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Prostate-specific membrane antigen (PSMA) is the most promising target for radioligand therapy of prostate cancer. The aim of this study was to prepare a small molecular ligand p-SCN-Bn-TCMC-PSMA (NG001) and compare it with the commonly used DOTA-based PSMA-617. The PSMA-targeting ability of the 212 Pb-labelled ligands was evaluated using PSMA-positive C4-2 human prostate cancer cells. Lead-212 is an in vivo generator of alpha particles by its daughter nuclides 212 Bi and 212 Po. NG001 was synthesized by conjugating the isothiocyanato group of p-SCN-Bn-TCMC to the amino group of a glutamate-urea-based PSMA-binding entity. Molecular size, chelator unit and chelator linking method are different in NG001 and PSMA-617. Both ligands were efficiently labelled with 212 Pb using a 224 Ra/212 Pb-solution generator in transient equilibrium with progeny. Lead-212-labelled NG001 was purified with a yield of 85.9±4.7% and with 0.7±0.2% of 224 Ra. Compared with [212 Pb]Pb-PSMA-617, [212 Pb]Pb-NG001 displayed a similar binding and internalization in C4-2 cells, with comparable tumour uptake in mice bearing C4-2 tumours, but almost a 2.5-fold lower kidney uptake. Due to the rapid normal tissue clearance and tumour cell internalization, any significant translocalization of 212 Bi was not detected in mice. In conclusion, the obtained results warrant further preclinical studies to evaluate the therapeutic efficacy of [212 Pb]Pb-NG001.

Background Solar ultraviolet (UV) radiation varies with latitude, time of day, and season. Both spectral UV composition and ambient UV dose lead to different health outcomes at different latitudes. Finding the optimal time for sun exposure, whereby the positive effects of UV exposure (vitamin D) are facilitated and the negative effects (skin cancer, photoimmunosuppression) avoided are the most important consideration in modern skin cancer prevention programs. Objectives This paper focuses on the latitude dependency of UVB, UVA, vitamin D production, and skin cancer risk in Caucasians. Methods Biologically effective UVB (280–315 nm) and UVA (315–400 nm) doses were calculated using radiative transfer models with appropriate climatologic data for selected locations. Incidences of squamous cell carcinoma (SCC) and cutaneous melanoma (CM) were retrieved from cancer registries and published articles. Results Annual doses of UVA radiation decrease much less with increasing latitude than annual doses of UVB. Incidences of CM also decrease less steeply with increasing latitude than incidences of SCC. As SCC is caused mainly by UVB, these observations support the assumption that UVA plays an important role in the development of CM. The variations in UVA (relevant to CM) and UVB (relevant to vitamin D production) over 1 day differ: the UVB : UVA ratio is maximal at noon. Conclusions The best way to obtain a given dose of vitamin D with minimal carcinogenic risk is through a non-burning exposure in the middle of the day, rather than in the afternoon or morning.

Summary Background The incidence rates of skin cancer increase with decreasing latitude in most western countries. Ultraviolet (UV) radiation is a main risk factor for skin cancer. Methods We have studied the relationship between UV exposure and skin cancer incidence rates of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma (CM), and tried to fit different mathematical models to the experimental data. Results The incidence–UV exposure relationship for all three cancers is best described by the power law: ln(RTD) = Ab·ln(annual UVEry dose), with relative tumor density (RTD) being age-adjusted incidence rate per unit area of skin, and the power parameter Ab being the biological amplification factor. For SCC, the RTD is a factor of 16–19 times larger on the head than on the trunk. For BCC, this factor is 7 and for CM it is 0.9–1.3. Ab for CM has remained almost unchanged from the 1960s until recently. Conclusions The incidence–sun exposure relationship for all three cancers is well described by the power law. SCC is dependent on total UV exposures, while BCC, and even more CM, is dependent also on exposure patterns, with intermittent exposures being most carcinogenic.

The evolution of dark human skin colors in tropical areas is possibly related to photoprotection of folates. However, natural folates absorb mainly UVB radiation, and too little UVB can penetrate down to folates in dermal vessels to cause serious damage. However, endogenous photosensitizers, like riboflavin and uroporphyrin, absorbing UVA and visible light, can cause photosensitization of folates. Immediate pigment darkening (IPD), generated by UVA, has an absorption spectrum covering those of the endogenous photosensitizers. IPD is most prominent for darker skin types, which were typical for populations living under tropical solar fluences. We here propose that the biological role of IPD is protection of folates against photodegradation, which would be of large evolutionary importance for early hominids.

