The potential applicability of calmodulin inhibitors in the treatment of hyperproliferative skin diseases is discussed.

A novel synthetic vitamin-A-like compound (a polyprenoic acid derivative: E-5166) inhibits UVB-stimulated epidermal ornithine decarboxylase activity.

Irradiation of skin with ultraviolet B (UVB) stimulates epidermal activity of ornithine decarboxylase (ODC), a rate limiting polyamine biosynthesing enzyme. The maximum stimulation of ODC activity by UVB was found at 24 after irradiation. Systemic administration of a polyprenoic acid derivative (E-5166) significantly inhibited the UVB-stimulated ODC activity in a dose-dependent manner. The inhibitory effect of E-5166 on the UVB-stimulated ODC activity was found to begin at 5 mg/kg body weight. These results indicate that because it inhibits ODC activity E-5166 can be utilized for the treatment of hyperproliferative skin diseases.