pep005 and Skin-Neoplasms

While a wide range of treatments exist for actinic keratosis and skin field cancerisation, the long-term benefits of the most common topical therapies are poorly defined. This report reviews the efficacy of the most commonly used topical therapies to treat regional or field lesions. Limited clinical and histopathological data are available on clearance rates at 12 months post-treatment for the most commonly used agents, with varied outcome measures making any comparison difficult. In general, total field clearance rates at 12 months are suboptimal for the most commonly employed agents. Given the increasing incidence of actinic keratosis and skin field cancerisation due to an ageing population, further research into the efficacy of therapies is critical to guide treatment choice.

Topics: Antineoplastic Agents; Diclofenac; Disease Progression; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Recurrence; Skin Neoplasms

Skin cancer is a broad term used to describe a number of different malignant indications of the skin. Skin cancers mostly comprise of the keratinocyte cancers [Basal Cell Carcinoma (BCC) and cutaneous Squamous Cell Carcinoma (SCC)], and melanoma. Surgical excision of these malignancies has been the preferred treatment of patients for decades. However, the decision to perform surgery can be affected by various considerations, including co-morbidities of the patient, the anatomical site of the lesion and potential intolerance for repeated excisions. Topical treatment of skin cancer may therefore be more appropriate in certain instances. Topical treatment potentially allows for higher drug levels at the tumor site, and may result in less overall toxicity than systemic agents. This review will specifically address the current agents used in topical treatment of skin cancers, and introduce emerging treatments from the natural product field that may also find utility in these indications.

Topics: Administration, Cutaneous; Antineoplastic Agents; Carcinoma, Basal Cell; Clinical Trials as Topic; Diterpenes; Drug Delivery Systems; Fluorouracil; Humans; Hutchinson's Melanotic Freckle; Imiquimod; Keratosis, Actinic; Melanoma; Neoplasms, Squamous Cell; Photochemotherapy; Retinoids; Skin; Skin Neoplasms; Ultraviolet Rays

Although surgical intervention remains the standard of care for nonmelanoma skin cancer, other treatment modalities have been studied and used. Nonsurgical treatment methods include cryotherapy, topical medications, photodynamic therapy, radiation therapy, Hedgehog pathway inhibitors, programmed cell death protein 1 inhibitors, and active nonintervention. Despite the favorable efficacy of surgical treatment methods, many factors, including but not limited to patient age, preference, and severity of disease, must be taken into consideration when choosing the most appropriate, patient-centered treatment approach.

Topics: Administration, Cutaneous; Anilides; Antineoplastic Agents; Antineoplastic Agents, Immunological; Biphenyl Compounds; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cryosurgery; Cyclooxygenase Inhibitors; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Photochemotherapy; Programmed Cell Death 1 Receptor; Pyridines; Radiotherapy; Skin Neoplasms; Watchful Waiting

Taking into consideration that the immune system plays a very important role in the development of melanoma and non-melanoma skin cancers, which have a high prevalence in immunosuppressed patients and after prolonged ultraviolet radiation, the interest in developing novel therapies, in particular targeting the inflammation in cancer, has increased in the past years. The latest data suggest that therapies such as imiquimod (IMQ), ingenol mebutate (IM), 5-fluorouracil (5-FU), retinoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been used with success in the topical treatment of some cancers. Herein, we review the topical treatment targeting the inflammation in skin cancer and the mechanisms involved in these processes. Currently, various associations have shown a superior success rate than monotherapy, such as systemic acitretin and topical IMQ, topical 5-FU with tretinoin cream, or IMQ with checkpoint inhibitor cytotoxic T lymphocyte antigen 4. Novel therapies targeting Toll-like receptor-7 (TLR-7) with higher selectivity than IMQ are also of great interest.

Topics: Administration, Topical; Aminoquinolines; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cytokines; Diterpenes; Fluorouracil; Humans; Imiquimod; Inflammation; Melanoma; Neoplasm Metastasis; Skin; Skin Neoplasms; Toll-Like Receptor 7

Chemoprevention of nonmelanoma skin cancer should be considered in patients likely to develop numerous, invasive, or metastatic nonmelanoma skin cancers. This article reviews the various topical and systemic substances studied as chemopreventive agents.

Topics: Administration, Cutaneous; Administration, Oral; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Chemoprevention; Cyclooxygenase Inhibitors; Diclofenac; Diterpenes; Fluorouracil; Humans; Imiquimod; Niacinamide; Photochemotherapy; Retinoids; Skin Neoplasms

A wide range of treatments is now available for nonmelanoma skin cancer (NMSC), including 5-fluorouracil, ingenol mebutate, imiquimod, diclofenac, photodynamic therapy, methotrexate, cetuximab, vismodegib, and radiotherapy. All are associated with high clinical and histologic response rates. However, some tumors do not respond due to resistance, which may be primary or acquired. Study of the resistance processes is a broad area of research that aims to increase our understanding of the nature of each tumor and the biologic features that make it resistant, as well as to facilitate the design of new therapies directed against these tumors. In this article we review resistance to the authorized topical treatments for NMSC.

Topics: Adjuvants, Immunologic; Administration, Cutaneous; Aminoquinolines; Anti-Inflammatory Agents, Non-Steroidal; Antigen-Presenting Cells; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma; Clinical Trials as Topic; Dermatologic Agents; Diclofenac; Diterpenes; Drug Resistance, Neoplasm; Fluorouracil; Humans; Imiquimod; Meta-Analysis as Topic; Neoplasm Proteins; Neoplastic Stem Cells; Skin Neoplasms

Actinic keratosis (AK) is a common premalignant skin lesion that is frequently treated by cryosurgery. Basal cell carcinoma is the most common malignancy of man, and early-stage lesions are usually cured via surgery. Advanced basal cell carcinoma may require more extensive surgery resulting in deformity, and many advanced lesions cannot be treated surgically. Several recent developments have improved therapeutic options for both conditions. Cryosurgery is still a mainstay of treatment for AK, but the introduction of effective topical agents, imiquimod cream and ingenol mebutate, has provided alternatives to cryosurgery. For advanced basal cell carcinoma, the small-molecule inhibitor vismodegib has proven to be an effective therapy for lesions that are not amenable to surgery and has demonstrated ability to achieve dramatic improvement in advanced, potentially disfiguring cancer.

Topics: Aminoquinolines; Anilides; Antineoplastic Agents; Carcinoma, Basal Cell; Cryosurgery; Diterpenes; Humans; Imiquimod; Keratosis, Actinic; Mutation; Patched Receptors; Pyridines; Receptors, Cell Surface; Skin Neoplasms; Treatment Outcome

To present a brief review of periorbital cutaneous tumorogenesis, highlighting the steps which might be amenable to topical treatments and then discuss the use of topical agents in the management of periorbital skin malignancy.. A rapid expansion in the understanding of the pathogenesis of melanoma and nonmelanoma skin cancer has allowed the development of a number of topical agents targeting specific tumor-forming processes. Topical agents have been shown to be effective in the management of periorbital skin malignancy.. 5-Fluorouracil and imiquimod have established roles in the management of periorbital skin malignancy. Newer agents such as ingenol mebutate, tazarotene, and diclofenac gel probably have evolving roles that require further research but show promise.

