Johan Moan

Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway)

Objective: To investigate whether prognosis of breast-, colon- and prostate cancer may be related to vitamin D3, induced from solar ultra-violet (UV) radiation, through studies on geographical and seasonal variations in UV radiation. Methods: This study includes 115,096 cases of breast-, colon- or prostate cancer, diagnosed between 1964 and 1992. Among these, 45,667 deaths due to the cancer were registered. On the basis of a north–south gradient in solar UV radiation and geographical climatic differences, Norway was divided into eight residential regions. According to seasonal variations in UV radiation, four periods of diagnosis during the year were used. Case fatality according to residential region and to season of diagnosis was estimated using Cox regression. The effects of occupational sun exposure, childbearing pattern and educational level were also evaluated. Results: No geographic variation in case fatality was observed for the three cancer types studied. A significant variation in prognosis by season of diagnosis was observed. Diagnoses during summer and fall, the seasons with the highest level of vitamin D3, revealed the lowest risk of cancer death. Conclusion: The results suggest that a high level of vitamin D3 at the time of diagnosis, and thus, during cancer treatment, may improve prognosis of the three cancer types studied.

On the Selectivity of 5-Aminolevulinic Acid-Induced Protoporphyrin IX Formation

Due to its capability to induce accumulation of protoporphyrin IX (PpIX) selectively in a multitude of different pathologies, 5-aminolevulinic acid (ALA) and its derivatives have attracted enormous attention in the field of photodynamic therapy (PDT) in the past two decades. The photochemical and photophysical properties of PpIX have been used for the fluorescence photodetection and photodynamic treatment of neoplasms in several medical indications in which conversion of ALA into PpIX seems to take place preferentially. Recently, this has led to the approval of this therapy for the treatment of actinic keratosis and basal cell carcinoma. When applied topically or systemically, ALA bypasses the negative feedback control that haem exerts on the enzyme ALA synthase (ALAS), which catalyses the natural production of this delta-amino acid, thereby temporarily boosting the generation of PpIX, the direct precursor of haem. Despite considerable interest in this treatment methodology, only little is known concerning the reasons for the selective accumulation of PpIX in neoplastic tissue upon ALA administration. Following an introduction into the biochemical as well as the chemical principles of haem synthesis, the present review tries to summarise experimental evidences of the mechanisms underlying preferential production of PpIX in neoplastic tissues. Thereby, morphological, environmental, enzymatic, as well as cell-specific factors will be discussed.

Ultraviolet Radiation and Malignant Melanoma

Essential features of the epidemiology and photobiology of cutaneous malignant melanoma (CMM) in Norway were studied in comparison with data from countries at lower latitudes. Arguments for and against a relationship between ultraviolet radiation (UV) from sun and sun beds are discussed. Our data indicate that UV is a carcinogen for CMM and that intermittent exposures are notably melanomagenic. This hypothesis was supported both by latitude gradients, by time trends and by changing patterns of tumor density on different body localizations. However, even though UV radiation generates CMM, it may also have a protective action and/or an action that improves prognosis. The same may be true for a number of internal cancers. There appears to be no, or even an inverse latitude gradient for CMM arising on non-UV exposed body localizations (uveal melanoma). Furthermore, CMM prognosis was gradually improved over all years of increasing incidence (up to 1990), but during the last 10 to 15 years, incidence rates decreased and prognosis was not further improved. While CMM incidence rates are twice as high in South Norway as in North Norway, the ratios of death rates to incidence rates are higher in the North, where the annual UV fluences are lower. Death- and incidence rates in Australia and New Zealand fully support this. Comparisons of skin cancer data from Norway and Australia/New Zealand indicate that squamous cell carcinoma and basal cell carcinoma are mainly related to annual solar UVB fluences, while UVA fluences play a larger role for CMM.

Changes in risk of death from breast cancer with season and latitude: Sun exposure and breast cancer survival in Norway

The Norwegian counties can conveniently be divided in three groups with different annual UV exposures and different incidence rates of squamous cell carcinoma (SCC) of the skin. In view of the hypothesis that latitude and season of diagnosis may play a role for breast cancer progression, the prognosis of breast cancer as determined for summer and winter diagnosis, were evaluated in the three residential regions. Two age groups were analysed separately (stratification at 50xa0years). For all regions, and for all ages, the prognosis was best for women diagnosed in the summer season (Relative risk (RR) of death was 15–25% lower for summer diagnosis versus winter diagnosis). There was no significant seasonal variation of the number of new cases. For women diagnosed before the age of 50, a geographical gradient in cancer prognosis was also found (RR of death 0.6, 95% CI: 0.5–0.7 for cases diagnosed in southeast Norway and RR of death 0.8, 95% CI: 0.6–1.1 for diagnosis in the north of Norway). This is in agreement with a 1.5 times larger annual UV exposures and 3–4 times larger incidence rates of SCC in the southeast region when compared with the north region. For women diagnosed after the age of 50, no significant difference was found between the three regions. Despite a 17% higher vitamin D intake from food in north of Norway no difference in cancer survival was found for diagnosis during winter (when no significant differences in the levels of UV exposure can be detected between regions).The overall data support our earlier hypothesis that season of diagnosis and therapy start improves the survival for breast cancer.

Effectiveness of different light sources for 5-aminolevulinic acid photodynamic therapy.

