David R. Bickers

Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome.

BACKGROUND Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

Topical capsaicin treatment of chronic postherpetic neuralgia

Uncontrolled studies have indicated that topically applied capsaicin may be a safe and effective treatment for postherpetic neuralgia. In a double-blind study 32 elderly patients with chronic postherpetic neuralgia were treated with either capsaicin cream or its vehicle for a 6-week period. Response to treatment was evaluated by visual analogue scales of pain and of pain relief, together with changes in a categoric pain scale and in a physicians global evaluation. Significantly greater relief in the capsaicin-treated group compared with vehicle was observed for all efficacy variables. After 6 weeks almost 80% of capsaicin-treated patients experienced some relief from their pain. Because capsaicin avoids problems with drug interactions and systemic toxicity, we suggest that topical capsaicin be considered for initial management of postherpetic neuralgia.

Antimutagenic activity of green tea polyphenols

For centuries green tea has been a widely consumed beverage throughout the world. It is known to contain a number of pharmacologically active compounds. In this study water extracts of green tea (WEGT) and their major constituents, green tea polyphenols (GTP), were examined for antimutagenic activity. WEGT and GTP were found to significantly inhibit the reverse mutation induced by benzo[alpha]pyrene (BP), aflatoxin B1 (AFB1), 2-aminofluorene, and methanol extracts of coal tar pitch in Salmonella typhimurium TA100 and/or TA98 in the presence of a rat-liver microsomal activation system. GTP also inhibited gene forward mutation in V79 cells treated with AFB1 and BP, and also decreased the frequency of sister-chromatid exchanges and chromosomal aberrations in V79 cells treated with AFB1. The addition of GTP during and after nitrosation of methylurea resulted in a dose-dependent inhibition of mutagenicity. Studies to define the mechanism of the antimutagenic activity of GTP suggest that it may affect carcinogen metabolism, DNA adduct formation, the interaction of ultimate carcinogen or the scavenging of free radicals.

Porphyria cutanea tarda. Clinical features and laboratory findings in 40 patients.

Porphyria cutanea tarda is the most common disorder of porphyrin metabolism in the United States and Europe. This report presents the clinical, laboratory and pathologic features of 40 patients with porphyria cutanea tarda. Each patient was followed up for variable times during 1960-76 at the Clinical Research Center and the Dermatology Service of the Columbia-Presbyterian Medical Center; at the New York University Medical Center; or at the Rockefeller University Hospital. Earlier age at onset; diminution of alcohol ingestion as the major etiologic factor; and, an increased incidence in females indicate new environmental influences. The most frequently associated etiologic factor, aside from alcohol intake, was use of estrogens for contraception; postmenopausal syndrome; or treatment of prostatic carcinoma. Cutaneous findings in the patients included bullae (85%); increased skin fragility (75%); facial hypertrichosis (63%); hyperpigmentation (55%); sclerodermoid changes (18%); and, dystrophic calcification with ulceration (8%). Diabetes mellitus was found in 15%; systemic lupus erythematosus in 5%; elevated serum iron level in 62%; and, abnormal liver function test results in 60%. Histologic abnormalities were seen in liver biopsies of 34 patients. Phlebotomy is the treatment of choice. In 32 patients so treated, clinical remissions averaged 30.9 months. 31% (10 patients) had a relapse but additional phlebotomies resulted in 2nd remissions. Chloroquine and plasmaphoresis treatments were also briefly discussed.

Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis

Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces (∼66%) UVBinduced basal cell carcinoma formation in Ptch1+/− mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1+/− mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis.

Cyclooxygenase-2 Expression in Murine and Human Nonmelanoma Skin Cancers: Implications for Therapeutic Approaches¶

Abstract Inflammatory stimuli result in the production of cutaneous eicosanoids, which are known to contribute to the process of tumor promotion. Cyclooxygenase (COX), the rate-limiting enzyme for the production of prostaglandins (PG) from arachidonic acid, exists in at least two isoforms, COX-1 and COX-2. COX-1 is constitutively expressed in most tissues and plays various physiological roles, whereas increased COX-2 expression is known to occur in several types of epithelial neoplasms. Enhanced PG synthesis is a potential contributing factor in UVB-induced nonmelanoma skin cancers (NMSC). Increased COX-2 staining occurs in murine skin neoplasms after chronic exposure to carcinogenic doses of UVB. In this study, immunohistochemical and Western blot analyses were employed to assess longitudinally COX-2 expression in a standard mouse UVB complete carcinogenesis protocol and in human basal cell carcinomas (BCC) and squamous cell carcinomas (SCC). During UVB irradiation of mice, COX-2 expression consistently increased in the hyperplastic skin, the benign papillomas and the SCC. COX-2 expression was also increased in human actinic keratoses, SCC and BCC as well as in murine SCC and BCC. The pattern of COX-2 expression was quite variable, occurring in a patchy distribution in some lesions with staining confined mainly to suprabasal cell layers. In general, COX-2 expression progressively became more extensive in benign papillomas and well-differentiated murine SCC. The staining was predominantly cytoplasmic and perinuclear in some focal areas in tissue stroma around both murine and human tumors. Western blot analysis confirmed negative COX-2 expression in normal skin, whereas acute UVB exposure resulted in increased enzyme expression, which continued to increase in developing papillomas and SCC. Because of the evidence indicating a pathogenic role for eicosanoids in murine and human skin neoplasms, we performed studies to assess the anti-inflammatory and anticarcinogenic effects of green tea extracts, which are potent antioxidants. Acute exposure of the human skin to UVB (minimum erythema dose × 4) caused a transient enhancement of the COX-2 expression, which reverted to baseline within hours; however, in murine skin the expression persisted for several days. Pretreatment with the topically applied green tea extract (1 mg/cm2) largely abrogated the acute COX-2 response to UVB in mice or humans. In summary, enhanced COX-2 expression serves as a marker of epidermal UVB exposure for murine and human NMSC. These results suggest that COX-2 inhibitors could have potent anticarcinogenic effects in UVB-induced skin cancer.