Background Cutaneous malignant melanoma (CMM) incidence continues to increase in many parts of the world. Solar ultraviolet (UV) radiation is the main environmental risk factor for CMM. Different body locations are subjected to different doses and exposure patterns of solar UV. Time and latitudinal trends of CMMs on shielded and exposed skin give valuable information about the aetiology of these cancers. In this study, we have compared the time and latitudinal trends of CMM incidence on skin areas which are chronically (head and neck) and rarely (foot) exposed to UV radiation, to gain more information about the relationship between sun doses, exposure patterns and melanomagenesis. Methods We have analysed epidemiological data from the Cancer Registry of Norway, for foot and head and neck CMM for two time periods: 1966–1986 and 1987–2007. Results Cutaneous malignant melanoma incidence rate on head and neck has increased with time, while incidence rates of foot CMM have remained almost constant with time in Norway. There is a large north–south gradient in incidence rates of CMM on head and neck in Norway, while there is almost no north–south gradient for CMM incidence on foot. Conclusions Comparisons of time trends and latitudinal trends of the incidence rates of CMM on head/neck and on foot indicate that solar radiation plays a role in the induction of the former CMM but probably not for the latter.

Background Melanoma incidence is increasing in many parts of the world. The main environmental risk factor is exposure to solar radiation. However, melanomas may arise also on non-sun-exposed areas (uveal and mucosal melanomas) and little is known about a possible relationship between sun exposure and melanoma on such locations. Objectives We have compared the time and latitude trends of melanoma incidence in the anorectal region and perianal skin (non-sun-exposed sites) with those of cutaneous malignant melanoma (CMM) (sun-exposed skin) to gain more information about the relationship between sun exposure and melanoma on such sites. Methods We analysed epidemiological data from the Cancer Registry of Norway for melanomas of the anorectal mucosa, perianal skin and overall CMM for the time period 1966–2007. Results We found that melanoma incidence on these shielded sites tends to decrease or remain constant over a period during which the CMM rates increase. This is true both in the North and in the South regions of Norway. Comparison of latitudinal trends of the incidence rates of CMM and melanoma on these shielded sites shows that there is no latitude gradient for melanoma of the anorectal mucosa and perianal skin, whereas there is a strong one for CMM. Conclusions The time and latitudinal trends are likely to support the assumption that melanomas on these shielded sites are not generated by ultraviolet radiation. Possible causes and significances of these trends are discussed.

Please cite this paper as: Influence of narrowband UVB phototherapy on vitamin D and folate status. Experimental Dermatology 2010; 19: e67–e72. Abstract Background: A variety of studies have shown beneficial effects of different types of phototherapy in skin disorders. Such therapy leads to enhanced cutaneous vitamin D synthesis, which may be one of the mechanisms of action. Furthermore, another nutrient, folate, can probably also be influenced by UV radiation. Objective: The aim of our study was to investigate the influence of low-dose narrowband UVB (nUVB) phototherapy of patients with psoriasis, atopic eczema and other skin disorders on serum levels of 25(OH) vitamin D (the serum marker for vitamin D status) and on serum and erythrocyte-folate. Methods: 25(OH) vitamin D (25(OH)D), serum and erythrocyte-folate levels were measured before and after low-dose nUVB (TL-01 tubes) phototherapy of these patients. The spectrum of the TL-01 tube was compared with the solar spectrum, and the efficiency spectra of vitamin D photosynthesis were calculated. Results: For patients with a high initial 25(OH)D serum level (> 80 nmol/l), no significant (P = 0.36) increase in 25(OH)D levels was seen, in contrast to patients with a low initial level (

A novel 5-aminolevulinic acid (ALA)-containing microparticulate system was produced recently, based on incorporation of ALA into particles prepared from a suppository base that maintains drug stability during storage and melts at skin temperature to release its drug payload. The novel particulate system was applied to the skin of living animals, followed by study of protoporphyrin IX (PpIX) production. The effect of formulating the microparticles in different vehicles was investigated and also the phototoxicity of the PpIX produced using a model tumour. Particles formulated in propylene glycol gels (10% w/w ALA loading) generated the highest peak PpIX fluorescence levels in normal mouse skin. Peak PpIX levels induced in skin overlying subcutaneously implanted WiDr tumours were significantly lower than in normal skin for both the 10% w/w ALA microparticles alone and the 10% w/w ALA microparticles in propylene glycol gels during continuous 12h applications. Tumours not treated with photodynamic therapy continued to grow over the 17 days of the anti-tumour study. However, those treated with 12h applications of either the 10% w/w ALA microparticles alone or the 10% w/w ALA microparticles in propylene glycol gel followed by a single laser irradiation showed no growth. The gel formulation performed slightly better once again, reducing the tumour growth rate by approximately 105%, compared with the 89% reduction achieved using particles alone. Following the promising results obtained in this study, work is now going on to prepare particle-loaded gels under GMP conditions with the aim of initiating an exploratory clinical trial. Copyright r 2009 John Wiley & Sons, Ltd.

