Novel approaches to chemoprevention of skin cancer.

Protection against sun-induced damage leading to photocarcinogenesis in skin is a highly desirable goal. Among various strategies, chemopreventive approaches utilizing non-toxic agents to prevent the occurrence of precancerous lesions or their surrogate markers are potentially attractive. Epidemiological and experimental studies provide evidence that some naturally occurring chemical agents in the human diet can diminish cancer risk. Aside from water, tea is the most common beverage consumed worldwide. Black tea accounts for nearly 80% of total tea production. Black tea and green tea are derived from the same plant, Camelia sinensis. Green tea contains monomeric polyphenols known as flavanols and black tea contains dimeric flavanols and polymeric polyphenols known as theaflavins (TFs) and thearubigins (TRs). Over the past fifteen years our laboratory has been exploring the feasibility of using tea and its constitutents as an approach to skin cancer prevention. We demonstrated that green tea, black tea and constituent polyphenols protect against chemical- and ultraviolet B (UVB)-induced carcinogenesis and reduce the growth of established tumors in skin. We have also shown the efficacy of green and black tea extracts against UVB and psoralen + ultraviolet A (PUVA)-induced early damage in skin. Although PUVA is highly effective in treating certain skin diseases, careful follow-up studies of cohorts of patients have shown that similar to UVB, PUVA treatment increases the risk for cutaneous squamous cell carcinoma and melanoma. We have found that oral administration of a standardized green tea extract (SGTE) prior to and during treatment of SKH-1 mice diminished PUVA-induced skin hyperplasia and hyperkeratosis. SGTE-treatment also inhibited PUVA-induced accumulation of c-fos and p53 proteins and epithelial hyperproliferation. Both topical application and oral administration of SGTE after PUVA-treatment reduced skin inflammation and cell hyperproliferation. Topical application of SGTE to human skin prior to PUVA-treatment inhibited the delayed skin inflammatory response. Similarly, oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic sub-fractions protect against UVB-induced erythema in SKH-1 mice. Furthermore, topical application of tea extracts to human volunteers protects against UVB-induced erythema. In summary, these studies indicate that tea extracts are effective in reducing UVB- and PUVA-mediated DNA damage, expression of early response genes and early inflammatory changes in skin. These studies verify a conceptual rationale for employing naturally occurring dietary constitutents as an approach to cancer chemoprevention.

Green tea protects against psoralen plus ultraviolet A-induced photochemical damage to skin.

The use of psoralens combined with exposure to ultraviolet A radiation is a major form of treatment for psoriasis and a number of other common skin diseases. Although psoralen plus ultraviolet A treatment is highly effective, careful follow-up cohort studies have shown that it greatly increases risk for the development of cutaneous squamous cell carcinoma and melanoma. Strategies to reduce the risk of cancer development in psoralen plus ultraviolet A-treated populations are highly desirable. In prior studies, we demonstrated that green tea and constituent polyphenols protect against ultraviolet B-induced carcinogenesis and reduce the growth rate of established tumors in skin. In this study, we show that pre- and post-treatment with standardized green tea extract in psoralen plus ultraviolet A treatment populations abrogates the psoralen plus ultraviolet A-induced photochemical damage to skin. Intact mouse and human skin and reconstituted human skin were employed to assess the effect of both topical and oral administration of standardized green tea extract against psoralen plus ultraviolet A-induced photodamage. Oral administration of standardized green tea extract prior to and during multiple psoralen plus ultraviolet A treatments reduced hyperplasia and hyperkeratosis in murine skin. Standardized green tea extract treatment also inhibited accumulation of c-fos and p53 protein induction following a single exposure to psoralen plus ultraviolet A. c-fos and p53 positive cells in psoralen plus ultraviolet A-treated skin were found to be increased by 55.4 +/- 13. 6% and 62.3 +/- 10.5%, respectively, compared with saline-treated unexposed control skin. Oral administration of 0.4 or 0.8% standardized green tea extract inhibited c-fos protein accumulation by 18.5% and 46.2% (p < 0.05), respectively, and p53 protein accumulation by 26.1% and 54.3% (p < 0.05), respectively. Similarly proliferating cell nuclear antigen staining, a marker of cell proliferation was induced (73.7%) in psoralen plus ultraviolet A-treated skin. Oral administration of 0.4% or 0.8% standardized green tea extract 1 d after psoralen plus ultraviolet A treatment was effective in reducing psoralen plus ultraviolet A-induced inflammatory responses including erythema and edema formation. When standardized green tea extract was applied to EpiDerm, a reconstituted human skin equivalent, psoralen plus ultraviolet A-induced 8-methoxypsoralen-DNA adduct formation and p53 protein accumulation were inhibited. Topical application of 0.2 mg 8-methoxypsoralen per cm2 followed by exposure to ultraviolet A (2.5 J per cm2) resulted in delayed erythema formation in human subjects. Pretreatment of human skin with topical application of 0.2 mg standardized green tea extract per cm2 30 min prior to psoralen plus ultraviolet A treatment resulted in an almost complete abrogation of psoralen plus ultraviolet A-induced erythema. In summary, these data demonstrate that standardized green tea extract protects against psoralen plus ultraviolet A-induced phototoxicity by inhibiting DNA damage and diminishing the inflammatory effects of this modality.