Topics: Administration, Topical; Aminoquinolines; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Fluorouracil; Humans; Imiquimod; Mitomycin; Orbital Neoplasms; Skin Neoplasms

Topical antineoplastic agents have a well-established role in the treatment of several dermatological conditions. Their use in the treatment of mucosal skin disease also has gained increasing recognition. Topical 5-fluorouracil (5-FU), an antimetabolite, and imiquimod, an immunomodulatory agent with antitumor properties, are the two principal topical antineoplastic agents used in the treatment of mucocutaneous diseases. Although the vast majority of their mucosal uses are currently not approved by the Federal Drug Administration, there are numerous case series, open-label studies and randomized controlled trials supporting their uses in the treatment of mucocutaneous diseases. Both topical 5-FU and imiquimod have been successfully utilized in the treatment of a wide range of mucosal diseases, including actinic cheilitis, Bowen's disease of the anal and vulvar mucosa, and genital and perianal condyloma. Reports of their uses in the treatment of mucocutaneous diseases indicate that these agents can be safely administered, though adverse effects such as local inflammation may be augmented when these agents are applied to mucosal surfaces. Additionally, locally acting intralesional chemotherapeutic agents, such as bleomycin and interferon, have well-defined applications in the treatment of mucosal skin diseases such as condyloma acuminata. As further studies are conducted, these topical and intralesional neoplastic agents, in addition to emerging agents that are in various stages of development, such as Toll-like receptor 9 agonists and ingenol mebutate, may play an increasingly important role in the future treatment of mucocutaneous diseases.

Topics: Administration, Topical; Aminoquinolines; Antineoplastic Agents; Diterpenes; Fluorouracil; Humans; Imiquimod; Keratosis, Actinic; Mucositis; Mucous Membrane; Skin Diseases; Skin Neoplasms

Ingenol mebutate gel is approved for actinic keratosis field therapy, but little has been published as a treatment of basal cell carcinoma (BCC). Our objective is to characterise the histopathological changes and the infiltrating cell populations to better understand its mechanism of action.. Sixteen patients with various BCC subtypes were prospectively evaluated and treated once daily for two consecutive days with ingenol mebutate gel 0.05% under occlusion. Patients were randomised to two arms: the first arm was biopsied between the third and the tenth day after treatment initiation ('early immune response'), and the second arm was biopsied at day 30 after treatment initiation ('late immune response'). The immunopathology was evaluated by immunohistochemistry: anti-CD3, anti-CD4, anti-CD8, anti-CD20, anti-CD56, anti-CD68, anti-Bcl-2, anti-CASP3, anti-FoxP3, anti-GrzB and anti-TIA-1.. Ten BCCs were in complete remission after 2 years of follow-up. The early immune response was characterised by a quick recruitment of T lymphocytes, macrophages and natural killer cells. At later time-points, T-regulatory cells and some pro-apoptotic markers were detected. Treatment-related adverse events were described.. Ingenol mebutate gel produces a transient immuno-inflammatory response and an important necrosis reaction in BCCs. Larger studies will be required to determine the maximum effective tolerated dose of ingenol mebutate gel for BCC.

Topics: Administration, Cutaneous; Aged; Antineoplastic Agents; Carcinoma, Basal Cell; Diterpenes; Female; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Skin Neoplasms; Treatment Outcome

Topics: Aged; Aged, 80 and over; Diterpenes; Facial Neoplasms; Female; Head and Neck Neoplasms; Humans; Hutchinson's Melanotic Freckle; Male; Middle Aged; Prospective Studies; Scalp; Skin Neoplasms; Treatment Outcome

To evaluate the safety of two applications of PEP005 (ingenol mebutate) gel in superficial basal cell carcinoma. Efficacy was a secondary end-point.. Randomized, vehicle-controlled, phase IIa study conducted at eight private dermatology clinics in Australia. A total of 60 patients with histologically confirmed superficial basal cell carcinoma (lesion size, 4-15 mm) were randomized to treatment on days 1 and 2 (Arm A) or days 1 and 8 (Arm B) and, within each arm, to ingenol mebutate gel, 0.0025%, 0.01% or 0.05%, or vehicle gel. The main outcome measures were the incidence and severity of adverse events and local skin responses in Arms A and B; lesion clearance at day 85 was a secondary measure.. The incidence of adverse events was low. One patient treated with ingenol mebutate gel, 0.05% in Arm A experienced severe flaking/scaling/dryness extending beyond the application site. Non-severe, potentially treatment-related events included erythema extending beyond the application site, application-site pain and headache in two patients each. Six patients in Arm A had one or more severe local skin responses. Efficacy appeared to be dose-related and there was a trend towards higher clinical and histological lesion clearance rates in Arm A compared with Arm B. Histological clearance occurred in five of eight patients (63%) randomized to ingenol mebutate gel, 0.05% in Arm A.. Two applications of ingenol mebutate gel, 0.05%, are safe and have efficacy in patients with superficial basal cell carcinoma.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Diterpenes; Dose-Response Relationship, Drug; Female; Gels; Headache; Humans; Male; Middle Aged; Pain; Remission Induction; Skin Diseases; Skin Neoplasms; Treatment Outcome

Actinic keratoses (AKs) are common skin lesions association with increased exposure to ultraviolet radiation; these lesions have the potential to transform into squamous cell carcinomas (SCCs).1.

Topics: Aminolevulinic Acid; Carcinoma, Squamous Cell; Clinical Trials as Topic; Diterpenes; Fluorouracil; Humans; Imiquimod; Incidence; Keratosis, Actinic; Patient Preference; Photochemotherapy; Photosensitizing Agents; Risk Assessment; Skin Neoplasms; Treatment Outcome

Ingenol mebutate (IM) is a novel drug currently only FDA-approved for the treatment of actinic keratosis. However, it has been extensively used off-label to treat multiple other skin disorders. In recent years, literature has emerged providing evidence for IM’s use as treatment for dermatologic disorders beyond actinic keratosis, including squamous cell carcinoma in situ. Here, we report a case series in which topical 0.05% ingenol mebutate was used to treat squamous cell carcinoma in situ, with five of six patients demonstrating successful results. J Drugs Dermatol. 2021;20(2):169-171. doi:10.36849/JDD.5602.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Carcinoma in Situ; Carcinoma, Squamous Cell; Diterpenes; Female; Follow-Up Studies; Humans; Male; Middle Aged; Off-Label Use; Protein Kinase Inhibitors; Skin; Skin Neoplasms; Treatment Outcome

