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Biomedical subjects

J Moan

Publications and source records attributed to J Moan.

At least 109 records · Page 6Linked to original sources
PubMed1992

Plateau distributions of DNA fragment lengths produced by extended light exposure of extranuclear photosensitizers in human cells.

We have exploited properties of photosensitizers to study an aspect of the packing of chromatin in the cell nucleus. The fluorescent photosensitizers mesotetra(3-hydroxyphenyl) porphyrin and Photofrin II were both localized in the nuclear membrane and other membrane structures, but could not be found inside the nuclei. Light exposure of cells at 1 degrees C in the presence of the sensitizers induced DNA double-strand breaks. The length distributions of DNA fragments were determined by pulsed field gel electrophoresis. Because DNA damage is produced mainly via singlet oxygen diffusing less than 0.1 microns from the sensitizer, DNA double-strand breaks were supposedly produced within this distance of the nuclear membrane. Consistent with this, with prolonged illumination and with increasing concentrations of sensitizer the distribution of DNA fragment lengths reached a plateau level. In contrast, with the hydrophilic, intranuclear sensitizer meso-tetra(4-sulphonatophenyl)porphyrin, no such plateau level was found. The plateau distributions of DNA fragment lengths of different cell types had the same general shape with average fragment lengths ranging from 174 to 194 kilobasepairs. Particular genes, c-myc, fos and p53, were found on broad distributions of photocleaved fragment lengths. The results indicate that on each side of the genes the locus of the chromatin fibre situated close to the nuclear membrane, varied randomly.

Cell Line↗
PubMed1992

Distribution and photosensitizing efficiency of porphyrins induced by application of exogenous 5-aminolevulinic acid in mice bearing mammary carcinoma.

By means of a chemical extraction procedure and confocal laser scanning microscopy, we investigated the kinetic patterns of uptake and biolocalization of 5-aminolevulinic acid (ALA)-induced porphyrins in s.c. transplanted tumors, adjacent normal skin and muscle, and liver of mice bearing mammary carcinoma, after i.p. injection of 250 mg/kg ALA or topical application of ALA (20% in an oil-in-water emulsion). Furthermore, we evaluated the tumor responses after either i.p. injection or topical application of 5-ALA followed by laser irradiation (632 nm, 150 mW/cm2, 25 min) by measuring the treated tumor regression/regrowth time and by light and electron microscopy. Strong fluorescence of ALA-induced porphyrins was detected in the tumor, skin and liver tissues, while little fluorescence was seen in the adjacent muscle tissue. Moreover, the highest amounts of ALA-induced porphyrins in the tumor and skin tissues were found 1 hr after i.p. injection, whereas the amounts of the porphyrins in both tissues increased with increasing time after topical application of ALA. The fluorescence of the porphyrins was localized in several components of the skin tissue (epidermis, hair follicles and their associated sebaceous glands). Furthermore, the fluorescence was diffusely distributed in the s.c. transplanted tumor tissue. Little could be observed under a confocal laser scan microscope (CLSM) in the muscle tissue. The uptake and biolocalization data correlate well with the results of PCT efficiency of the same tumor model with ALA-induced porphyrins. Light and electron microscopy showed that the mitochondria of the tumor cells and of the endothelial cells and the basal lamina of vascular walls beneath the endothelium in the tumor tissue were initially extensively destroyed after PCT with ALA-induced porphyrins. Thereafter, diffuse degeneration followed by local and/or diffuse severe necrosis of the tumor cells was found. This may be due mainly to the initial damage to mitochondria in the cancerous and endothelial cells and also to the destruction of the vascular wall in the tumor tissue.

Aminolevulinic Acid↗
PubMed1992

Effects of light exposure on the uptake of photofrin II in tumors and normal tissues.

DBA mice bearing CaD2 mammary carcinomas were used to determine the effect of giving small doses of light to the tumor area 1.5 hr after injecting Photofrin II (PII). The smallest light dose applied (12.5 J/cm2) had no effect on the uptake of PII in the tumor and its surrounding tissues, as measured 24 hr after the i.p. injection. However, several higher light doses increased the uptake of PII in the tumor significantly, the uptake in skin slightly, while the uptake in muscle tissue was decreased rather than increased. Thus, the PII concentration ratio between the tumor and the surrounding normal tissues was significantly improved. The rates of clearance of PII from irradiated tissues and non-irradiated tissues were not significantly different. Most likely, the present observations are due to transient pH lowering in the tumor resulting from vascular damage.

