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At least 19 recordsLinked to original sources

Systemic lupus erythematosus: association with psoralen--ultraviolet-A treatment of psoriasis.

Systemic lupus erythematosus (SLE) developed in as 23-year-old woman with psoriasis during treatment with psoralen-ultraviolet-A (PUVA). The connective tissue disease was characterized by an erythematous rash, hair loss, nephritis, splenomegaly, seizures, and coma. Serum antinuclear antibodies were present in high titer, and hypocomplementemia developed. Antibodies to native or ultraviolet-irradiated DNA were not demonstrated. While the association of psoriasis and lupus may have been fortuitous, the temporal relationships suggest that PUVA treatment in this case may have been of pathogenetic importance in the development of the connective tissue disease.

Adult

Antimutagenic activities of naturally occurring polyamines in Chinese hamster ovary cells in vitro.

Spermine and spermidine, ubiquitous polyamines present in bacteria and animal cells, are also involved in cell growth. Since they interact with the double helix, they can stabilize the DNA molecule. Recent evidence of the antimutagenic and anticarcinogenic capacity of spermine has focused attention on the mechanism(s) by which such agents can protect cells from induced damages. In the present paper we show the ability of spermine and spermidine to decrease the level of sister chromatid exchanges induced in Chinese hamster ovary cells cultivated in vitro, by treating them with Psoralen + UVA irradiation (able to induce mainly monoadducts and DNA cross-links). Two different mechanisms of polyamine action can be invoked to explain the preservative activity of this class of agents.

Animals

Mutagenicity of cross-links and monoadducts of furocoumarins (psoralen and angelicin) induced by 360-nm radiation in excision-repair-defective and radiation-insensitive strains of Saccharomyces cerevisiae.

The furocoumarin psoralen can form both monoadducts and cross-links with DNA when combined with 360-nm radiation, whereas the analog angelicin can form monoadducts only. Psoralen plus 360-nm radiation causes mutation induction with a slope of 2 (log-log plot) for a radiation-insensitive strain, whereas angelicin action with 360-nm radiation displays a slope of unity. For a radiation-sensitive mutant defective in the excision-repair pathway, the actions of both angelicin and psoralen plus 360-nm radiation exhibit one-target kinetics, but at higher exposures psoralen plus 360-nm radiation assumes a slope of 2. The excision-repair-defective strain is considerably more sensitive to the furocoumarins plus 360-nm radiation than is the radiation-insensitive strain, both for killing and mutation induction. The simplest explanation for the data is that both cross-links and monoadducts, formed by furocoumarins with DNA when exposed to 360-nm radiation, are capable of inducing mutations, and that monoadducts are repaired 20 times more efficiently than cross-links by the excision-repair pathway.

DNA Repair

Specific cellular defects in patients with Fanconi anemia.

Measurements of plating efficiency, accumulation of metaphases and generation times have shown that fibroblast from patients with Fanconi anemia (FA) have decreased probability of completing a further division after successful mitosis. Thus FA cells show decreased growth rates and increased generation times. We have also measured the survival of FA fibroblasts and lymphoblasts after treatment with a variety of mutagens. All FA cells show an increased sensitivity to drugs such as MMC and psoralen plus long wave length UV which cause DNA interstrand crosslinks. FA strains show varying degrees of sensitivity to these drugs and the extent of this sensitivity seems to be characteristic of each patient. FA cells are equal to controls in their sensitivity to other alkylating agents such as ethyl methane sulfonate, N-methyl-N1-nitro-N-nitrosoguanidine and actinomycin D. Both the decreased growth and increased drug sensitivity may result from defect in DNA replication or repair.

Adolescent

Preparation and skin-photosensitizing activity of substituted psoralens.

8-Monosubstituted and 5,8-disubstituted psoralen derivatives were prepared, and their skin-photosensitizing activity was evaluated. The results were correlated in terms of molecular configuration, and 8-allyloxypsoralen can be considered was a new agent of potent photodynamic activity.

Adjuvants, Pharmaceutic

Repair of cross-linked DNA in Escherichia coli.

The repair of DNA containing interstrand cross-links in Escherichia coli was studied by following the temporal sequence of DNA-related metabolic events in cells exposed to psoralen plus light. Mutations in some genes controlling replication, recombination, and repair strongly influence these specific events. Results reported here are consistent with a cross-link repair mechanism involving sequential excision and recombination.

Binding Sites

A practical procedure for the determination of electrostatic charges of large molecules.

A practical procedure for the precise determination of electrostatic charges, which are evaluated by fitting the rigorous quantum mechanical molecular electrostatic potential to a monopole-monopole expression, is presented. The proposal of this procedure arises from the study of the minimum requirements necessary to obtain reliable electrostatic charges. Such a study is focused on: (i) the dependence of the electrostatic charges on the set of points where the quantum mechanical and the monopole-monopole molecular electrostatic potentials are fitted; thus, both the influence of the number of points and their distribution in layers located out of the van der Waals radii of the atoms are examined, and (ii) the reliability of the use of fractional models for the evaluation of electrostatic charges of large molecules. Results point out that the optimum number of points is defined by a density of points ranging from 0.45 to 0.60 points/A2 when four layers (separated by 0.2 A) are considered. Nevertheless, the use of only two layers (separated by 0.4 A) for large molecules is recommended, thus enabling one to obtain reliable charges at a reduced computational cost. Moreover, results justify the use of fractional models for the determination of electrostatic charges of extremely large molecules, even when aromatic structures exist.

Adenosine

Preferential deletion of a specific region of mitochondrial DNA in Saccharomyces cerevisiae by ethidium bromide and 3-carbethoxy-psoralen: directional retention of DNA sequence.