New therapeutic strategies are needed for cutaneous T-cell lymphoma (CTCL), and the plant extract ingenol mebutate (PEP005) may be considered. PEP005 has been approved for actinic keratosis, and proapoptotic activities were described in different cancer cells. Here, we aimed to investigate its efficacy in four CTCL cell lines and its mode of action. While HuT-78 and HH responded with induced apoptosis as well as with loss of cell viability and cell proliferation, MyLa and SeAx remained resistant. Interestingly, both sensitive and resistant cells showed caspase-8 activation and enhanced levels of reactive oxygen species (ROS), while final caspase-3 activation was restricted to sensitive cells. Apoptosis induction was prevented by the caspase inhibitor QVD-Oph as well as by the antioxidant vitamin E. Caspase activation by PEP005 may be explained to some extent by the downregulation of the caspase antagonistic proteins c-FLIP and XIAP in sensitive cells, whereas both proteins were strongly expressed in resistant cells. Finally, PEP005 resulted in the activation of proapoptotic PKCδ, and the PKC inhibitor bisindolylmaleimide I reduced apoptosis, caspase-3 processing and ROS production, as well as restored cell viability. In conclusion, PKCδ appeared as a central player in apoptosis regulation in CTCL cells, also suggesting its therapeutic targeting.

Topics: Apoptosis; CASP8 and FADD-Like Apoptosis Regulating Protein; Cell Cycle; Cell Movement; Cell Proliferation; Diterpenes; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, T-Cell, Cutaneous; Protein Kinase C-delta; Reactive Oxygen Species; Skin Neoplasms; Tumor Cells, Cultured; X-Linked Inhibitor of Apoptosis Protein

Basal cell carcinomas (BCCs) have previously been treated off-label with ingenol mebutate (IM). Ablative fractional laser (AFL) may improve efficacy of IM by increasing drug uptake in the tumour. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) detect BCC non-invasively. Our aim was to investigate BCC response and tolerability after combined AFL and IM treatment of low-risk BCCs.. Twenty patients with histologically verified superficial (n = 7) and nodular (n = 13) BCCs were treated with combined fractional CO. At day 29, 18/20 patients received a second treatment due to residual BCC detected clinically, by OCT or RCM. OCT and RCM presented subclinical BCCs in five of 20 cases (25%). At day 90, overall histological cure rate was 70%, corresponding to clinical (65%) and OCT/RCM (60%) cure rates, and agreement between evaluation methods was substantial (kappa ≥ 0.796, P < 0.0001). Clearance rates were similar for sBCCs and nBCCs (P = 0.354) and for lesions treated with IM 0.015% and 0.05% (P = 0.141). LSRs were tolerable, but scarring was observed in the majority of cleared patients.. Two treatments of combined AFL and IM show potential to treat low-risk BCCs with acceptable tolerability. OCT and RCM show promise to detect subclinical BCCs at short-term follow-up.

Topics: Aged; Combined Modality Therapy; Diterpenes; Female; Humans; Laser Therapy; Lasers, Gas; Male; Microscopy, Confocal; Middle Aged; Neoplasms, Basal Cell; Skin Neoplasms; Tomography, Optical Coherence

Topics: Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Diterpenes; Humans; Keratosis, Actinic; Male; Scalp; Skin Neoplasms

Topics: Administration, Cutaneous; Antineoplastic Agents, Phytogenic; Biopsy; Dermatitis, Irritant; Diterpenes; Euphorbia; Humans; Mycosis Fungoides; Severity of Illness Index; Skin; Skin Neoplasms; Treatment Outcome

The incidence of nonmelanoma skin cancer continues to increase. Surgical excision remains the best choice of treatment but the demand of patients is to have tissue-sparing approaches with good cosmetic results; these aims led to the development of novel therapeutic agents such as topical ingenol mebutate gel. We report the successful treatment with ingenol mebutate gel 0.05% of three pigmented basal cell carcinomas. Lesions were evaluated by dermoscopy and confocal microscopy before, during and after the treatment.

Topics: Antineoplastic Agents; Carcinoma, Basal Cell; Dermoscopy; Diterpenes; Female; Humans; Male; Microscopy, Confocal; Middle Aged; Skin Neoplasms; Treatment Outcome

Topics: Administration, Cutaneous; Aged; Aminoquinolines; Antineoplastic Agents; Carcinoma, Basal Cell; Cryotherapy; Diterpenes; Female; Gels; Humans; Imiquimod; Neoplasms, Multiple Primary; Nevus, Sebaceous of Jadassohn; Skin Neoplasms; Treatment Outcome

BACKGROUND A recent focus in skin cancer prevention intervenes though modulating molecular links between inflammation and cell growth signaling, such as NF-κB. This study elucidates the effect of a non-tumor promoting phorbol ester, ingenol-3-angelate (I3A), on the growth of human melanoma cells and on the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation and 7,12-Dimethylbenz(a)anthracene (DMBA)-induced skin carcinoma in mice. MATERIAL AND METHODS Cell viability was assessed by MTT assay, cell proliferation by clonogenic assay, apoptosis and cell cycle arrest was analyzed by flow cytometry, protein expression was studied by IHC and Western blotting, and gene expression by qPCR. RESULTS I3A suppressed the survival and proliferation of human melanoma cells with estimated IC50 values around 38 and 46 μM for A2058 and HT144 cell, respectively. I3A activated the protein levels of PKCδ and PKCε, which induced apoptosis by activating caspase-9 and caspace-3 followed by lowering of mitochondrial membrane potential and enhancing DNA fragmentation. I3A induced G1 phase cell cycle arrest as well as G2/M phase arrest in both cell lines. I3A inhibited the levels of NFκB p65 protein as well as phosphorylation of p65 and its nuclear translocation. I3A suppressed the gene expression of NF-κB, COX-2 and iNOS. I3A inhibited TPA-induced inflammation and epidermal hyperplasia in female ICR mice by downregulating NF-κB and iNOS. I3A suppressed the growth of skin tumor in DMBA-induced mice in dose-dependent manner. CONCLUSIONS The mechanism of I3A induces apoptosis in human melanoma cells and suppresses skin inflammation and carcinoma via downregulation of NF-κB-iNOS-COX-2 signaling.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Apoptosis; Apoptosis Regulatory Proteins; Carcinogenesis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclooxygenase 2; Diterpenes; Down-Regulation; Epidermis; Female; Hyperplasia; Inflammation; Melanoma; Mice, Inbred ICR; NF-kappa B; Signal Transduction; Skin Neoplasms; Tetradecanoylphorbol Acetate

Topics: Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Skin Neoplasms

Ingenol mebutate is an actinic keratosis treatment, which has a dual action mechanism. It allows a rapid cellular death and a severe inflammation.. We report the case of a 75 years old patient with a rapidly growing tumor 5 weeks after application of ingenol mebutate on typical actinic keratosis. Histological analysis after surgical excision showed an invasive squamous cell carcinoma (SCC); with aggressiveness signs: perineural infiltration and vascular permeation.. Ingenol mebutate's common side effects are benign and regressive within 2 to 4 weeks. There are erythema, edema, crusts, and ulcerations/erosions. Squamous cell carcinoma development was rarely reported. We have tried to collect other cases in the literature and in pharmacovigilance centres: three similar cases were recently published in the literature, 21 cases were notified to the European Medicines Agency and we asked French pharmacovigilance centres and found 5 cases of SCC after ingenol mebutate application. The role of the molecule in SCC development is currently unknown. Induced inflammation could take part in the development of these tumors. We compare this case with other situations of inflammation, such skin graft donor site or surgical incision, complicated of rapidly growing SCC. Our case, literature's and pharmacovigilance's cases encourage us to follow ingenol mebutate's side effects. Careful follow-up and registration of such cases are important to gain further insight on this topic.