Animals↗
PubMed1992

Effect of mitomycin C on the uptake of photofrin II in a human colon adenocarcinoma cell line.

Flow cytometry (FCM) was used to investigate the effect of mitomycin C (MC) on the cellular uptake of Photofrin II (PII) in a cultured human colon adenocarcinoma cell line (WiDr). The surface area of the cells increased as they passed through the cell cycle from G0/G1 to G2/M phase. MC retarded the cells in G2/M phase and enhanced the surface area of the cells. A 1.3-2.3-fold increase in the cell surface area and a 1.3-2.7-fold increase in the cellular uptake of PII in the tumor cells was observed after 2 h-8 h incubation with MC. Within each sample, an almost linear relationship between the intensity of PII fluorescence in the cells and the surface area of the cells was found. However, for the cells incubated with MC the surface area was not the only determinant of PII uptake. Effects of MC on the cell cycle, the cell surface area and the permeability of the cell membrane are suggested as possible reasons for the increase of cellular uptake of PII in the tumor cells.

Adenocarcinoma↗
PubMed1992

[Light therapy of newborns with hyperbilirubinemia].

In a significant fraction of newborns the skin becomes yellow for a few days after birth due to accumulation of bilirubin, a product of heme catabolism. If the concentration of bilirubin in the serum approaches the binding capacity of albumin, bilirubin may penetrate into the central nervous system and cause irreversible damage. Phototherapy is the most common form of therapy, used on 5-10% of all newborns in Norway. Three photochemical reactions are of importance in this treatment: Photooxydation of bilirubin followed by fragmentation of the molecule and formation of water-soluble products. Reversible formation of (4Z,15E) and (less important) (4E,15Z) configurational isomers. Irreversible formation of the structure isomer Z-lumirubin, which is relatively water-soluble and can be excreted. The (4E,15Z) isomer is probably an intermediate in the formation of Z-lumirubin, whose formation therefore requires the absorption of two photons. Irreversible formation of Z-lumirubin, which has a quantum yield that increases with increasing wavelength of the light, is believed to be the most important reaction in phototherapy. All known side-effects of phototherapy are transient and not serious.

Bilirubin↗
PubMed1992

Synergistic effects of photoactivated tetra(4-sulfonatophenyl)porphine and nocodazole on microtubule assembly, accumulation of cells in mitosis and cell survival.

Human carcinoma cells of the line NHIK 3025 were incubated with meso-tetra(4-sulfonatophenyl)porphine (TPPS4) for 18 h and exposed to light in the absence or presence of nocodazole. Nocodazole (1 microgram ml-1) was applied to the cells 15 min prior to light exposure and washed off the cells immediately afterwards. The presence of nocodazole during photoactivation of TPPS4-loaded cells leads to a significantly reduced ability of tubulin to repolymerize after withdrawal of nocodazole, an increased accumulation of the cells in mitosis with a larger fraction in c-metaphase and a higher yield of photoactivated cells. A higher proportion of the cells accumulating in mitosis 6-12 h after exposure to light is unable to form colonies when exposed to light in the presence of nocodazole than in its absence. The present results are consistent with a specific TPPS4-induced photodamage to the unpolymerized form of the microtubule components.

Carcinoma in Situ↗
PubMed1992

Fractionated treatment of CaD2 tumors in mice sensitized with aluminium phthlocyanine tetrasulfonate.

CaD2 mammary carcinomas transplanted into the feet of mice were treated with tetrasulfonated phthalocyanine (AlPcS4) and laser light at 680 nm. A light dose of 135 J/cm2 was either given as continuous radiation (15 min) or fractionated with 15 s exposure, 15 s darkness, 15 s exposure and so on for 30 min. The CaD2 tumors were found to respond better to a fractionated exposure than to the same energy given in one exposure. The reason for this is assumed to be a relocalization of the dye upon illumination, seen as a rapid decrease in fluorescence. When the laser light was turned off, the fluorescence returned to almost the initial value.

Animals↗
PubMed1992

Cytotoxicity and cytokinetic effects of mitomycin C and/or photochemotherapy in a human colon adenocarcinoma cell line.