Photoprotective effect of black tea extracts against UVB-induced phototoxicity in skin.

In previous studies, we showed that green tea and black tea extracts and their major polyphenolic constituents protect against UVB light-induced carcinogenesis in murine skin. All of these studies required chronic administration of tea extracts or specific constituents either topically or orally. However, it is not known whether acute or subchronic administration of black tea extracts or constituents can ameliorate UVB-induced early effects in skin. In the present study, cultured keratinocytes and mouse and human skin were employed to assess the effect of both oral and topical administration of standardized black tea extract (SBTE) and its two major polyphenolic subfractions namely BTF1 and BTF2 against UVB-induced photodamage. In SKH-1 hairless mice, topical application of SBTE (0.2 mg/cm2) prior to UVB exposure (180 mJ/cm2) resulted in 40% reduced incidence and 64% reduced severity of erythema and 50% reduction in skinfold thickness by day 6 when compared to nontreated UVB-exposed animals. The SBTE was also effective in protecting against UVB-induced erythema in human volunteers. Administration of SBTE 5 min after UVB irradiation was similarly effective in reducing UVB-induced inflammation in both murine and human skin. The major polyphenolic subfractions, BTF1 and BTF2, were also effective in protecting in mouse skin. The SBTE subfractions inhibited UVB-induced tyrosine phosphorylation of epidermal growth factor receptor (EGFR). The UVB irradiation of human epidermoid carcinoma cells resulted in 3.3-fold induction of tyrosine phosphorylation of EGFR. Pretreatment with BTF1 and BTF2 reduced tyrosine phosphorylation of EGFR by 53% and 31%, respectively. The UVB-mediated enhanced expression of the early response genes, c-fos and c-jun in human epidermal keratinocytes was reduced in a dose-dependent manner by SBTE. Topical application of SBTE was also effective in reducing accumulation of c-fos and p53 proteins by 82% and 78%, respectively, in UVB-exposed mouse skin. These data provide evidence that constituents of black tea can abrogate UVB-induced erythema and associated early events in murine and human skin.

A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia.

A large double-blind, vehicle-controlled study of 143 patients with chronic postherpetic neuralgia (PHN) was performed to evaluate the degree of efficacy of topically applied capsaicin 0.075% cream. In addition, the safety and efficacy of long-term application of topical capsaicin in PHN was assessed by following patients in an open-label study for up to 2 years. In the double-blind phase, 143 patients with PHN of 6 months' duration or longer were enrolled. Since epidemiologic studies of patients who receive no treatment have shown that only 10% to 25% of those with PHN after 1 month will still have pain at 1 year, two separate efficacy analyses were performed: one with all evaluable patients (n = 131) and the other with 93 patients whose PHN lasted for longer than 12 months prior to study startup. All efficacy variables, including the physician's global evaluation of reduction in PHN pain, changes in pain severity on the categoric scale, visual analogue scale for pain severity, visual analogue scale for pain relief, and functional capacity scale, showed significant improvement at nearly all time points throughout the study for both patient groups, based on duration of PHN pain. In contrast, the group receiving vehicle cream remained essentially unchanged. Data from the long-term, open-label phase (up to 2 years, n = 77), which immediately followed the 6-week blinded phase, showed that the clinical benefit in patients treated for a short (6-week) period with topical capsaicin could be maintained or amplified in most patients (86%) during prolonged therapy. There were no serious adverse effects observed or reported throughout the trial; in fact, the only side effect associated with capsaicin treatment was the burning or stinging at local sites of application (in 9% of patients) during exposures of up to 2 years (long-term phase). On the basis of these data, we conclude that capsaicin 0.075% cream is a safe and effective treatment for the pain of postherpetic neuralgia and should be considered for initial management of patients with this condition.

Protection against ultraviolet B radiation-induced photocarcinogenesis in hairless mice by green tea polyphenols.

Our recent studies have shown that polyphenols present in green tea (GTP) possess significant antigenotoxic activity and afford protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice. In this study we assessed the effect of oral feeding and topical application of GTP on ultraviolet B (UVB) radiation-induced skin carcinogenesis in female SKH-1 hairless mice. Chronic oral feeding of GTP (0.1%, w/v) in drinking water resulted in significantly (P less than 0.01) lower tumor yield (percent of animals with tumors and number of tumors per mouse) and extended TDT50 (P less than 0.05), as compared to animals receiving normal drinking water. Topical application of GTP before UVB irradiation also afforded protection against photocarcinogenesis; however, the protective response was lower than that observed by oral feeding of GTP in drinking water. These results, in conjunction with our prior publications, suggest that consumption of green tea may reduce the risk of some forms of human cancer induced by both physical and chemical environmental carcinogens.

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 physician's 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.

Protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice by green tea polyphenols.

