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Biomedical subjects

J Moan

Publications and source records attributed to J Moan.

At least 55 records · Page 3Linked to original sources
PubMed1998

[Solar radiation and melanomas--is there any doubt about the connection?].

Arguments for and against there being a connection between exposure to solar radiation and cutaneous, malignant melanoma are reviewed. Recent experiments with animals and epidemiological observations provide relatively strong arguments that solar radiation causes cutaneous, malignant melanoma. Furthermore, epidemiological data from Norway and Australia support the assumption that UVA-radiation plays a significant role in melanoma induction; this is in agreement with data from experiments with Xiphophorus and Monodelphis domestica. A new hypothesis for melanoma induction is presented: Radiation absorbed by melanin in melanocytes generates free radicals that may activate the carcinogenic process. Radicals produced by light absorption in melanin in the upper layers of the epidermis are not able to diffuse as far down as to the melanocytes. Thus, this melanin may be protective, while that in the melanocytes may be a photocarcinogen. Findings that support this hypothesis are discussed.

Animals↗
PubMed1998

[Use of 5-aminolevulinic acid in photochemotherapy and fluorescence diagnostics].

5-aminolevulinic acid is an early intermediate product in the synthesis of heme. Some of the enzymes in the heme synthesis chain have altered activities in tumor tissue, so that application of 5-aminolevulinic acid leads to an accumulation of protoporphyrin IX in tumors. This molecule absorbs light and acts as a potent photosensitizer; tumors containing the compound can therefore be destroyed by light. 5-aminolevulinic acid based photochemotherapy is presently being employed in the treatment of thin basal cell carcinomas in many countries. The cosmetic result of this treatment is excellent. Furthermore, it is a simple and inexpensive form of treatment with curative rates comparable to those of established therapy modalities. Experimentally, a number of other malignant lesions reachable by light via optical fibers are being treated. Since protoporphyrin IX has a characteristic red fluorescence, 5-aminolevulinic acid can also be applied for diagnostic purposes.

Aminolevulinic Acid↗
PubMed1998

Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid: dependence on cell density, cell size and cell cycle.

Human colon adenocarcinoma cells (WiDr) and Chinese hamster lung fibroblasts cells (V79) were incubated with different concentrations of 5-aminolevulinic acid (ALA), and the production of protoporphyrin IX (PpIX) was studied using several techniques. The amount of PpIX produced per cell increased with increasing ALA concentration according to different kinetics for the 2 cell lines. For both cell lines a cell density dependency of the PpIX synthesis was observed. For saturating ALA concentrations, 2-3 times more PpIX was produced per cell at a density of 5 x 10(4) than at a density of 5 x 10(3) cells/cm2. The photosensitivity of cells appeared to increase even more than the PpIX content, indicating a cooperative effect in inactivation. The PpIX production rate increased with cell size and was about 1.9 times higher for cells in the G2 + M phase than for cells in the G1 phase of the cell cycle. Neither cell size nor cell cycle distribution were significantly dependent on cell density.

Adenocarcinoma↗
PubMed1998

In vivo fluorescence of phthalocyanines during light exposure.

Nude mice were given AlPcS2a (aluminum phthalocyanine disulfonate) and AlPcS4 (aluminum phthalocyanine tetrasulfonate) by intraperitoneal injections. After time intervals of 1-48 hours the mice were exposed to 150 mW cm-2 light at 670 nm and the phthalocyanine fluorescence was measured during light exposure. During the first few minutes of light exposure the phthalocyanine fluorescence of the skin of the mice increased by up to a factor of two, indicating lysosomal localization of the dye and permeabilization of the lysosomes. The process did not occur in the skin of dead mice, indicating that the process was dependent on oxygen.

Aluminum↗
PubMed1998

Liposome-bound Zn (II)-phthalocyanine. Mechanisms for cellular uptake and photosensitization.

In the present study, cellular uptake of a liposomal formulation of ZnPc (CGP 55847) has been studied in human cervix carcinoma cells of the line NHIK 3025. The cellular uptake of ZnPc is found to be completed after 4-8 h of incubation. The maximum level of ZnPc in the cells after incubation with 1 microgram/ml ZnPc in E2a medium containing 3% serum is 60 ng/mg protein. The cellular uptake is attenuated by the presence of serum and at low temperature of the incubation medium, but the activation energy (30 kJ/mol) and fluorescence microscopic analysis of cells incubated with ZnPc at 0 degree C indicate that ZnPc is taken up into cells by a diffusion-mediated pathway. Measurements of subcellular marker enzymes have been performed immediately after light exposure of ZnPc-treated cells. The mitochondrial marker enzyme (cytochrome c oxidase) and the marker enzyme for the Golgi apparatus (UDP galactosyl transferase), but not those for lysosomes (beta-N-acetyl-D-glucosaminidase) and endoplasmic reticulum (NADPH cytochrome c reductase), are inactivated upon photodynamic treatment. These results indicate that ZnPc is mainly located in the Golgi apparatus and the mitochondria of NHIK 3025 cells. In contrast, photoactivated Photofrin is found to reduce the activity of UDP galactosyl transferase, but not that of NADPH cytochrome c reductase. The tetraphenylporphine TPPS2a and light reduce the activity of NADPH cytochrome c reductase, without influencing the activity of UDP galactosyl transferase. TPPS4 and light do not attenuate the activities of UDP galactosyl transferase and NADPH cytochrome c reductase.