Topics: Administration, Cutaneous; Aged; Carcinoma, Squamous Cell; Dermatologic Agents; Disease Progression; Diterpenes; Humans; Inflammation; Irritants; Keratosis, Actinic; Male; Neoplasm Invasiveness; Skin Neoplasms

Actinic keratosis (AK) is an in situ squamous cell carcinoma which is mostly found on sun-damaged skin, and it is prevalent among Caucasians. However, there is a lack of research on evaluating the treatment efficacy of ingenol mebutate (IM) on AK in Asians. This study was intended to analyze the treatment outcomes of IM on AK in Korean patients with regards to clinical, dermoscopic and histopathological aspects. A prospective study on 46 Korean patients who were diagnosed with AK and treated with IM was conducted. Clinically, 80% (24/30) of the patients showed an improvement at 8 weeks. Twenty out of the 30 (66.7%) patients were found to have achieved histopathological clearance. All local skin responses had disappeared at T4 in all patients. Patients with Fitzpatrick skin type III were proven to exhibit better treatment outcomes, both clinically (P = 0.001) and histopathologically (P = 0.001), than those with Fitzpatrick skin type IV. The clinical and histopathological clearance rate of AK with IM in Korean patients was 80% and 66.7%, respectively. The patients with Fitzpatrick skin type IV showed a tendency to have residual AK, histopathologically after treatment with IM. In conclusion, IM could be an effective and safe treatment option on AK in Korean patients. In addition, it would be helpful to carry out a cautious check-up when treating AK with IM in patients with a darker skin color.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Squamous Cell; Dermoscopy; Diterpenes; Female; Humans; Keratosis, Actinic; Male; Middle Aged; Prospective Studies; Republic of Korea; Skin; Skin Neoplasms; Treatment Outcome

Topics: Aged, 80 and over; Carcinoma, Squamous Cell; Diterpenes; Granulation Tissue; Humans; Male; Scalp; Skin Diseases; Skin Neoplasms; Treatment Outcome

Squamous cell carcinoma of the skin is the second most common cutaneous malignancy. Despite various available treatment methods and advances in noninvasive diagnostic techniques, the incidence of metastatic cutaneous squamous cell carcinoma is rising. Deficiency in effective preventive or treatment methods of transformed keratinocytes leads to necessity of searching for new anticancer agents. The present study aims to evaluate the possibility of using wool hydrolysates as such agents. Commercially available compounds such as 5-fluorouracil, ingenol mebutate, diclofenac sodium salt were also used in this study. The process of wool degradation was based on chemical pre-activation and enzymatic digestion of wool. The effect of mentioned compounds on cell viability of squamous carcinoma cell line and healthy keratinocytes was evaluated. The obtained data show a significantly stronger effect of selected wool hydrolysates compared to commercial compounds (p<0.05) on viability of cells. The wool hydrolysates decreased squamous cell carcinoma cells viability by up to 67% comparing to untreated cells. These results indicate bioactive properties of wool hydrolysates, which affect the viability of squamous carcinoma cells and decrease their number. We hypothesize that these agents may be used topically for treatment of transformed keratinocytes in actinic keratosis and invasive squamous skin cancer in humans.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Diclofenac; Diterpenes; Fluorouracil; Humans; Keratinocytes; Protein Hydrolysates; Skin Neoplasms; Wool

Non-melanoma skin cancer is the most frequently occurring cancer in Caucasians today. Incidence rates in Europe have increased steadily since the 1960s and more than tripled over the last 50 years. Despite primary preventative efforts, incidences of non-melanoma skin cancer continue to rise and development of effective chemopreventative strategies is needed. In 2013, ingenol mebutate was approved in Denmark as a new topical drug for field-directed treatment for actinic keratoses. Ingenol mebutate has a dual mechanism of action, causing initial cell death, followed by an immune activation. The treatment induces an acute inflammation, manifesting as local skin responses, often accompanied by pain and pruritus. The severity of local skin responses for a given patient is unpredictable, and some individuals may develop insufferable inflammation. The overall aim of the thesis was to investigate if ingenol mebutate could be used as a chemopreventive agent to prevent development of non-melanoma skin cancer with minimal side effects. Specific aims included: Determine if ingenol mebutate can prevent progression of histological photodamage and squamous cell carcinoma (murine). Determine if ingenol mebutate can reverse clinical actinic damage in patients with multiple actinic keratoses and fieldcancerized skin (clinical). Determine if a topical glucocorticoid (clobetasol propionate) can reduce ingenol mebutate-induced local skin responses, pain, and pruritus without compromising the treatment efficacy (murine clinical). In two in vivo murine studies, ingenol mebutate's effect on photodamage and squamous cell carcinoma formation was investigated. Mice were irradiated with solar simulated ultraviolet radiation. During the first 20 weeks, 5 single applications with ingenol mebutate were given at four-week intervals with and without concurrent application of clobetasol propionate. Prophylactic treatments with ingenol mebutate prevented progression of histological photodamage of all investigated characteristics, including keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage. In addition, tumor formation was postponed by 3 weeks. In the clinical trial, patients with multiple actinic keratoses and field-cancerized skin were treated with ingenol mebutate, according to label, with and without sequential application of clobetasol propionate. Ingenol mebutate treatments were found to clear overall 86% of all actinic keratoses, exerting a therapeutic effe

Topics: Administration, Cutaneous; Animals; Carcinoma, Squamous Cell; Denmark; Dermatologic Agents; Diterpenes; Glucocorticoids; Humans; Keratosis, Actinic; Mice; Pain; Pruritus; Skin Neoplasms; Treatment Outcome; Ultraviolet Rays

Topics: Aged, 80 and over; Carcinoma, Basal Cell; Diterpenes; Drug Monitoring; Hamartoma Syndrome, Multiple; Humans; Male; Microscopy; Microscopy, Confocal; Skin Neoplasms; Time Factors

Basal cell carcinoma is the most common non-melanoma skin cancer, and its incidence continues to raise. Although surgery can be considered the mainstay of therapy, new current pharmacological options are available and focus on tumor eradication, maximizing cosmetic results, and functional capacity. Several studies have recently reported on safety and efficacy of topical ingenol mebutate gel, a derivative of the plant Euphorbia Peplus, used to treat actinic keratosis and superficial basal cell carcinoma. In our knowledge, we report for the first time the dermoscopic evaluation of outcome and monitoring of superficial pigmented and non-pigmented basal cell carcinomas in four patients treated by this novel non-ablative agent. Ingenol mebutate gel therapy has showed to be effective and without important side-effects for pigmented and non-pigmented superficial basal cell carcinomas. We emphasize the usefulness of dermoscopy in supporting the clinical diagnosis and excluding the presence of tumor residue or recurrence. In a future scenario, we hope it will be soon possible to follow-up the lesions, after treatment, avoiding post-control biopsy punch.