Many medical applications, including photodynamic therapy for cancer (PDT), involve the use of lasers. However, the coherence of laser light is not necessary for PDT, and attempts have been made to construct non-coherent light sources for PDT, which are relatively inexpensive, stable and easy to operate, require simple maintenance but differ fundamentally from the lasers in their output characteristics. In the present work we compared two clinically used lamps, CureLight1, which is a broadband source (560–740xa0nm) based on a filtered halogen lamp, and CureLight2, which is a narrowband source based on light-emitting diodes (LEDs), with respect to several parameters of crucial significance for PDT efficiency in vivo: (a) depth of action in tissues, (b) heating effects, (c) pain generation, (d) photodegradation of PpIX in solution, in cells and in mouse skin and (e) photo-inactivation of cells in vitro. We conclude that CureLight2 (LED), relative to CureLight1 (halogen) has deeper PDT action in tissue, similar efficiency for bleaching PpIX in mouse skin, better efficiency for bleaching PpIX in cells and solutions and good efficiency for inactivating cells in vitro. CureLight2 gives less heating of the tissue and less pain in unsensitised human skin. All these differences are related to difference in the spectra of the lamps. Thus, PDT light sources with emissions that are visually similar have significantly different photobiological properties.

Solar radiation and human health

The Sun has played a major role in the development of life on Earth. In Western culture, people are warned against Sun exposure because of its adverse effects: erythema, photoimmunosuppression, photoageing, photocarcinogenesis, cataracts and photokeratitis. However, Sun exposure is also beneficial, since moderate doses give beneficial physiological effects: vitamin D synthesis, reduction of blood pressure and mental health. Shortage of Sun exposure may be even more dangerous to human health than excessive exposure. Avoiding Sun exposure leads to vitamin D deficiency which is associated not only with rickets and osteomalacia, but also with increased risk of cardiovascular disease, multiple sclerosis, rheumatoid arthritis, diabetes, influenza, many types of cancer and adverse pregnancy outcomes. Solar radiation induces nitric oxide release in tissue and immediate pigment darkening which certainly play important roles, although these are still unknown. Action spectra relevant for health are described. We will also review what is known about spectral and intensity variations of terrestrial solar radiation as well as its penetration through the atmosphere and into human skin and tissue.

Microneedle Pre-treatment of Human Skin Improves 5-Aminolevulininc Acid (ALA)- and 5-Aminolevulinic Acid Methyl Ester (MAL)-Induced PpIX Production for Topical Photodynamic Therapy Without Increase in Pain or Erythema

ABSTRACTPurposeTo determine the impact of skin pretreatment with microneedles (MNs) on ALA- and MAL-induced protoporphyrin IX (PpIX) production, as well as MN impact on pain sensations during light exposure and erythema after PDT.MethodsThe skin of 14 healthy volunteers was preteated with MNs. Equal amounts of creams containing 2%, 8% and 16% (w/w) ALA and MAL were applied on 1xa0cm2 areas for 4xa0h. Additionally, 16% ALA and MAL creams were applied for 24xa0h. Afterwards, PpIX fluorescence spectra were measured. Sixteen percent ALA and MAL spots were exposed to red light (632xa0nm, 77xa0mW/cm2). Time for pain to occur was measured in seconds, and erythemal response was monitored up to 6xa0h after the end of the light exposure.ResultsUse of MNs increased the PpIX fluorescence after 4xa0h incubation time with 2% and 8% ALA or MAL, but not with 16% ALA or MAL. Pretreatment with MNs did not increase the pain sensations during light exposure, nor did it influence erythema occurrence.ConclusionsMNs are a promising tool for improving the efficiency of topical PDT by improving the cutaneous delivery of ALA and MAL, without increase in side effects.

Beneficial effects of UV radiation other than via vitamin D production

Most of the positive effects of solar radiation are mediated via ultraviolet-B (UVB) induced production of vitamin D in skin. However, several other pathways may exist for the action of ultraviolet (UV) radiation on humans as focused on in this review. One is induction of cosmetic tanning (immediate pigment darkening, persistent pigment darkening and delayed tanning). UVB-induced, delayed tanning (increases melanin in skin after several days), acts as a sunscreen. Several human skin diseases, like psoriasis, vitiligo, atopic dermatitis and localized scleroderma, can be treated with solar radiation (heliotherapy) or artificial UV radiation (phototherapy). UV exposure can suppress the clinical symptoms of multiple sclerosis independently of vitamin D synthesis. Furthermore, UV generates nitric oxide (NO), which may reduce blood pressure and generally improve cardiovascular health. UVA-induced NO may also have antimicrobial effects and furthermore, act as a neurotransmitter. Finally, UV exposure may improve mood through the release of endorphins.

Topical application of 5‐aminolaevulinic acid, methyl 5‐aminolaevulinate and hexyl 5‐aminolaevulinate on normal human skin

Backgroundu2002 5‐Aminolaevulinic acid (ALA) and its ester derivatives are used in photodynamic therapy. Despite extensive investigations, the differences in biodistribution and pharmacokinetics of protoporphyrin IX (PpIX) induced by ALA and its derivatives are still not well understood, notably for humans.

pH effects on the cellular uptake of four photosensitizing drugs evaluated for use in photodynamic therapy of cancer

The difference in extracellular pH in malignant as compared to normal healthy tissues has been proposed to contribute to selective uptake of photosensitizers in tumors. Hematoporphyrin IX (HpIX), disulfonated meso-tetraphenylporphine (TPPS(2a)), meso-tetra(3-hydroxyphenyl)porphine (mTHPP) and meso-tetra(3-hydroxyphenyl)chlorin (mTHPC) were chosen to examine the pH dependence of their cellular drug uptake. The study was performed in the pH range 6.5-8.0 and showed that significantly higher amounts of the drug are taken up by T-47D cells at low pH values only in the case of HpIX. The pH value of the incubation medium did not influence the cellular uptake of mTHPP, mTHPC and TPPS(2a) significantly. The present work indicates that tumor selectivity of dyes, which get more lipophilic with decreasing pH value, may be related to the low extracellular pH value.