Grande strains of Saccharomyces cerevisiae were mutagenized either by ethidium bromide or by 3-carbethoxy-psoralen (a monofunctional furocoumarin derivative) activated by 365nm light. 973 primary rho- clones induced were randomly collected and analyzed individually for the presence or absence of fifteen mitochondrial genetic markers. 1. Under mild conditions of mutagenesis, 83% of the primary clones showed single-deletion genotypes; a unique order of 14 markers could be deduced from the patterns of the deletion. The gene order confirmed our previous map constructed from the analysis of established non-random petite clones. From the frequencies of disjunction between markers, the distance separating 14 mitochondrial markers were estimated. 2. One region, carrying oxi-3, pho-1 and mit 175 loci, was preferentially lost in rho- mutants: there is a strong constraint in the frequencies of various genotypes found in rho- clones. On each side of this particular region, a bidirectionally oriented pattern of retention of markers is observed.

Base Sequence

Differential repair and recombination of psoralen damaged plasmid DNA in Saccharomyces cerevisiae.

Psoralen photoreaction with DNA produces interstrand crosslinks, which require the activity of excision and recombinational pathways for repair. Yeast replicating plasmids, carrying the HIS3, TRP1, and URA3 genes, were photoreacted with psoralen in vitro and transfected into Saccharomyces cerevisiae cells. Repair was assayed as the relative transformation efficiency. A recombination-deficient rad52 strain was the least efficient in the repair of psoralen-damaged plasmids; excision repair-deficient rad1 and rad3 strains had repair efficiencies intermediate between those of rad52 and RAD cells. The level of repair also depended on the conditions of transformant selection; repair was more efficient in medium lacking tryptophan than in medium from which either histidine or uracil was omitted. The plasmid repair differential between these selective media was greatest in rad1 cells, and depended on RAD52. Plasmid-chromosome recombination was stimulated by psoralen damage, and required RAD52 function. Chromosome to plasmid gene conversion was seen most frequently at the HIS3 locus. In RAD and rad3 cells, the majority of the conversions were associated with plasmid integration, while in rad1 cells most were non-crossover events. Plasmid to chromosome gene conversion was observed most frequently at the TRP1 locus, and was accompanied by plasmid loss.

DNA

Mitochondrial genetic damage induced in yeast by a photoactivated furocoumarin in combination with ethidium bromide or ultraviolet light.

Ethidium bromide (EB) and ultraviolet light (UV) in combination are known to produce a synergistic induction of "petite" mutants in yeast. Two other agents were combined with EB, 3-Carbethoxypsoralene (3 CPs) activated by 365 nm light or gamma rays. EB in combination with 3 CPs also resulted in an enhanced production of "petite" mutants. After the photoaddition of 3 CPs in exponential phase cells, recovery of the "petite" mutation during dark liquid holding was inhibited by the presence of EB producing an enhanced number of "petite" mutants. The behavior of mitochondrial antibiotic resistance markers after individual and combined treatments with EB and 3 CPs indicates a random loss of markers after EB and a preferential loss of a certain region for the 3 CPs photoaddition. The combination of the two agents leads to an additivity of total drug marker losses rather than a synergistic loss. The combination of EB with gamma rays produced no enhancement in "petite" induction. A combination of UV and 3 CPs showed a synergistic interaction for "petite" induction. These results indicate that the three agents, EB, UV and 3 CPs photoaddition may share a common repair step for mitochondrial lesions.

Coumarins

Photoprotective effect of a psoralen-UVA-induced tan.

To determine whether a tan produced by 8-MOP and UVA protects from subsequent solar light irradiation, volunteers were irradiated with unfiltered Xenon arc light before and 10 days after a 1 week's course of four 8-MOP-UVA treatments. Evaluation of the minimal erythema doses and of histological changes before and after 8-MOP-UVA treatment revealed that the 8-MOP-UVA induced tan protected against the erythemogenic and cell damaging effects of Xenon arc light. Unscheduled repair DNA synthesis, used as a measure for UVB-induced DNA damage and repair, was also investigated in skin irradiated with the Xenon arc before and after 8-MOP-UVA induced tanning. Both the number of grains per sparse labeled cell and the number of sparse labeled cells per 1000 cells, were found to be significantly lower in tanned skin; taking decreased unschedules repair DNA synthesis as a measure for decreased DNA-damage, these findings also demonstrate a photoprotective effect of the 8--MOP-UVA induced tan.

DNA Repair

Psoralen/UVA treatment and chromosomes. II. Analyses of psoriasis patients.

Five psoriasis patients treated with 8-methoxypsoralen and UVA (PUVA) were studied by lymphocyte cultures at the 1st, 5th, 10th and 20th treatment and at a maintenance treatment 6 months later. Abnormal amounts of chromosome aberrations were not found, and the frequency of sister chromatid exchange (examined at the last treatment) was not increased. In vitro experiments with nanogram doses of psoralen (similar to plasma levels in patients) showed no increase in chromosome aberration or SCE freqency. The results indicate that therapeutic doses of PUVA have no clastogenic effect.

Adult

Impairement of thymus derived rosette forming cells during photochemotherapy (psoralen--U.V.A.).

Lymphocyte subpopulations were studied in 45 PUVA treated patients and in 45 controls matched for sex and age. The results demonstrate that, in vivo PUVA induces a decrease in the capacity of the E-Rosette formation by lymphocytes separated from the peripheral blood. However, the circulating lymphocytes count remains unchanged. Mitogen induced blastogenesis is not affected. No correlation is found between the decrease in the level of E-rosettes, the disease which motivated PUVA therapy, the energy in UVA and the number of irradiation. Electrical and/or chemical modifications on the cell surface of the lymphocytes during PUVA therapy are postulated to explain this phenomenon.

Coumarins