Ross StC Barnetson

DNAzyme targeting c-jun suppresses skin cancer growth

Catalytic DNA molecules that target the transcription factor c-jun inhibit skin cancer growth in mice. Getting Under Cancer’s Skin Summer brings to mind barbecues, baseball, and trips to the local pool. Yet, outdoor fun can be hazardous to one’s health—too much sun exposure can increase the risk of developing skin cancer. Indeed, one in three cancers worldwide is skin-related, and currently available treatments may induce scarring or other toxicities. Cai et al. now report that the DNAzyme Dz13—which targets an mRNA that encodes a cancer-associated transcription factor, c-Jun—inhibits the growth of two common types of skin cancers: basal cell and squamous cell carcinomas. DNAzymes are single-stranded, all-DNA, catalytic molecules that specifically bind and cleave their target RNAs. The authors examined the effects of Dz13, which destroys c-jun mRNA, on animal models of skin cancer. Dz13 inhibited tumor growth, blocked neovascularization, and prevented metastasis in mouse models of skin cancer—effects that were mediated, in part, through the induction of antitumor immunity. Minimal toxicity was observed in Dz13-treated cynomolgus monkeys, minipigs, and rodents, and there were no off-target effects in more than 70 in vitro bioassays. Thus, Dz13 may prove to be a safe, effective therapy for skin cancer. Nonetheless, one is advised to pack the sun block in preparation for extra innings—or a fifth set. Worldwide, one in three cancers is skin-related, with increasing incidence in many populations. Here, we demonstrate the capacity of a DNAzyme-targeting c-jun mRNA, Dz13, to inhibit growth of two common skin cancer types—basal cell and squamous cell carcinomas—in a therapeutic setting with established tumors. Dz13 inhibited tumor growth in both immunodeficient and immunocompetent syngeneic mice and reduced lung nodule formation in a model of metastasis. In addition, Dz13 suppressed neovascularization in tumor-bearing mice and zebrafish and increased apoptosis of tumor cells. Dz13 inhibition of tumor growth, which required an intact catalytic domain, was due in part to the induction of tumor immunity. In a series of good laboratory practice–compliant toxicology studies in cynomolgus monkeys, minipigs, and rodents, the DNAzyme was found to be safe and well tolerated. It also did not interfere in more than 70 physiologically relevant in vitro bioassays, suggesting a reduced propensity for off-target effects. If these findings hold true in clinical trials, Dz13 may provide a safe, effective therapy for human skin cancer.

Childhood atopic eczema

Atopic eczema is a common condition that affects more than one in ten children in developed countries, and the incidence is increasing. There are probably several reasons for this, including higher exposure to air pollution, smaller families with less exposure to infections, more pets, higher maternal age, and a wider range of foods. There is clearly also an important hereditary component to atopic eczema. This is complex because not all affected children are atopic, though the genes implicated in atopy are likely to be involved, together with others as yet unknown. Atopic eczema usually presents during the first year of life, and when it is severe it is extremely disabling. It may also cause major psychological problems. Most affected children are also allergic to house dust mite, and this is probably a major cause of exacerbation of the condition. Probably less than 10% overall have IgE mediated food allergy, but some have late phase reactions with positive results on patch tests to foods. #### Summary points Atopic eczema in children is a complex condition Four in five children with atopic eczema have IgE mediated allergy to inhalants or foods House dust mite exacerbates atopic eczema Food allergy exacerbates eczema in less than one in ten children To reduce the need for admission to hospital children with severe eczema can be treated with topical or oral immunosuppression We searched Medline for entries on atopic eczema and atopic dermatitis in children and adults. We also relied on our personal experience in treating children with atopic eczema over the past 30 years. Atopic eczema is usually the first manifestation of atopy and may coincide with food allergy; asthma often follows, then allergic rhinitis (fig 1). Fig 1. Incidence of different types of atopy by age (adapted with permission from W B Saunders1) There is a …

