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Biomedical subjects

J Moan

Publications and source records attributed to J Moan.

At least 163 records · Page 9Linked to original sources
PubMed1987

Hematoporphyrin ethers--I. Generalized synthesis and chemical properties.

A series of hematoporphyrin di-ethers, from methyl to hexyl, has been prepared by a generalized procedure based on reaction of the selected carbinol with the HBr adduct of protoporphyrin, followed by hydrolysis of ester functions and chromatographic purification. Spectroscopic and other properties are reported. They crystallize well. HPLC retention time increases linearly with the number of carbon atoms in the alcohol employed. In previous work we have shown that the more hydrophobic ethers are very efficient photosensitizers of malignant cells.

Chemical Phenomena↗
PubMed1987

A comparison of different photosensitizing dyes with respect to uptake C3H-tumors and tissues of mice.

Nine dyes, all potential sensitizers for photodynamic cancer therapy (PDT), were injected in mice with C3H mammary carcinomas. Twenty-four hours later the animals were sacrificed and the dye concentrations in tumors and 9 other tissues were measured by means of spectrofluorimetry. The 9 dyes were: Photofrin II (PII), hematoporphyrin (HP)-di-hexyl-ether, PSD-007 (a sensitizer used in clinical trials in China), tetraphenyl porphine tetrasulfonate (TPPS4), tetra(3-hydroxy phenyl)porphyrin (3THPP), aluminium phthalocyanine tetrasulfonate (AlPCTS), aluminium phthalocyanine (AlPC), chlorin e6 (Chl e6) and merocyanine 540 (MC 540). The porphyrin precursor delta-aminolevulinic acid was also tested and found to induce porphyrin fluorescence in tumors and some other tissues. The best tumorlocalizer of those tested was 3THPP. This drug also showed a favorable tissue distribution. The following dyes showed lower skin/tumor concentration ratios than PII (the most widely used dye for PDT): Chl e6, PSD-007, HP-di-hexyl-ether and 3THPP. Low brain/tumor ratios were found for: PSD-007, HP-di-hexyl-ether, 3THPP, TPPS4 and AlPCTS.

Animals↗
PubMed1987

Cellular uptake and photosensitizing properties of hematoporphyrin di-ethers with similar chromatographic properties as the tumorlocalizing fraction of hematoporphyrin derivative.

The di-methyl-, di-ethyl-, di-propyl-, di-normal butyl-, and di-iso-butyl-ethers of hematoporphyrin were synthesized and shown to possess chromatographic properties similar to those of the tumorlocalizing components of hematoporphyrin derivative (Hpd). The cellular uptake of these ethers, as well as their retention in cells during incubation with porphyrin free medium, increased with decreasing polarity and so did their efficiency in sensitizing cultured cells to photoinactivation. The least polar of the porphyrin ethers tested showed up to a 10-fold stronger efficiency in sensitizing cultured cells to photoinactivation than Hpd and Photofrin II (P II).

Cell Line↗
PubMed1987

Porphyrin derivatives having physical and chemical characteristics similar to those of the active components of hematoporphyrin derivative and with very strong photosensitizing effects.

The tumour-localizing fraction of hematoporphyrin derivative (Hpd) is thought to possess an essentially diporphyrin ether structure or, alternatively, a diporphyrin ester structure, the properties of which facilitate its retention in malignant cells and its biological activity on irradiation. To elucidate this problem further, we have synthesized the dimethyl, diethyl, dipropyl, di-n-butyl and di-iso-butyl ethers of hematoporphyrin. These ethers show chromatographic properties very similar to those of the active components of Hpd. Furthermore, they are much better photosensitizers in a cellular system than are crude Hpd or Photofrin II, and, like the components of Hpd, they are taken up and retained by cells according to their degree of non-polarity.

Carcinoma in Situ↗
PubMed1987

Photodynamic therapy of C3H mouse mammary carcinoma with haematoporphyrin di-ethers as sensitizers.

Haematoporphyrin di-ethers were synthesized and tested as sensitizers for photodynamic therapy of C3H/Tif mammary tumours in mice. Growth curves of the tumours were determined by measuring the tumour volume. The animals were given 25 mg porphyrins kg-1 body weight i.p. and 24 h later exposed to 135 J cm-2 of 630 nm light at a fluence rate of 150 mW cm-2. The sensitizing efficiency of the ethers was measured in terms of the increase in growth time of the treated tumours, as compared with that of untreated controls, needed to reach a volume 5 times larger than that at the time of the treatment. This sensitizing efficiency increased with decreasing polarity, i.e. in the order di-methyl ether, di-propyl ether, dibutyl ether and di-amyl ether. Haematoporphyrin di-amyl ether was more efficient than haematoporphyrin derivative and insignificantly less efficient than photofrin II (DHE). This was true for sensitization of both tumours and normal tissue.

Animals↗
PubMed1987

Toxic and phototoxic effects of tetraphenylporphinesulphonate and haematoporphyrin derivative in vitro.

The toxic and phototoxic effects of tetraphenylporphinesulphonate (TPPS4) and haematoporphyrin derivative (HpD) have been examined in vitro. TPPS4 was found to have less dark toxicity to the cells than HpD as measured by inhibition of cell multiplication and colony formation at comparable extracellular concentrations. TPPS4 was also less effective than was HpD in photoinactivating NHIK 3025 cells by more than a factor 2 which should be expected on the basis of cellular uptake. Spectrofluorometric data suggest that HpD in cells interacts more with lipids than TPPS4. This might explain the large photosensitizing effect of HpD compared to TPPS4 since the lifetime of singlet oxygen is about a factor of 10 longer in a lipid environment than in an aqueous environment. The uptake of TPPS4 and HpD by cancer cells in vitro does not correlate with previous in vivo data, indicating retention of TPPS4 in the tumour stroma. This makes in vitro/in vivo extrapolation difficult with regard to the use of TPPS4 as an agent for photodynamic therapy.