Topics: Aged, 80 and over; Antineoplastic Agents; Biopsy; Carcinoma, Basal Cell; Dermoscopy; Diterpenes; Female; Humans; Male; Middle Aged; Nevus, Pigmented; Skin Neoplasms; Time Factors; Treatment Outcome

Topics: Administration, Cutaneous; Dermatologic Agents; Diterpenes; Drug Delivery Systems; Female; Humans; Keratosis, Actinic; Leg; Middle Aged; Needles; Skin Neoplasms

Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by widespread human papillomavirus (HPV) associated lesions and an increase susceptibility to cutaneous malignancies. A host of medications traditionally used to treat warty lesions have been used with variable results and limited success. To our knowledge, we describe the first reported case of a patient with Imiquimod resistant EV successfully treated with topical ingenol mebutate (Picato).. A patient with a 5 year history of EV failed to respond to a 6 week course of 5% imiquimod on the forehead and was subsequently treated with a 3 day course of 0.015% Picato gel which resulted in significant clinical improvement. A one month follow-up examination showed no reoccurrence of the lesions with the patient reporting continued satisfaction of the outcome.. Our case provides insight into the potential use of ingenol mebutate for EV patients unresponsive to traditional medical treatments.

Topics: Acitretin; Adult; Aminoquinolines; Antineoplastic Agents; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Drug Resistance; Epidermodysplasia Verruciformis; Female; Gels; Humans; Imiquimod; Keratolytic Agents; Rare Diseases; Skin Neoplasms; Treatment Outcome; Tretinoin

Non-melanoma skin cancer (NMSC) is the most frequent human cancer with continuously rising incidences worldwide. Herein, we investigated the molecular basis for the impaired skin barrier function of organotypic NMSC models. We unraveled disturbed epidermal differentiation by reflectance confocal microscopy and histopathological evaluation. While the presence of claudin-4 and occludin were distinctly reduced, zonula occludens protein-1 was more wide-spread, and claudin-1 was heterogeneously distributed within the NMSC models compared with normal reconstructed human skin. Moreover, the cancer altered stratum corneum lipid packing and profile with decreased cholesterol content, increased phospholipid amount, and altered ceramide subclasses. These alterations contributed to increased surface pH and to 1.5 to 2.6-fold enhanced caffeine permeability of the NMSC models. Three topical applications of ingenol mebutate gel (0.015%) caused abundant epidermal cell necrosis, decreased Ki-67 indices, and increased lactate dehydrogenase activity. Taken together, our study provides new biological insights into the microenvironment of organotypic NMSC models, improves the understanding of the disease model by revealing causes for impaired skin barrier function in NMSC models at the molecular level, and fosters human cell-based approaches in preclinical drug evaluation.

Topics: Caffeine; Cell Line, Tumor; Cell Survival; Coculture Techniques; Diterpenes; Esterases; Fibroblasts; Humans; Keratinocytes; Lipid Metabolism; Male; Skin; Skin Neoplasms; Tight Junction Proteins

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis. We report a case with off-label use of IM where Bowen's disease has been successfully treated with physician-directed IM 0.015% gel under occlusion over the chest area.

Topics: Administration, Cutaneous; Aged, 80 and over; Antineoplastic Agents; Bowen's Disease; Diterpenes; Humans; Male; Off-Label Use; Skin Neoplasms; Thorax

We present the case of a 73-year-old male patient who had received a first renal transplant at 36 years and a second one at the age of 55 years. He is currently under immunosuppression with everolimus 2.5 mg/day and prednisone 5 mg/day. The patient presented with multiple actinic keratoses on both cheeks and the forehead and received treatment by ingenol mebutate 150 µg/g gel daily on 3 consecutive days on his right cheek and methyl aminolevulinate (MAL) photodynamic therapy activated by daylight (MAL-dPDT) on the forehead and the left cheek. MAL-dPDT treatment proved a feasible, repeatable, physician-directed method of treating field cancerization with limited morbidity for a period of 6 days. Treatment with ingenol mebutate gel was a feasible, possibly self-directed method of treating field cancerization with limited morbidity for 10 days in this immunosuppressed patient. Both treatments showed similar efficacy. At the time of treatment, the MAL daylight PDT ran at 3 times the cost of ingenol mebutate gel.

Topics: Aged; Aminolevulinic Acid; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Face; Humans; Keratosis, Actinic; Kidney Transplantation; Male; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms; Transplant Recipients

Lentigo maligna (LM) is a melanoma in situ on sun-damaged skin, with a strong predilection to the head and neck area of the elderly. Many therapeutic modalities have been proposed in the treatment of this pathology, including surgery, cryotherapy, radiotherapy and topical imiquimod. Up to date surgical excision remains the treatment of choice with the lowest recurrence rate. Recently, a new topical treatment with ingenol mebutate has been described to be efficacious and well tolerated in the treatment of melanoma in situ.. We sought to demonstrate that ingenol mebutate might be an efficacious and well-tolerated treatment in a patient suffering from LM on an aesthetically challenging location.. Case report.. After therapeutic failure with imiquimod 5% cream, a new topical treatment with ingenol mebutate gel 0.015% once daily on 3 consecutive days was initiated. Despite visible inflammation, no macroscopic lesion clearance was observed. While the first follow-up using reflectance confocal microscopy (RCM) performed at 6 weeks after the completion of the therapy showed no signs of LM, the second follow-up examination at 12 weeks using RCM and biopsy confirmed recurrence of the lesion.. Ingenol mebutate cannot be considered a standard treatment modality for all types of LM. Further studies are needed to evaluate the prerequisites that can ensure therapeutic success.

Topics: Aged; Antineoplastic Agents; Diterpenes; Female; Humans; Hutchinson's Melanotic Freckle; Microscopy, Confocal; Neoplasm Recurrence, Local; Skin Neoplasms; Treatment Failure

We present the case of a healthy 76-year-old man with a whitish, hyperkeratotic lesion of the lower lip diagnosed as actinic cheilitis (AC) previously treated with classic red light photodynamic therapy 5 years ago. Initial treatment with 5% imiquimod cream - also with intensified application - failed. After 2 cycles thrice daily, consecutive applications of 150 μg/g ingenol mebutate gel at 3 weeks' interval, the lesions cleared completely. Surprisingly, no pustular or crusting reaction or other side effect occurred contrary to expectation. Remission was stable for 10 months, when recurrence occurred. Ingenol mebutate proved to be a feasible and safe treatment in this otherwise refractory case of AC.