1. The cytotoxicity and cytokinetic effects of Mitomycin C (MC) and/or photochemotherapy (PCT) in cultured human colon adenocarcinoma (WiDr) cells were investigated using colony formation to determine cell survival and DNA flow cytometry to analyze cell kinetics. 2. A low concentration of MC (0.01 micrograms/ml) caused accumulation of cells in late S and early G2 phase; higher concentrations (0.05-0.5 micrograms/ml) induced accumulation of the cells in mid and early S phase. 3. The effects of the lowest concentration of MC (0.01 micrograms/ml) were reversible upon removal of the drug, whereas a higher concentration of MC (0.1 micrograms/ml) resulted in a permanent inhibition of cell cycle progression. 4. The sensitivity of Photofrin II-loaded cells to PCT can be enhanced significantly by the addition of MC. 5. The MC-induced accumulation of the cells in S phase may be one reason for the increased cytotoxicity of PCT combined with MC. 6. The data suggest that MC may also inhibit repair of PCT-induced DNA damage.

Adenocarcinoma↗
PubMed1992

The relationship between skin cancers, solar radiation and ozone depletion.

During the period 1957-1984 the annual age-adjusted incidence rate of cutaneous malignant melanoma (CMM) increased by 350% for men and 440% for women in Norway. The annual exposure to carcinogenic sunlight in Norway, calculated by use of measured ozone levels, showed no increasing trend during the same period. Thus, ozone depletion is not a cause of the increasing trend of the incidence rates of skin cancers. The incidence rates of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) increase with decreasing latitude in Norway. The same is true for CMM in Norway, Sweden, and Finland. Our data were used to estimate the implications of a future ozone depletion for the incidence rates of skin cancer: a 10% ozone depletion was found to give rise to a 16-18% increase in the incidence rate of SCC (men and women), a 19% increase in the incidence rate of CMM for men and a 32% increase in the incidence rate of CMM for women. The difference between the numbers for men and women is almost significant and may be related to a different intermittent exposure pattern to sunlight of the two sexes. The increasing trend in the incidence rates of CMM is strongest for the trunk and lower extremities of women, followed by that for the trunk of men. The increasing incidence rates of skin cancers as well as the changing pattern of incidence on different parts of the body is most likely due to changing habits of sun exposure. Comparisons of relative densities of CMM, SCC, LMM and SCC falling per unit area of skin at different parts of the body indicate that sun exposure is the main cause of these cancer forms although other unknown factors may play significant roles as well. For the population as a whole sun exposure during vacations to sunny countries has so far been of minor importance in skin cancer induction.

Environmental Exposure↗
PubMed1992

Action spectra of phthalocyanines with respect to photosensitization of cells.

Human carcinoma cells (NHIK 3025 cells) and Chinese hamster cells (V79 cells) were incubated with AlPcS1, AlPcS2 and AlPcS4, phthalocyanines with different lipophilicity but with similar photochemical properties when in monomeric solutions. The absorption- and fluorescence spectra of the dyes in the cells were recorded as well as their action spectra with respect to sensitizing cells to photoinactivation. These spectra show that under the present conditions AlPcS1 is strongly aggregated in both cell lines; AlPcS2 is aggregated in V79 cells but much less so in NHIK 3025 cells. A main finding is that the shapes of the action spectra are similar to that of the fluorescence excitation spectra, but not to the absorption spectra, indicating that the photosensitizing effects of the dyes are mainly due to their monomeric fraction in the cells. AlPcS2 and AlPcS4 localize intracellularly mainly in lysosomes while AlPcS1 was found to be more diffusely distributed in cells. As measured per quantum of fluorescence emitted, AlPcS1 and AlPcS2 are more efficient sensitizers than AlPcS4. The difference in efficiency between AlPcS2 and AlPcS4 is supposedly due to a different localization pattern on the suborganelle level.

Animals↗
PubMed1992

Retention and phototoxicity of tetra(4-sulfonatophenyl)porphine in cultivated human cells. The effect of fractionation of light.

Human cervix carcinoma cells of the line NHIK 3025 were incubated for 18 h with tetra(4-sulfonatophenyl)porphine (TPPS4) and further incubated for 1-29 h in sensitizer free medium before exposure to light. After 1 h in sensitizer free medium only a 20% further loss of TPPS4 was observed within the next 28 h. During the time in sensitizer free medium, each TPPS4 molecule became more efficient in sensitizing single cells to photoinactivation. This enhanced photosensitizing efficiency of TPPS4 correlated well with the enhanced fluorescence yield of TPPS4. In some experiments the cells were exposed to a light dose inactivating 10% of the cells after incubation for 1 h in sensitizer free medium and a second graded light dose given 4-28 h later. Exposure of the cells to the first light dose led to loss of 60% of TPPS4 from the cells. Despite the significant loss of sensitizer from the cells the fluorescence yield of TPPS4 from each cell was found to increase (e.g. by 100% 4 h after light exposure). The enhanced fluorescence yield of cell bound TPPS4 was followed by a 1.6-2.5-fold increase in sensitivity of each cell to second light dose. Thus, a small light dose increased the photosensitivity of TPPS4-loaded NHIK 3025 cells for several hours after the first light exposure. The advantageous effect of light fractionation was reduced by a significantly enhanced loss of sensitizer induced by the first light exposure. The optimal time between the two fractions of light seems to be 30-90 min.