Biological Transport↗
PubMed1986

Effect of bleaching of porphyrin sensitizers during photodynamic therapy.

Cells of the line NHIK 3025 were incubated with the tumor-localizing porphyrin preparation DHE (Photofrin II). Exposure of light within the porphyrin absorption spectrum resulted in a change of the fluorescence spectra indicative of a movement of porphyrins from binding sites on proteins to more lipid environments, a degradation of the porphyrins in the cells without any significant formation of new porphyrin species. The photodegradation of the porphyrins resulted in a reduced yield of inactivation of cells per incident photon. Several independent estimations indicate that bleaching may play a role in clinical situations.

Cell Line↗
PubMed1986

Changes in antigen expression on human FME melanoma cells after exposure to photoactivated hematoporphyrin derivative.

Exponentially growing melanoma cells of the line FME were incubated with hematoporphyrin derivative (HpD) for 1 and 18 h and subsequently exposed to light in the presence of HpD. Quantitative changes in the expression of the melanoma-associated surface antigen p250 recognized by the monoclonal antibody 9.2.27 were studied by flow cytometry. Treatment with HpD and light resulted in no immediate changes in the antigen expression. However, a few hours after light exposure a significant reduction in antigen expression was observed. For cells incubated with HpD for 1 h, the minimum expression of the antigen was observed 6 h after the irradiation, and the duration of the reduced expression was almost dose independent. On the other hand, the duration of the reduced antigen expression increased strongly with light dose for cells incubated with HpD for 18 h. In both cases antigen expression decreased exponentially with the product of drug concentration and light dose, indicating that there is no rapid mechanism by which the cells can repair the damage which leads to reduced antigen expression. Days were needed before the cells expressed a normal level of the antigen. A slight overshoot of the level of antigen expression above that for untreated cells was observed 2-5 days after light exposure depending on the incubation conditions with HpD and the light dose. At a given cell survival level (greater than 0.1), the decrease in antigen expression was more pronounced on cells incubated with HpD for 1 h than on cells incubated with the drug for 18 h.

Antigens, Neoplasm↗
PubMed1985

The binding of dihematoporphyrin ether (photofrin II) to human serum albumin.

The variable aggregation of porphyrins such as Hp and Hpd introduces uncertainties and errors into attempts to measure their binding to proteins. Methods such as dialysis, ultrafiltration and gel chromatography, so frequently used, proved to be unreliable when applied to the binding of Hp to serum albumin. Quenching of tryptophan fluorescence will only occur at porphyrin binding sites which are closely situated to the tryptophan residue (1.7 nm). Porphyrin bound to more distant sites may not be included in this analytical procedure which must therefore be applied with reserve. In the present work, photofrin II (PII) was shown to consist of large aggregates greater than 20 000-30 000 Mr, solutions of which did not disaggregate on dilution down to 1 mumol/1. Addition of albumin resulted in a change in the absorption spectrum of PII. Thus, it was assumed that measurements of differential absorption gave the proportion of free-to-bound PII when serum albumin was added in graded amounts to its solution. By applying suitable calculations to the data, an association constant of 0.3 1/mumol +/- 30% was deducted. Hill plots of the binding data were linear with slopes close to unity. Experimentally determined uptake of PII by NHIK 3025 cells from solutions containing different amounts of HSA showed that the amount bound to the cells was proportional to the free PII. The kinetics of quenching of tryptophan fluorescence in HSA by PII indicates that there is one main porphyrin-binding site affecting this fluorescence. This binding site seems to have a slightly higher affinity for PII than the remaining sites. Up to 8 porphyrin rings of PII can be bound to an HSA molecule.

Cell Line↗
PubMed1985

Photodynamic effects and hyperthermia in vitro.

Cells from the established human line NHIK 3025 were labelled with hematoporphyrin derivative in vitro. Subsequently, the cells were treated with light and hyperthermia. The cells could be irradiated either before, during or after the incubation at a hyperthermic temperature. It was shown that hyperthermia given shortly after the light exposure gave a synergistic killing effect. In spite of some loss of porphyrins from the cells, the light sensitivity increased 20 min after a light irradiation. At later times, the cells apparently repaired some of the photodynamic damage at 37 degrees C. At higher temperatures, the repair was inhibited.

Carcinoma in Situ↗
PubMed1985

Oxygen dependence of the photosensitizing effect of hematoporphyrin derivative in NHIK 3025 cells.

Cells of the established line NHIK 3025 were incubated with hematoporphyrin derivative and exposed to light at different concentrations of oxygen. The efficiency of photoinactivation of the sensitized cells decreased with decreasing oxygen concentration. No photoinactivation was observed when the atmosphere above the medium overlying the cells was pure N2 gas. With 1% O2 in the atmosphere, the quantum yield of photoinactivation was reduced by 50% compared to the yield in air-saturated medium. It is hardly possible to inactivate cells in anoxic regions of a tumor by means of porphyrin sensitized photochemotherapy. In spite of this, the therapy seems to be efficient in several cases. Thus, it seems that anoxic tumor cells are inactivated in secondary reactions, probably due to breakdown of the circulatory system in the tumor.

Carcinoma in Situ↗