Aminolevulinic acid (ALA), ALA methylester (ALA-Me) and ALA hexylester (ALA-Hex) were topically applied for 5 and 20 hr, respectively, on normal skin of mice. The distribution of protoporphyrin IX (PpIX) induced in 7 different tissues by these drugs was determined either by spectrofluorometric measurements with an optical fibre probe or by chemical extraction of PpIX from the tissues. The results from these 2 types of measurements were compared. Both methods showed that ALA and the esters induced similar amounts of PpIX at the skin spot where they were applied and that the esters produced much less PpIX at remote skin spots (i.e., spots outside the location where the drugs were applied) than ALA did, notably after 20 hr application. After 20 hr of drug application ALA produced much more PpIX in liver, intestine and lungs than the esters did. In contrast with the direct fluorescence measurements, the extraction method showed detectable amounts of PpIX in liver, intestine and lung after application of the esters, notably of ALA-Me. The discrepancy is probably related to the fact that the pigmented tissues absorb light and, therefore, the direct fluorescence readings are misleading. Notably in the liver, which contains high concentration of light-absorbing pigments, very weak direct fluorescence was seen. In no case there was any accumulation of PpIX in muscle tissue nor in brain. The esters seem to penetrate less into the circulation than ALA, and PpIX formed by them in the skin is faster cleared than PpIX formed from ALA. This is also true after oral and i.p. administration of the drugs. © 2002 Wiley-Liss, Inc.

5-aminolevulinic acid heptyl ester was investigated in human adenocarcinoma WiDr cells and in healthy skin of athymic nude mice in comparison with 5-aminolevulinic acid (ALA). Incubation of WiDr cells with ALA and ALA heptyl ester resulted in production of protoporphyrin IX (PpIX). Concentrations higher than 0.01 mm of ALA heptyl ester and higher than 1 mm of ALA were cytotoxic. The dark cytotoxicity was not related to PpIX. Intracellular localization, photocytoxicity and photobleaching rate of PpIX were the same for both drugs, although a 100 times lower concentration of ALA heptyl ester (0.01 mm) was needed in comparison with ALA (1 mm) to induce the same level of PpIX. ALA heptyl ester, topically (but not systemically) applied, is a promising candidate for fluorescence diagnosis and photodynamic therapy. Special attention must be focused on the concentrations of ALA heptyl ester; as excess may lead to cytotoxicity and inefficient PpIX generation.

We have investigated the role of tissue oxygenation on light penetration into tissue at different wavelengths. As a field of application we have chosen aminolevulinic acid-photodynamic therapy (ALA-PDT). To calculate efficiency spectra of PDT on human skin one needs to know the excitation spectrum of the photosensitizer of interest and the relative fluence rate as a function of depth in the tissue. We measured the former and computed the latter with an accurate radiative transfer algorithm. In this way we determined the efficiency spectra as functions of depth for different types of basal cell carcinomas (BCC). Our results suggest that ALA-PDT works best for nodular BCC at a wavelength of 630 nm, whereas it works best for pigmented superficial BCC at a wavelength of 390 nm. At 630 nm the light penetration into a tumor depends strongly on the oxygenation of the blood. Below a 2 mm thick, well-oxygenated, nodular BCC, we find the efficiency to be an order of magnitude larger than below a poorly oxygenated tumor. At 390 nm, the light penetration into a tumor does not depend on the oxygenation of the blood.

The kinetics of accumulation of protoporphyrin IX (PpIX) after topical application of 5-aminolevulinic acid (ALA) and its methylester (5-aminolevulinic acid methylester [ALA-Me]) was studied on rat oral mucosa. The accumulation of PpIX in mucosa and skin after intravenous injection of ALA and ALA-Me was also studied. The elimination rate of PpIX was dependent on drug and dose as well as on administration route. Application of ALA on rat oral mucosa and skin caused a systemic effect with PpIX building up in remote skin sites not exposed to the drugs. No such systemic effect was seen after application of ALA-Me either in mucosa or on skin. Intravenous injection of the drugs (0.2 g/kg) leads to more fluorescence in the skin than topical application of the drug (20%). For mucosa, the opposite is true. Maximal PpIX fluorescence appeared later after application of high concentrations of the drugs (around 8 h for 5% and 20% wt/wt) than after application of low concentrations (around 3-5 h for 1% and 2% wt/wt).