Cyclooxygenases in the skin: pharmacological and toxicological implications

Cyclooxygenase (COX), a prostaglandin-endoperoxide synthase (PTGS), catalyzes the formation of prostaglandins from arachidonic acid. Prostaglandins are lipid signaling mediators that play a central role in a broad range of diverse physiological and pathophysiological processes, including inflammation, reproduction, nocioception, and gastrointestinal protection. Inhibition of cyclooxygenase activity is the mechanism by which nonsteroidal antiinflammatory drugs (NSAIDS) exert their analgesic, antipyretic, antiinflammatory, and antithrombotic effects. COX is currently believed to exist in three isoforms. In this review, we provide a concise state-of-the-art description of the role of COX in pharmacology and toxicology of skin including its involvement in normal physiology, cutaneous inflammation, nociception, wound healing, and tumorigenesis. COX-dependent pathways influence keratinocyte differentiation, hair follicle development, and hair growth. The critical role of COX-2 in pathophysiology of skin is also addressed. COX-2 mediates inflammatory processes in skin, including inflammatory hyperalgesia and nociception, and administration of specific COX-2 inhibitors reduces edema, vascular permeability, and other markers of cutaneous inflammation. A number of studies in animal models and in humans show that COX-2 inhibitors possess cancer chemopreventive properties. Selective COX-2 inhibitors have a more favorable side-effect profile. Topical formulations of COX-2 inhibitors are being developed as a novel pharmacologic approach for the treatment of COX-2 mediated skin diseases.

A toxicologic and dermatologic assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredients ☆

University of Missouri (Kansas City), c/o American Dermatology Associates, LLC, 6333 Long Avenue, Third Floor, Shawnee, KS 66216, USA Columbia University Medical Center, Department of Dermatology, 161 Fort Washington Avenue, New York, NY 10032, USA Malmo University Hospital, Department of Occupational and Environmental Dermatology, Sodra Forstadsgatan 101, Entrance 47, Malmo SE-20502, Sweden d Institute for Miliovurdering, Environmental Assessment Institute, Linnesgade 18, 1st Floor, Copenhagen 1361K, Denmark e Technical University of Munich, Institute for Toxicology and Environmental Hygiene, Hohenbachernstrasse 15-17, Freising-Weihenstephan D-85354, Germany Oregon Health Sciences University, Department of Dermatology L468, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA Boston University School of Medicine, Department of Pathology and Laboratory Medicine, 715 Albany Street, L-804, Boston, MA 02118-2526, USA Hospital Cantonal Universitaire, Clinique et Policlinique de Dermatologie, 24, Rue Micheli-du-Crest, Geneve 14 1211, Switzerland Department of Pharmacology, University of Arizona, College of Medicine, 1501 North Campbell Avenue, P.O. Box 245050, Tucson, AZ 85724-5050, USA 3-27-1 Kaigamori, Aoba-ku, Sendai 981-0942, Japan

Treatment of chronic postherpetic neuralgia with topical capsaicin. A preliminary study.

Continuing pain following herpes zoster is common in patients 60 years of age or older. Current treatments are generally unsatisfactory. The endogenous neuropeptide substance P is an important chemomediator of nociceptive impulses from the periphery to the central nervous system and has been demonstrated in high levels in sensory nerves supplying sites of chronic inflammation. In an attempt to alleviate the pain of 14 patients with postherpetic neuralgia, capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), known to deplete substance P, was applied topically to painful areas of skin for 4 weeks. Of the 12 patients completing this preliminary study, 9 (75%) experienced substantial relief of their pain. The only adverse reaction was an intermittent, localized burning sensation experienced by one patient with application of capsaicin. Although these results are preliminary, they suggest that topical application of capsaicin may provide a useful approach for alleviating postherpetic neuralgia and other syndromes characterized by severe localized pain.

Cutaneous lesions of dermatomyositis are improved by hydroxychloroquine

Dermatomyositis (DM) is a collagen vascular disease with prominent cutaneous findings. Although the myositis often responds to therapy with corticosteroids and/or immunosuppressives, the cutaneous disease may not respond. Seven patients with cutaneous lesions of DM that had not responded to therapy were treated with hydroxychloroquine in an open study. Three patients had idiopathic DM, one had DM without myositis, one had DM with malignancy, and one had adolescent DM. The response to the addition of hydroxychloroquine was good in all of the patients, and three had total resolution of their skin lesions. In two patients the corticosteroid dosage could be tapered. Therapy with hydroxychloroquine did not appear to have any beneficial effect on the myositis. We conclude that hydroxychloroquine may have a role as an adjuvant to the therapy of patients with cutaneous lesions of DM.