TEA TREE OIL IN THE TREATMENT OF TINEA PEDIS

Tea tree oil (an essential oil derived primarily from the Australian native Melaleuca alternifolia) has been used as a topical antiseptic agent since the early part of this century for a wide variety of skin infections; however, to date, the evidence for its efficacy in fungal infections is still largely anecdotal. One hundred and four patients completed a randomized, double‐blind trial to evaluate the efficacy of 10% w/w tea tree oil cream compared with 1% tolnaftate and placebo creams in the treatment of tinea pedia. Significantly more tolnaftate‐treated patients (85%) than tea tree oil (30%) and placebo‐treated patients (21%) showed conversion to negative culture at the end of therapy (p◂0.001); there was no statistically significant difference between tea tree oil and placebo groups. All three groups demonstrated improvement in clinical condition based on the four clinical parameters of scaling, inflammation, itching and burning. The tea tree oil group (24/37) and the tolnaftate group (19/33) showed significant improvement in clinical condition when compared to the placebo group (14/34; p = 0.022 and p = 0.018 respectively). Tea tree oil cream (10% w/w) appears to reduce the symptomatology of tinea pedis as effectively as tolnaftate 1% but is no more effective than placebo in achieving a mycological cure. This may be the basis for the popular use of tea tree oil in the treatment of tinea pedis.

Cytokine profiles in spontaneously regressing basal cell carcinomas

Background Basal cell carcinomas (BCCs) can cause considerable morbidity due to their ability to enlarge progressively and to destroy underlying tissues. However, some BCCs may undergo spontaneous regression in the absence of therapy capable of inducing antineoplastic effects. Histological criteria for this process have been described, and previous studies have suggested that it may be mediated by infiltrating activated CD4‐positive T cells. Objectives The purpose of this study was to compare the expression of cytokines in actively regressing and non‐regressing BCCs, to ascertain if active regression is associated with a particular cytokine profile. Methods Reverse transcriptase–polymerase chain reaction, a sensitive, quantitative technique allowing analysis of multiple cytokines from small tumour samples, was used. Results Interferon (IFN)‐γ was significantly elevated in actively regressing BCCs compared with non‐regressing BCCs. Furthermore, interleukin (IL)‐2, tumour necrosis factor (TNF)‐β and CD3δ tended to be elevated in actively regressing tumours, although not to statistically significant levels. IFN‐γ, IL‐2, IL‐10, TNF‐β, granulocyte‐macrophage colony‐stimulating factor and Fas ligand showed strong positive correlations with CD3δ, indicating an association between infiltrating T cells and these cytokines. Conclusions These findings support a role for T‐helper 1 type cytokines in mediating spontaneous regression of BCCs.

Treatment of interdigital tinea pedis with 25% and 50% tea tree oil solution: a randomized, placebo-controlled, blinded study

Tea tree oil has been shown to have activity against dermatophytes in vitro. We have conducted a randomized, controlled, double‐blinded study to determine the efficacy and safety of 25% and 50% tea tree oil in the treatment of interdigital tinea pedis. One hundred and fifty‐eight patients with tinea pedis clinically and microscopy suggestive of a dermatophyte infection were randomized to receive either placebo, 25% or 50% tea tree oil solution. Patients applied the solution twice daily to affected areas for 4 weeks and were reviewed after 2 and 4 weeks of treatment. There was a marked clinical response seen in 68% of the 50% tea tree oil group and 72% of the 25% tea tree oil group, compared to 39% in the placebo group. Mycological cure was assessed by culture of skin scrapings taken at baseline and after 4 weeks of treatment. The mycological cure rate was 64% in the 50% tea tree oil group, compared to 31% in the placebo group. Four (3.8%) patients applying tea tree oil developed moderate to severe dermatitis that improved quickly on stopping the study medication.

Photodynamic therapy with methyl aminolevulinate for primary nodular basal cell carcinoma: results of two randomized studies

Background  Data suggest that photodynamic therapy using topical methyl aminolevulinate (MAL PDT) may be a noninvasive alternative to excisional surgery for nodular basal cell carcinoma (BCC). In the studies described here, we investigated the histologic response, tolerability, and cosmetic outcome with MAL PDT for primary nodular BCC (≤ 5 mm in depth).

The suppression of immunity by ultraviolet radiation: UVA, nitric oxide and DNA damage

We have examined the mechanism by which solar-simulated ultraviolet radiation (ssUV) suppresses memory immunity to nickel in allergic humans. In initial studies, we used inbred mice to determine the contribution of different wavebands to sunlight-induced immunosuppression. We found that low dose UVA can enhance memory, medium dose UVA (half the amount in one minimum erythemal dose of ssUV) is immunosuppressive, but higher doses protect from UVB. This is genetically dependent, as it is not observed in all mouse strains. UVA caused a similar dose-related change in recall immunity in humans. ssUV dose responses determined the limits of protection provided by sunscreens from immunosuppression in humans. Immune protection factors calculated from these data correlated with UVA protection, but not with sun protection factor, showing that in commercial sunscreens that provide good UVB protection, UVA protection limits prevention of immunosuppression. N(G)-monomethyl-l-arginine acetate (l-NMMA) was used to inhibit nitric oxide (NO) production and T4N5 liposomes containing T4 endonuclease V to enhance DNA repair. Sub-erythemal ssUV caused a dose-related local suppression of recall immunity to nickel in humans. l-NMMA and the liposomes protected the nickel reaction, suggesting that NO and DNA damage are mediators of UV-induced immunosuppression in humans.

UV-A Fingerprint Mutations in Human Skin Cancer¶

This review of our work, presented at the Photocarcinogenesis Symposium of the 14th International Congress on Photobiology, shows that UV‐A causes a similar number of gene mutations as UV‐B in human skin cancer. Areas of about 20 keratinocytes from solar keratoses and squamous cell carcinomas, which are benign and malignant skin cancers, respectively, were sampled by laser capture microdissection. Automated sequencing of the p53 gene was used to detect mutations in these tumor areas, and the cause of the mutations was attributed on the basis of previously published studies. UV‐A and UV‐B caused similar numbers of p53 gene mutations in both benign and malignant human skin tumors, with UV‐B–induced mutations being restricted to the upper areas of the tumors and UV‐A–induced mutations predominating at the basal layer. Furthermore, each microdissected region within a tumor had distinct mutations showing that the skin tumors consisted of different clones of cells. This is not consistent with how human skin carcinogenesis is currently understood, and hypotheses to explain our data are presented. We propose that the UV‐A waveband of sunlight is as important as UV‐B in causing skin cancer in humans.

Dendritic epidermal T‐cell involvement in induction of CD8+ T cell‐mediated immunity against an ultraviolet radiation‐induced skin tumor

Murine epidermis contains 2 distinct cell populations which contribute to the skin immune system, Langerhans cells (LC), and dendritic epidermal T cells (DETC). LCs are important in the induction of immunity against a wide range of antigens; however, the function of DETC is unclear. To investigate the roles of these epidermal cells (EC) in protective antitumor immunity, an in vivo model of an ultraviolet radiation‐induced fibrosarcoma, UV‐13‐1, was used. Mice were immunized with tumor antigen‐pulsed EC followed 10 days later by an injection into the ear of 105 tumor cells, which did not lead to formation of a detectable tumor, but was intended to simulate the influence of a developing tumor on the ensuing immune response. The mice were then challenged with 2 × 106 viable tumor cells in each flank, sufficient to result in growth of a measurable tumor. Protective immunity was induced by DETC, and shown to be long‐lasting, with tumors inoculated 160 days after immunization being effectively rejected. The effector cells responsible for protective immunity were CD8+ T cells. Delayed‐type hypersensitivity generated by tumor antigen‐pulsed EC was dependent on Lcs, with no involvement of DETCs. This response, in contrast to that of DETC, required prior culture of EC with GM‐CSF, but failed to inhibit tumor growth or incidence. Thus DETC and LC can both activate antitumor immune responses, although only the DETC‐dependent response results in protective immunity in the presence of a developing tumor.

Pravastatin-induced lichenoid drug eruption.

A 64‐year‐old woman presented with diffuse and numerous pigmented macules on her face and upper back. Histopathological examination of a skin punch biopsy of the rash showed a lichenoid dermatitis. The most likely offending drug was pravastatin. Cessation of pravastatin resulted in gradual fading of the pigmentation. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors have previously been reported to cause lichenoid drug eruptions.