Topics: Administration, Cutaneous; Aged; Antineoplastic Agents; Cheilitis; Chronic Disease; Diterpenes; Humans; Lip; Lip Neoplasms; Male; Neoplasm Recurrence, Local; Precancerous Conditions; Skin Neoplasms

Patients suffering from chronic lymphocytic leukemia often develop actinic keratosis (AK) and squamous cell carcinoma in sun-exposed areas. In these particular patients, who have a suboptimal immune function, AK treatment can be particularly challenging. We report the case of a patient who failed to respond to most AK treatments, including 5-FU, imiquimod and photodynamic therapy, but responded to ingenol mebutate. We started with 3 applications of 150 μg/g (registered treatment of the scalp) and also 2 applications of 500 μg/g (registered in for trunk and extremities). Both treatments were well tolerated, but only the latter led to significant clinical success. This suggests that 500 μg/g of ingenol mebutate may represent an interesting therapeutic option in patients with mild immunosuppression.

Topics: Aged; Antineoplastic Agents; Carcinogenesis; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Diterpenes; Humans; Keratosis, Actinic; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Scalp; Skin Neoplasms

Ingenol mebutate (IM) has recently been approved for the topical treatment of actinic keratoses. It appears to have a dual mechanism of action: rapid necrosis after gel application and a subsequent immune-mediated response, which targets any residual dysplastic epidermal cells. We report the successful treatment of a woman, who had been relapsing into Bowen's disease (BD) on her right forefinger for 8 years. During her clinical history, she had received an allogeneic, HLA-identical stem cell transplant for myeloproliferative syndrome with a JAK2V617F mutation and lobectomy of the pulmonary right lower lobe for adenocarcinoma. We used dermoscopy to monitor the therapeutic response of BD. We discuss IM gel as a possible therapeutic option for BD.

Topics: Adenocarcinoma; Administration, Cutaneous; Aged; Antineoplastic Agents; Bowen's Disease; Dermoscopy; Diterpenes; Female; Fingers; Gels; Humans; Lung Neoplasms; Myeloproliferative Disorders; Neoplasm Recurrence, Local; Pneumonectomy; Skin Neoplasms; Stem Cell Transplantation

Ingenol mebutate (IM) is a topical pharmacotherapy approved in Switzerland since 2012 for treating non-hypertrophic, non-hyperkeratotic actinic keratosis (AK). We report 2 cases with off-label use of IM. The first case of bowenoid AK was treated with 150 μg IM for 3 consecutive days with an almost complete clinical remission of the lesion. The second case of Bowen's disease was treated with 500 μg IM for 2 consecutive days leading to complete clinical remission.

Topics: Administration, Cutaneous; Aged; Antineoplastic Agents; Bowen's Disease; Diterpenes; Eyelids; Female; Gels; Hand; Humans; Keratosis, Actinic; Male; Skin Neoplasms

Surgery is the therapy of choice in the guidelines to treat basal cell carcinomas (BCCs) but a variety of non-surgical options are available. The objective of this study is to evaluate the efficacy and safety of ingenol mebutate 0.05% gel for the treatment of superficial BCCs. We accepted twenty patients with superficial BCCs on the body and we treated them once daily for two consecutive days with ingenol mebutate 0.05% gel. We examined the lesions at the screening visit and after four days from the gel application to describe the local skin reaction due to the therapy. Then we followed the patients after two and six months from the first visit. All the lesions were clinically and dermoscopically documented with a digital camera and we used the LSR (local skin reaction) grading scale based on a 0-4 numerical index of severity with specific clinical parameters and a characteristic photographic image for each rating, to assess the local side effects related to the therapy.

Topics: Administration, Cutaneous; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Basal Cell; Dermoscopy; Diterpenes; Female; Gels; Humans; Male; Middle Aged; Photography; Skin Neoplasms; Time Factors; Treatment Outcome

The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement.. Hairless mice (n=150; 6 groups á 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5days prior to IngMeb, as well as 6h and 1day post treatment. Tumor formation was evaluated weekly for 52weeks. LSR (scale 0-24) were assessed at baseline, 1h, 6h, 1-, 2-, 3-, 4-, 5-, 6-, and 7days after each IngMeb treatment.. IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR+IngMeb day 189; p=0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1-5: 1.5-2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR+IngMeb 1.8; p<0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r(2)=0.257, p<0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1-5: UVR+CP+IngMeb 3.2-4.9 vs. UVR+IngMeb 1.3-2.2, p<0.001) and postponed tumor development compared to IngMeb alone (UVR+CP+IngMeb day 217 vs. UVR+IngMeb day 189, p<0.001).. Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans.

Topics: Animals; Carcinogenesis; Carcinoma, Squamous Cell; Diterpenes; Female; Mice; Mice, Hairless; Pigmentation; Skin; Skin Neoplasms; Ultraviolet Rays

Actinic keratoses (AKs) are defined as cutaneous areas of atypical squamous transformation that are regarded as an early step in the continuum of alterations leading from normal skin to invasive and metastatic squamous cell carcinoma (SCC). AKs are classified as precancerous lesions by some authors and in situ SCC by others. The rate of evolution of a given AK to an invasive SCC has been estimated as 0·075-0·096% per lesion per year. These rates are similar to those estimated for gynaecological intraepithelial neoplasia. We describe two cases of SCC with rapid onset that developed after the application of ingenol mebutate gel for the treatment of AKs.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Dermatologic Agents; Diterpenes; Drug Eruptions; Facial Dermatoses; Facial Neoplasms; Female; Head and Neck Neoplasms; Humans; Keratosis, Actinic; Skin Neoplasms

Actinic keratoses (AKs) are premalignant skin lesions caused by cumulative ultraviolet-light exposure that may progress to invasive squamous cell carcinoma (SCC). As the clinical presentation of AKs varies widely, only a histopathologic analysis of a biopsied sample can eliminate or confirm a diagnosis of invasive SCC. Reducing the burden of AK with a combination of lesion-directed and field-directed treatments may help to identify persistent, suspicious lesions that require further evaluation. We present 10 cases of SCC that were identified and histologically confirmed in 7 patients after complete or substantial clearance of AKs by sequential treatment of sun-damaged skin with cryosurgery and ingenol mebutate.

Topics: Aged; Antineoplastic Agents; Biopsy; Carcinoma, Squamous Cell; Combined Modality Therapy; Cryosurgery; Diterpenes; Facial Neoplasms; Female; Gels; Humans; Keratosis, Actinic; Male; Middle Aged; Scalp; Skin; Skin Neoplasms

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.

Topics: Antineoplastic Agents; Benzoates; Cell Death; Cytokines; Diterpenes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Keratosis, Actinic; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Protein Kinase C-delta; Protein Kinase Inhibitors; Skin Neoplasms; Structure-Activity Relationship

Ingenol mebutate is a novel cytotoxic drug extracted from the plant Euphorbia peplus. Since November 2012 it is approved in Germany for the treatment of superficial actinic keratoses. We report the successful treatment of Bowen disease with ingenol mebutate in a patient being treated with the multikinase inhibitor sunitinib for to metastatic clear cell renal carcinoma.