Humans↗
PubMed1992

Mitotic inhibition by phenylporphines and tetrasulfonated aluminium phthalocyanine in combination with light.

This work relates to studies on modes of phototoxicity by tetrasulfonated aluminium phthalocyanine (AlPcS4), tetrahydroxy- and monosulfonated meso-tetraphenylporphines (3-THPP and TPPS1) on culture cells. Toxicity at moderate light exposures appears to be related to inhibition of microtubule function. Treatment of human cervix carcinoma cells of the line NHIK 3025 incubated for 18 h with the sensitizers and exposed to light inhibits multiplication for the first hours after light exposure, a significant fraction of the cells accumulating in mitosis. For the first hours after treatment, the mitotic cells were always mainly found in metaphase; generally seen as c-metaphases and three-group metaphases. During this time, anaphase and telophase cells were absent or greatly reduced in number. Indirect immunofluorescence staining of beta-tubulin showed that the spindle apparatus of mitotic cells was perturbed in all cases. The accumulation in mitosis was more extensive after treatment with AlPcS4 and light than after treatment with 3-THPP or TPPS1 and light. This may be related to the great difference in the lipophilic properties of these sensitizers; i.e. AlPcS4 being highly water soluble while TPPS1 and 3-THPP are lipophilic sensitizers. The lipophilicity of several sensitizers has been measured by two different methods, the partition between an aqueous and a lipophilic phase (Triton X-114) and the binding strength to a reverse phase column. The results show that the measured relative lipophilicity of the sensitizers may be influenced by the method of analysis.

Carcinoma in Situ↗
PubMed1991

[Photochemotherapy of cancer].

Photochemotherapy of cancer is a new modality of cancer treatment now being evaluated in clinical trials worldwide. It is based on injection of photosensitizing and tumour-localizing dyes followed by exposure of the tumour region to intense light, usually from a laser. A large number of different types of tumours respond to photochemotherapy. However, for photochemotherapy to be efficient, it is absolutely essential that the entire tumour can be reached by light. Thus photochemotherapy is rarely efficient for tumours thicker than 5-7 mm, unless the light is applied interstitially through fibres. Fibre optics can also be used for endoscopic applications. It has been reported that extracorporeal photochemotherapy of T-cells, using 8-methoxypsoralene as sensitizer, has given good clinical results in patients suffering from the erythrodermic form of cutaneous T-cell lymphoma. Extracorporeal photochemotherapy for elimination of residual tumour cells from autologous bone marrow grafts is also being evaluated.

Humans↗
PubMed1991

Subcellular localization, redistribution and photobleaching of sulfonated aluminum phthalocyanines in a human melanoma cell line.

Intracellular localization, intracellular translocation and photobleaching following non-lethal laser microirradiation of the fluorescing derivatives of sulfonated aluminum phthalocyanines (Al-PcSn, n = 1-4) in a human melanoma cell line (LOX) were studied by means of confocal laser scanning microscopy (LSM) and image processing. Use of confocal microscopy allowed 3-dimensional information to be obtained. Both Al-PcS1 and Al-PcS2 localized diffusely in the cytoplasm of the cells, while Al-PcS3 and Al-PcS4 exhibited a granular pattern in the extranuclear fraction of the cells. None of the Al-PcSn family was observed in the nuclei of the cells except that a small fraction of fluorescence was occasionally detected in nuclei of some cells treated with Al-PcS1 and Al-PcS2. Furthermore, exactly the same granular localization patterns and positions in the same cells were found after incubation initially with Al-PcS3 (or Al-PcS4) followed by acridine orange (AO) which emits red fluorescence from lysosomes of cells. Thus, the granular fluorescence of Al-PcS3 and Al-PcS4 is confined to the lysosomes of the LOX cells. Non-lethal laser exposure of cells incubated with high concentrations of the 2 dyes resulted in a translocation of the dyes from the lysosomes to the whole cytoplasm and an increase in total intracellular fluorescence intensity. Finally, a small fraction of the dyes localized into the nuclei of the cells. The laser exposure of cells incubated with low concentrations of the lysosomally localized dyes resulted in an increase in the intracellular fluorescence intensity with no translocation of the dyes. Under all conditions, high laser exposure resulted in a decrease in the total intracellular fluorescence intensity.