Drug Carriers↗
PubMed1998

Kinetics of photobleaching of protoporphyrin IX in the skin of nude mice exposed to different fluence rates of red light.

The purpose of the present study was to determine the kinetics and the fluence rate dependency of the photobleaching of protoporphyrin IX (PpIX) in normal skin of Balb/c nude mice after systemic and topical application of 5-aminolevulinic acid (ALA). ALA was administered systemically (200 mg/kg body weight, i.p.) and topically (20% w/w ALA cream) to the mice. Fluences of up to 40 J/cm2 were delivered by a dye laser (636 nm) at fluence rates of 37.5, 75, 150, 300 and 500 mW/cm2. The photo-bleaching rate was constant within this range of fluence rates. This result suggests that there is no oxygen effect for PpIX photobleaching in this region for the skin of Balb/c nude mice. During light exposure the fluorescence decay followed neither first- nor second-order kinetics. The decay rate was slightly faster after systemic application than after topical application of ALA, but did not depend on the time (1-8 h) between application and analysis.

Administration, Topical↗
PubMed1997

5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.

BACKGROUND: Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25-years. PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light. Although several photosensitizers other than ALA-derived protoprophyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years. Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis. However, no review updating the clinical data has appeared so far. METHODS: A review of recently published data on clinical ALA-based PDT and diagnosis was conducted. RESULTS: Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results. However, the modality with present protocols does not in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors. Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity. Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases. Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain. The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs. CONCLUSIONS: Promising results of ALA-based clinical PDT and diagnosis have been obtained. The modality has advantages over conventional treatments. However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue: improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems.

Aminolevulinic Acid↗
PubMed1997

Use of 5-aminolevulinic acid esters to improve photodynamic therapy on cells in culture.

Human tumor cells of the lines WiDr (adenocarcinoma of the rectosigmoid colon), NHIK 3025 (carcinoma of the cervix), and V79 Chinese hamster fibroblasts were treated with 5-aminolevulinic acid (ALA) and ALA esterified to C1-C3 and C6-C8 chained aliphatic alcohols (ALA-esters). In the human cell lines, esterification of ALA with the long-chain (C6-C8) alcohols was found to reduce 30-150-fold the amount of ALA needed to reach the same level of protoporphyrin IX (PpIX) accumulation as with non-esterified ALA. The long-chained ALA-esters were less efficient in stimulating PpIX formation in V79 cells, i.e., the same amount of PpIX was formed by a 1-2.6-fold lower concentration of long-chained ALA-esters than with ALA. Short-chained ALA-esters (C1-C3) induced 5 to 10 times lower PpIX accumulation than ALA in all of the cell lines. High-performance liquid chromatography and fluorescence microscopic studies indicated that esterification of ALA has neither impact on the fluorescing porphyrin species formed nor impact on their intracellular localization. The PpIX formed from ALA-esters and ALA was found to be equally efficient in sensitizing cells to photoinactivation. The present results indicate that esterified ALAs are new and promising drugs for use in photochemotherapy of cancer.

Adenocarcinoma↗
PubMed1997

Cooperative effects of photodynamic treatment of cells in microcolonies.

Microcolonies of 2-8 Madison-Darby canine kidney cells (MDCK II) and Chinese hamster lung fibroblasts (V79) cells were incubated with the photosensitizer Photofrin and exposed to light, and the resulting number of dead cells per colony was determined. The distribution of this number was found to be incompatible with the assumption that cells are inactivated independently. The experimental distributions were significantly different from the binomial distribution expected from this assumption, but in accordance with a model in which an inactivated cell can inactivate adjacent cells with a certain probability. These findings are contrary to the common view that damage caused by radiation is limited to the cell in which the primary damage takes place. Our findings clearly indicate some kind of cooperativity between cells treated with Photofrin and light.

Animals↗
PubMed1997

The pH dependency of protoporphyrin IX formation in cells incubated with 5-aminolevulinic acid.

Chinese hamster cells (V79) and human adenocarcinoma cells (WiDr) were incubated with 5-aminolevulinic acid (ALA) at different pH values and the rate of production of protoporphyrin IX (PpIX) was measured. The rate of production increased with pH in the range 6.0-7.5. Above pH 7.5 the rate decreased, possibly due to a reduced metabolic activity of the cells. The observations may be explained by the known pH-dependency of the activity of porphobilinogen deaminase (PBGD) and are in agreement with the assumption that PBGD constitutes a rate-limiting step in the synthesis of PpIX from ALA.

Adenocarcinoma↗
PubMed1997

Pharmacokinetic studies on 5-aminolevulinic acid-induced protoporphyrin IX accumulation in tumours and normal tissues.

Laser-induced fluorescence (LIF) for in vivo point monitoring and fluorescence microscopy incorporating a CCD camera were used to study the fluorescence distribution of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) in tumours. Fluorescence in a chemically-induced adenocarcinoma in the liver of rats and in an aggressive basal cell carcinoma in a patient were studied after intravenous injection of ALA at a dose of 30 mg/kg body weight. The LIF technique demonstrated slightly more ALA-induced PpIX fluorescence in the tumour than in the surrounding normal liver and abdominal muscle of rats. The visible parts of the human basal cell carcinoma exhibited strong ALA-induced fluorescence, while this fluorescence was much weaker in the necrotic areas of the tumour and in the surrounding normal skin.

Adenocarcinoma↗
PubMed1997

Photobleaching of protoporphyrin IX in cells incubated with 5-aminolevulinic acid.

Protoporphyrin IX (Pp IX) is the main photosensitizer in photochemotherapy with 5-aminolevulinic acid (ALA). Pp IX is photolabile and the present work shows that 70-95% of Pp IX in cells is degraded by clinically relevant light exposures (40-200 J cm(-2) at 630 nm). During light exposure a small yield of photoprotoporphyrin, which is also photolabile, is formed. A substantial fraction of Pp IX in cells incubated with ALA is bound to proteins. During light exposure these binding sites are destroyed, those close to tryptophan residues being the most sensitive. The rate of photodegradation of Pp IX in the cells is dependent on the initial concentration of Pp IX. The degradation mechanisms are therefore not only first order processes. Different degradation rates appear to be related to different types of binding sites. During light exposure, Pp IX molecules appear to move to different binding sites, evidently sites that are more vital for cell survival. Thus, the yield of photoinactivation of the cells, as measured per emitted photon of Pp IX fluorescence, increased during light exposure.

Aminolevulinic Acid↗
PubMed1997

Inhibiting effects of antioxidants on drug-induced phototoxicity in cell cultures. Investigations with sulphonamide-derived oral antidiabetics and diuretics.

The sulphonamide-derived oral antidiabetics chlorpropamide, glibenclamide, glipizide, gliquidone, glymidine, tolazamide and tolbutamide, and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlortalidone, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, piretanide, polythiazide, trichlormethiazide and xipamide were investigated for phototoxicity in a cell culture model. Cell death dependent on ultraviolet A (UVA) radiation fluence and test substance concentration was observed in the presence of the oral antidiabetics glibenclamide and gliquidone, as well as the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, hydrochlorothiazide, hydroflumethiazide, piretanide, polythiazide and trichlormethiazide. Bendroflumethiazide was phototoxic at concentrations of 0.05 mM and above; bemetizide, benzylhydrochlorothiazide, bumetanide and hydroflumethiazide were phototoxic at concentrations of 0.25 mM or more; the oral antidiabetics glibenclamide and gliquidone, as well as the diuretics butizide, hydrochlorothiazide, piretanide, polythiazide and trichlormethiazide were phototoxic at concentrations of 0.5 mM. To evaluate the effects of antioxidants, ascorbic acid, alpha-tocopherol, beta-carotene or ubiquinone was added to the tissue culture flasks before irradiation. The phototoxic inhibition of the colony-forming ability was largely reduced by the addition of ascorbic acid and alpha-tocopherole, indicating the involvement of reactive oxygen species in the phototoxic process.

Antioxidants↗
PubMed1997

A hydroxypyridinone (CP94) enhances protoporphyrin IX formation in 5-aminolaevulinic acid treated cells.

Different cell lines were given photodynamic treatment with 5-aminolaevulinic acid (ALA) and light. In addition, the iron chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94) was used. The porphyrin species produced was spectrofluorimetrically identified as protoporphyrin IX. All the cell lines responded to treatment, including a multidrug resistance gene expressing bladder cancer line and, to a lesser degree, cells derived from untransformed human skin fibroblasts. CP94 enhanced both porphyrin fluorescence, total porphyrin content and photosensitivity of the cells. CCD fluorescence microscopy showed a granular extranuclear porphyrin fluorescence distribution for all the cell lines involved, but the untransformed cells showed a distribution pattern different from the ones seen in the other cells.

Aminolevulinic Acid↗
PubMed1997

Photoprotection by furocoumarin-induced melanogenesis against DNA photodamage in mouse epidermis in vivo.

The photoprotective properties of furocoumarin plus UVA-induced epidermal melanogenesis were assessed in hairless mice. The ear and dorsal surfaces were topically treated with 6,4,4'-trimethylangelicin (TMA), 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP) or psoralen and exposed to UVA for 12 consecutive week-days. The TMA treatment induced intense tanning whereas modest tanning was seen with the other compounds. Seven days after the last treatment, the mice were challenged with a DNA damaging dose of UV radiation. Single strand breaks (SSB) in epidermal DNA were assessed by alkaline elution. Photoprotection was assessed by comparing SSB in furocoumarin-treated mice with control mice (vehicle plus UVA and also no treatment). No photoprotection was seen, with any compound, in dorsal epidermis despite intense pigmentation induced by TMA. Modest photoprotection with all compounds was seen in ear epidermis that was independent of the level of pigmentation. These data show that induced melanogenesis is not always associated, with photoprotection.

Animals↗