Topics: Aged; Antineoplastic Agents; Bowen's Disease; Diterpenes; Humans; Male; Skin Neoplasms

Ingenol mebutate is the active ingredient in Picato® a new drug for the treatment of actinic keratosis. A number of derivatives related to ingenol mebutate were prepared by chemical synthesis from ingenol with the purpose of investigating the SAR and potency in assays relating to pro-inflammatory effects (induction of PMN oxidative burst and keratinocyte cytokine release), the potential of cell death induction, as well as the chemical stability. By modifications of the ingenol scaffold several prerequisites for activity were identified. The chemical stability of the compounds could be linked to an acyl migration mechanism. We were able to find analogues of ingenol mebutate with comparable in vitro properties. Some key features for potent and more stable ingenol derivatives have been identified.

Topics: Antineoplastic Agents; Apoptosis; Cell Line; Diterpenes; Humans; Interleukin-8; Keratinocytes; Keratosis, Actinic; Leukocytes, Mononuclear; Melanoma; Oxidative Stress; Reactive Oxygen Species; Skin Neoplasms; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

Topics: Aminoquinolines; Carcinoma, Squamous Cell; Case Management; Clinical Trials as Topic; Cryosurgery; Diagnosis, Differential; Diclofenac; Disease Management; Disease Progression; Diterpenes; Fluorouracil; Humans; Imiquimod; Italy; Keratosis, Actinic; Laser Therapy; Neoplasms, Radiation-Induced; Photochemotherapy; Practice Guidelines as Topic; Skin Neoplasms; Sunscreening Agents; United Kingdom; United States; Watchful Waiting

Ingenol mebutate has recently been approved by the Federal Drug Administration (USA) as a topical treatment for actinic keratoses. Herein, we describe the efficacy of ingenol mebutate for the topical treatment of squamous cell carcinoma (SCC) using a wild-type mouse model (SKH1) and the UV-induced mouse SCC cell line, T7. Daily treatment for 2 days with 0.25 % ingenol mebutate gel produced a cure rate of 70 %, with 0 % for placebo gel. Electron microscopy revealed swelling of cancer cell mitochondria within 1 h, with disruption of the inner mitochondrial membranes evident at 6 h post treatment. Primary necrosis of cancer cells was clearly evident by 24 h. Treatment was associated with local haemorrhage and a prodigious neutrophil infiltrate, with anti-T7 antibodies also detected. This is the first report of the successful treatment of SCC tumours with ingenol mebutate gel in wild-type mice, and supports the view that ingenol mebutate induces primary necrosis and activates the immune system.

Topics: Administration, Cutaneous; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Diterpenes; Female; Gels; Male; Mice; Mice, Hairless; Microscopy, Electron; Mitochondria; Mitochondrial Swelling; Necrosis; Neutrophil Infiltration; Skin Neoplasms; Time Factors

Actinic keratosis (AK) is a common ultraviolet light-induced skin lesion found on sun-exposed skin areas generally in older, fair-skinned people. It is part of a disease continuum observed in photodamaged skin that may lead to invasive squamous cell carcinoma. The presence of AK is associated with an increased risk of all skin cancers, as it is visible evidence of the carcinogenic effects of cumulative ultraviolet exposure. AKs are treated with lesion- and field-directed methods. Field-directed methods treat both the visible and subclinical lesions present in photodamaged skin, but treatment regimens are often lengthy and associated with poor tolerability because of vigorous local inflammatory reactions. Ingenol mebutate gel was recently approved by the Food and Drug Administration for topical treatment of AK. It induces cell death preferentially in transformed keratinocytes and promotes an inflammatory response that kills remaining tumor cells. In human studies, ingenol mebutate achieved high clearance rates of AK on the trunk or extremities and face or scalp after once-daily application for 2 or 3 consecutive daily treatments, when measured by complete or partial clearance of lesions. The localized inflammatory skin responses were generally mild to moderate and resolved in approximately 2 weeks on the face or scalp and 4 weeks on the trunk or extremities.

Topics: Aged; Clinical Trials as Topic; Diterpenes; Female; Humans; Keratinocytes; Keratosis, Actinic; Male; Skin; Skin Neoplasms

Skin cancer is the most prevalent cancer worldwide and is primarily caused by chronic UV exposure. Here, we describe the topical field-directed treatment of SKH1/hr mice with UVB-damaged skin with ingenol mebutate, a new topical drug shown to be effective for the treatment of actinic keratosis (AK). Application of 0.05% ingenol mebutate gel to photo-damaged skin resulted in a ≈70% reduction in the number of skin lesions that subsequently emerged compared with placebo treatment. Ingenol mebutate treatment also reduced the number of mutant p53 keratinocyte patches by ≈70%. The treatment resulted in epidermal cell death, acute inflammation, recruitment of neutrophils, hemorrhage, and eschar formation, all of which resolved over several weeks. Ingenol mebutate field-directed treatment might thus find utility in the removal of subclinical precancerous cells from UV-damaged skin. Field-directed treatment may be particularly suitable for patients who have AKs surrounded by UV-damaged skin.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Keratinocytes; Keratosis, Actinic; Male; Mice; Mice, Hairless; Mutation; Neoplasms, Radiation-Induced; Precancerous Conditions; Skin; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays

The incidence of nonmelanoma skin cancer continues to increase. While surgical excision remains the mainstay of treatment, growing demand from patients for effective, tissue-sparing approaches with good cosmetic results has led to the development of novel therapeutic agents. Several studies have reported on the safety and efficacy of topical ingenol mebutate gel, a derivative of the plant Euphorbia peplus, in the treatment of actinic keratosis and superficial basal cell carcinoma. An understanding of the history, mechanism of action, and recent trial evidence for this emerging therapy can assist physicians in counseling patients on available treatment options and in selecting appropriate therapy.

Topics: Administration, Cutaneous; Antineoplastic Agents, Phytogenic; Carcinoma, Basal Cell; Diterpenes; Euphorbia; Humans; Keratosis, Actinic; Skin Neoplasms

Ingenol mebutate is a diterpene ester derived from the plant Euphorbia peplus and is FDA approved for the topical treatment of actinic keratoses (AK). Shown to be efficacious with as little as a 3-day trial, this compound is being further tested for the topical treatment of other nonmelanoma skin cancers with promising preclinical data. In an effort to elucidate the molecular mechanism of this novel drug, Stahlhut et al. (2012) suggest a role for calcium and apoptosis. Further studies are needed to evaluate the intracellular mechanisms of ingenol mebutate-mediated cytotoxicity. Additionally, studies such as this not only shed light on the mechanism of ingenol mebutate and its derivatives, but also pave the way for evaluating the involvement of the immune system in eliminating drug-treated cells and tissues. This has important implications for the development of novel topical immune modulatory products and the field of topical immunotherapy.