Cell Nucleus↗
PubMed1991

Localization of potent photosensitizers in human tumor LOX by means of laser scanning microscopy.

By means of laser scanning fluorescence microscopy the intratumoral localization patterns of several photosensitizers in LOX tumors in nude mice were studied. Lipophilic dyes such as TPPS1 (tetraphenylporphine monosulfonate), TPPS2a (tetraphenylporphine disulfonates with the sulfonate groups on adjacent rings), AlPCS1 (aluminium phthalocyanine monosulfonate) and AlPCS2 (aluminium phthalocyanine disulfonates) localized mainly in tumor cells. The fluorescence intensity of these dyes increased from 4 h to 48 h postinjection and the fluorescence was still observable 120 h postinjection. The more hydrophilic dyes such as TPPS3 (tetraphenylporphine trisulfonates), TPPS4 (tetraphenylporphine tetrasulfonates), and AlPCS4 (aluminium phthalocyanine tetrasulfonates) localized mainly extracellularly in the tumorous stroma. The fluorescence intensity of these dyes decreased from 4 h to 48 h postinjection. 120 h postinjection no significant fluorescence of these dyes could be seen in the tumors. P-II (Photofrin II), 3-THPP [tetra(3-hydroxyphenyl)porphine], TPPS2o (tetraphenylporphine disulfonates with the sulfonate groups on opposite rings) and AlPCS3 (aluminum phthalocyanine trisulfonates) had a combined localization pattern, i.e. a strongly cytoplasmic membrane-localizing pattern and a weakly intracellular distribution pattern, although some fluorescence could be seen in the tumorous stroma. The data are discussed in relation to what is known about the in vivo photosensitizing efficiency of some of the dyes.

Animals↗
PubMed1991

The effect of glucose administration on the uptake of photofrin II in a human tumor xenograft.

Athymic BALB/c nude mice, bearing a human melanoma LOX, were given the photosensitizing drug Photofrin II (10 mg/kg body wt.) intraperitoneally. The mice were also given one of the following chemicals intraperitoneally: glucose, galactose and glucose plus nordihydroguaiaretic acid (NDGA) which is an inhibitor of glycolysis. Multiple injections of glucose (3 g/kg body wt. given at -1, 0, +1 and +3 h relative to the injection of 10 mg/kg of Photofrin II at time 0) resulted in a significant increase in the uptake of Photofrin II in the tumor 4 h after a Photofrin II injection, while the uptake of Photofrin II in the other tissues remained unchanged. Administration of galactose had no significant effect on the uptake of Photofrin II in the tissues studied (tumor, muscle, skin and liver). NDGA seemed to abolish the effect of glucose injection.

Animals↗
PubMed1991

Location of P-II and AlPCS4 in human tumor LOX in vitro and in vivo by means of computer-enhanced video fluorescence microscopy.

The patterns of in vitro intracellular and in vivo intratumoral localization of Photofrin II (P-II) and aluminum phthalocyanine tetrasulfonate (AlPCS4) in human melanoma LOX were studied by means of computer-enhanced video fluorescence microscopy (CEVFM). The hydrophobic drug P-II localized diffusely in the perinuclear fraction of the cytoplasm of the LOX cells cultivated in vitro. Light exposure did not result in any observable change in the localization pattern. The hydrophilic dye AlPCS4 was distributed as granular and grain patterns in the cytoplasm before light exposure, in exactly the same pattern as that of acridine orange incubated in the same cells, which is known to emit red fluorescence from lysosomes, thus indicating that AlPCS4 was also primarily localized in the lysosomes of the LOX cells. After light exposure the distribution of the intracellular AlPCS4 fluorescence was altered and the intensity increased. In vivo, P-II had a combined cellular localization pattern (i.e. a strongly cytoplasmic membrane-localizing pattern and a weakly intracellular distribution pattern) and an extracellular distribution pattern in the tumor tissue, while the AlPCS4 fluorescence was seen mainly in the stroma of the tumor. The total fluorescence intensity of P-II and AlPCS4 in the LOX tumor tissue at different times after injection was quantitatively determined by means of CEVFM.

Animals↗