Green tea is a popular beverage in China and Asia and has been shown to possess antipyretic, diuretic and several other pharmacological activities. The major constituents of green tea are polyphenols which have been found to possess antioxidant and antimutagenic properties. In this study green tea polyphenols (GTP) were evaluated as an anti-initiating agent against the skin tumorigenicity induced by polycyclic aromatic hydrocarbons (PAHs) in mice. In a complete skin tumorigenesis protocol using 3-methylcholanthrene the topical application of GTP to female BALB/c mice resulted in substantial protection against the onset and subsequent development of tumors. In the two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate; (TPA) as tumor promoter, topical application of GTP to female SENCAR mice afforded significant protection against skin tumorigenicity. Oral feeding of GTP in drinking water to female SENCAR mice also protected against skin tumorigenesis in DMBA - TPA-treated animals. GTP when administered topically or orally significantly inhibited PAH - DNA adduct formation in epidermis after topical application of [3H]benzo[a]pyrene or [3H]DMBA. Our results suggest that GTP has substantial anti-skin-tumor-initiating activity against PAHs and could prove useful in protecting against some forms of human cancer.

Interaction of epicatechins derived from green tea with rat hepatic cytochrome P-450.

Green tea has been used for generations in China and Asia as an antipyretic and diuretic. Prior studies have shown that extracts of green tea inhibit the mutagenicity of polycyclic aromatic hydrocarbons and aflatoxin B1. In this study, we investigated the interaction of certain flavonoid components of green tea epicatechin derivatives including (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epigallocatechin-3-gallate (EGCG) with rat hepatic microsomal cytochrome P-450 (P-450). The addition of EC, EGC, ECG, and EGCG to hepatic microsomes prepared from phenobarbital (PB)-treated rats resulted in spectral changes characterized by absorbance maxima at 420 nm and minima at 380 nm, typical of modified Type II (reverse Type I) binding. Of the epicatechin derivatives, EGCG and ECG showed greater spectral change with oxidized P-450 and time- and concentration-dependent inhibition of the binding of carbon monoxide to dithionite-reduced cytochrome P-450. The addition of EC, EGC, ECG, and EGCG to microsomes prepared from control, PB- or 3-methylcholanthrene-treated rats resulted in a dose-dependent inhibition of cytochrome P-450-dependent aryl hydrocarbon hydroxylase, 7-ethoxycoumarin O-deethylase, and 7-ethoxyresorufin O-deethylase activities. EGCG was the most potent in this regard. Green tea polyphenols and epicatechin derivatives also significantly inhibited NADPH-cytochrome c reductase activity. An examination of the structure activity relationship of epicatechin derivatives suggests that the inhibitory effect on the microsomal enzyme system may be due to the galloyl groups or hydroxyl groups on the molecule. Our data indicate that these extracts of green tea may have potential as anticarcinogens.

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.

Photoradiation diagnosis and therapy. Dermatologic and photobiologic aspects.

Photoradiation with photosensitizing porphyrins offers a potentially useful approach to the diagnosis and treatment of certain human cancers. The mechanism of porphyrin photosensitivity as studied in cultured cells or in the skin has been studied thoroughly. Possible targets that have been identified include membranous cellular organelles, DNA, and the plasma membrane. Mediators of the reaction include reactive oxygen species, particularly singlet oxygen, that may elicit lipid peroxidation and the activation of complement. Further research is needed to identify photosensitizers with greater selectivity for malignant cells and to develop even better sources of radiant energy.

Effect of continued ultraviolet B phototherapy on the duration of remission of psoriasis: a randomized study.

Phototherapy using sunburn spectrum ultraviolet radiation (UVB) is now a frequently utilized treatment for psoriasis that is extensive or has not responded to topical preparations. Four university centers performed a prospective randomized clinical trial to compare remission times of patients with psoriasis who continued UVB phototherapy after initial clearing with this therapy and patients whose UVB phototherapy was discontinued within 3 weeks of clearing. As assessed by life table methods, the time to flare after initial clearing for patients on UVB maintenance therapy was significantly longer than for patients who discontinued UVB within 3 weeks after initial clearing. Our data suggest that continuing UVB phototherapy after initial clearing contributes to the duration of disease control and is justified for many patients.

Position paper--PUVA therapy. American Academy of Dermatology.

PUVA, the combination of psoralen (P) and long-wave ultraviolet radiation (UVA), is being used increasingly in the management of psoriasis and several other dermatologic disorders. While the acute toxicity of this modality, which includes erythema and blistering of the skin, can be avoided with careful monitoring of the dosimetry of the administered radiation, the potential chronic toxicity remains a source of concern. Since psoralens and UVA are clearly mutagenic, carcinogenic, cataractogenic, and may have as yet poorly understood effects on the immune system, it is imperative that all patients treated with this modality be carefully monitored for the development of neoplasia and cataracts. PUVA therapy should only be administered using specialized equipment that can be accurately monitored for its spectral irradiance by physicians thoroughly familiar with the risks and benefits of the modality.