Topics: Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Diterpenes; Humans; Immunologic Factors; Keratosis, Actinic; Signal Transduction; Skin Neoplasms

Topics: Aminoquinolines; Antineoplastic Agents; Carcinoma, Squamous Cell; Cryotherapy; Diterpenes; Humans; Imiquimod; Keratosis, Actinic; Photochemotherapy; Skin Neoplasms

Ingenol-3-angelate (Ing3A), extracted from Euphorbia peplus, is currently in clinical trials for eradicating basal cell carcinoma, actinic keratosis, and squamous cell carcinoma (SCC) in situ by topical application. Although structurally related to phorbol esters and a protein kinase C activator, topical Ing3A, but not phorbol 12-myristate 13-acetate (PMA), inhibited the growth of subcutaneous tumors derived from PAM212 (mouse SCC) and B16 (mouse melanoma). Ing3A and PMA both induced acute neutrophilic inflammation on mouse skin, but only Ing3A caused subcutaneous hemorrhage and vascular damage. Both Ing3A and PMA activated extracellular signal-regulated kinase 1/2 (ERK1/2) in epidermis, but Ing3A also activated ERK1/2 in skin dermal fibroblasts and endothelial cells. Pretreatment with topical cyclosporin A (CsA), verapamil, or XR9576, modulators of P-glycoprotein (P-gp), prevented Ing3A-induced hemorrhage but not neutrophil infiltration. CsA also impaired the anticancer activity of Ing3A, whereas the anti-inflammatory dexamethasone did not. Ing3A, but not PMA, blocked photoaffinity labeling of human P-gp with [(125)I]iodoaryazidoprazosin and inhibited P-gp-mediated drug resistance to HCT-15 cells. The intracellular levels of Ing3A were significantly lower in P-gp-expressing cells, and treatment with XR9576 increased the levels to those of cells that do not express P-gp, showing that Ing3A binds to and is transported by P-gp. Taken together, our results suggest that P-gp-mediated absorptive transport, dermal penetration, and vascular damage contribute to the anticancer activity of Ing3A in vivo.

Topics: Administration, Topical; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Squamous Cell; Cell Line, Tumor; Diterpenes; Drug Eruptions; Enzyme Activation; Humans; Keratinocytes; Melanoma, Experimental; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Protein Binding; Protein Kinase C; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate

The sap of Euphorbia peplus, commonly know as 'petty spurge', 'radium weed' or 'milkweed' has been used for centuries as a traditional treatment for skin conditions, including warts, corns and cancers of the skin. Documentation of its use by medical professionals to treat basal cell carcinoma (BCC) dates from the early 19 century. Individuals who participated in a 1988 survey of home treatments for cancer indicated the sap of E. peplus was an effective cure for actinic lesions leading the investigators to suggest that this potential utility should be further explored in controlled clinical trials. The fractionation of the sap E. peplus using solvents of varying polarity yielded several macrocyclic diterpenes, many of which were found to have cytotoxic activity or the ability to influence cellular differentiation. Ultimately, ingenol 3-angelate (I3A) of PEP005, emerged as a promising potential new anti-cancer treatment. Here we report the proceedings from the First International Conference on PEP005, covering the exciting potential of PEP005 as the therapeutic agent for the treatment of skin cancer, leukemia and bladder cancer.

Topics: Administration, Topical; Animals; Antineoplastic Agents, Phytogenic; Diterpenes; Esters; Humans; Leukemia; Melanoma; Mice; Neoplasms; Skin Neoplasms; Urinary Bladder Neoplasms

Harnessing neutrophils for the eradication of cancer cells remains an attractive but still controversial notion. In this study, we provide evidence that neutrophils are required to prevent relapse of skin tumors following topical treatment with a new anticancer agent, ingenol-3-angelate (PEP005). Topical PEP005 treatment induces primary necrosis of tumor cells, potently activates protein kinase C, and was associated with an acute T cell-independent inflammatory response characterized by a pronounced neutrophil infiltrate. In Foxn1(nu) mice depleted of neutrophils and in CD18-deficient mice (in which neutrophil extravasation is severely impaired) PEP005 treatment was associated with a >70% increase in tumor relapse rates. NK cell or monocyte/macrophage deficiency had no effect on relapse rates. Both in vitro and in mice, PEP005 induced MIP-2/IL-8, TNF-alpha, and IL-1beta, all mediators of neutrophil recruitment and activation. In vitro, PEP005 activated human endothelial cells resulting in neutrophil adhesion and also induced human neutrophils to generate tumoricidal-reactive oxygen intermediates. Treatment of tumors with PEP005 significantly elevated the level of anticancer Abs, which were able to promote neutrophil-mediated Ab-dependent cellular cytotoxicity (ADCC) in vitro. PEP005 treatment of tumors grown in SCID mice was also associated with >70% increase in tumor relapse rates. Taken together, these data suggest a central role for neutrophil-mediated ADCC in preventing relapse. PEP005-mediated cure of tumors therefore appears to involve initial chemoablation followed by a neutrophil-dependent ADCC-mediated eradication of residual disease, illustrating that neutrophils can be induced to mediate important anticancer activity with specific chemotherapeutic agents.

Topics: Administration, Topical; Animals; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Diterpenes; Esters; Humans; Mice; Necrosis; Neutrophil Activation; Neutrophil Infiltration; Neutrophils; Protein Kinase C; Skin; Skin Neoplasms; T-Lymphocytes

Ingenol 3-angelate (PEP005), one of the active ingredients in an extract from Euphorbia peplus, was shown in preclinical studies to have activity against human melanoma xenografts in nude mice. In the present study, we have tested its ability to induce the apoptosis of melanoma cells in vitro in the absence or presence of tumor necrosis factor-related apoptosis inducing ligand (TRAIL). The results showed that at relatively high concentrations (100 microg/mL), PEP005 killed melanoma cells mainly by induction of necrosis. In 20% of cell lines, evidence of apoptosis was observed. Apoptosis was caspase-dependent and associated with changes in mitochondrial membrane potential that were not inhibitable by overexpression of Bcl-2 or inhibition of caspases but were blocked by inhibition of protein kinase C (PKC). Low concentrations (1 or 10 microg/mL) of PEP005 either increased or decreased TRAIL-induced apoptosis in a cell line-dependent manner. These changes in TRAIL-induced apoptosis seemed to be due to activation of PKC and varying levels of PKC isoenzymes in different melanoma cell lines. PEP005-mediated enhancement of apoptosis seemed to be associated with low expression of the PKCepsilon isoform. These results indicate that PEP005 may enhance or inhibit sensitivity of melanoma to treatments associated with TRAIL-induced apoptosis depending on the PKC isoform content of melanoma cells.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Caspases; Diterpenes; Enzyme Activation; Esters; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Membrane Glycoproteins; Membrane Potentials; Mitochondria; Protein Kinase C; Protein Kinase C-epsilon; Proto-Oncogene Proteins c-bcl-2; Skin Neoplasms; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha