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At least 253 records · Page 14Linked to original sources
PubMed2002

Photochemical treatment of donor lymphocytes inhibited their ability to facilitate donor engraftment or increase donor chimerism after nonmyeloablative conditioning or establishment of mixed chimerism.

Donor T-cells can provide a graft-versus-leukemia effect and help to promote donor engraftment after allogeneic BMT; however, these benefits can be outweighed by the ability of the cells to induce life-threatening GVHD. Photochemical treatment (PCT) of T-cells with S-59 psoralen and long-wavelength UV-A light can inhibit their proliferative capacity and significantly decrease their ability to induce acute GVHD after allogeneic BMT. PCT donor T-cells have been shown to facilitate donor engraftment in a myeloablative BMT model. In this study, we examined whether donor T-cells subjected to PCT ex vivo could retain the ability to facilitate engraftment or increase donor chimerism after nonmyeloablative BMT or after establishment of mixed hematopoietic chimerism. In a transplantation model in which mice were conditioned for BMT with sublethal (600 cGy) TBI, an infusion of PCT donor T-cells was unable to facilitate engraftment of donor BM. A BMT model was used in which a mixture of allogeneic and syngeneic marrow cells was infused into lethally irradiated recipients for establishment of mixed hematopoietic chimerism. The goal was to determine whether PCT donor splenocytes could increase levels of donor chimerism. Recipients of splenocytes treated with UV-A light only (no S-59 psoralen) and given at the time of BMT or in a donor lymphocyte infusion (DLI) had significantly higher levels of donor chimerism than did recipients of BM only. Although PCT donor splenocytes given at the time of BMT modestly increased donor chimerism, PCT donor splenocytes given in a DLI did not increase donor chimerism. A nonmyeloablative BMT model was employed for determining whether DLI given relatively late after BMT could increase donor chimerism. Recipient mice were conditioned for BMT with a combination of low-dose TBI (50 or 100 cGy) and anti-CD154 (anti-CD40L) monoclonal antibody for achievement of low levels of mixed chimerism. When control mixed chimeras were given a DLI 71 days after BMT, donor chimerism was significantly increased. In contrast, PCT of the donor cells eliminated the ability of the cells to increase donor chimerism after infusion. Together results from these 3 distinct BMT models indicate that PCT of donor T-cells significantly inhibited the ability of the cells to facilitate donor engraftment after nonmyeloablative BMT or to increase donor chimerism in mixed hematopoietic chimeras when the cells were administered in a DLI.

Animals↗
PubMed2006

Clinical experience: practical management of five patients with cutaneous T-cell lymphoma (CTCL)-related symptoms.

There are now a wide variety of therapeutic options for managing patients with cutaneous T-cell lymphoma-related symptoms. These include skin-directed therapies such as psoralen with UVA irradiation (PUVA), topical chemotherapies such as mechlorethamine (nitrogen mustard) and carmustine (BCNU), electron beam radiation, and systemic therapies such as chemotherapy, photopheresis, and interferons. Although treatment algorithms exist for patients with early stage disease, often treatments are individualized, based on patient specific factors, cost, and accessibility of referral centers for specialized therapies. This article provides details of five real-life case studies to illustrate how cutaneous T-cell lymphoma management can be tailored to the needs of each individual patient.

Aged↗
PubMed2001

Bakuchiol: a hepatoprotective compound of Psoralea corylifolia on tacrine-induced cytotoxicity in Hep G2 cells.

Bioassay-guided fractionation of the H(2)O extract of the seeds of Psoralea corylifolia furnished one hepatoprotective compound, bakuchiol (1), together with two moderately active compounds, bakuchicin (2) and psoralen (3), on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells. The EC(50) values of compounds 1 - 3 are 1.0, 47.0, 50.0 microg/ml, respectively. Silymarin as a positive control showed the EC(50) value with 5.0 microg/ml.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Photosensitization and mutation induced in Escherichia coli and Saccharomyces cerevisiae strains by dorstenin, a psoralen analog isolated from Dorstenia bahiensis.

Dorstenin, 5-[3-(4,5-dihydro-5,5-dimethyl-4-oxo-2-furanyl)-butoxy]-7H-furo[3, 2-g] benzopyran-7-one, is a psoralen analog recently isolated from Dorstenia species (Moraceae). In order to characterize its biological activity, its photosensitizing and mutational properties were measured in wild-type E. coli and S. cerevisiae and also in strains carrying mutations which affect DNA repair. Compared to the high activities of psoralen and bergapten, dorstenin showed lower genotoxic effect.

5-Methoxypsoralen↗
PubMed2004

DNA-psoralen interaction: a single molecule experiment.

By attaching one end of a single lambda-DNA molecule to a microscope coverslip and the other end to a polystyrene microsphere trapped by an optical tweezers, we can study the entropic elasticity of the lambda-DNA by measuring force versus extension as we stretch the molecule. This powerful method permits single molecule studies. We are particularly interested in the effects of the photosensitive drug psoralen on the elasticity of the DNA molecule. We have illuminated the sample with different light sources, studying how the different wavelengths affect the psoralen-DNA linkage. To do this, we measure the persistence length of individual DNA-psoralen complexes.

Chemistry, Physical↗
PubMed2006

A theoretical insight into the photophysics of psoralen.

Psoralen photophysics has been studied on quantum chemistry grounds using the multiconfigurational second-order perturbation method CASPT2. Absorption and emission spectra of the system have been rationalized by computing the energies and properties of the low-lying singlet and triplet excited states. The S1 pipi* state has been determined to be responsible of the lowest absorption and fluorescence bands and to initially carry the population in the photophysical processes related to the phototherapeutic properties of psoralen derivatives. The low-lying T1 pipi* state is, on the other hand, protagonist of the phosphorescence, and its prevalent role in the reactivity of psoralen is suggested to be related to the elongation of the pyrone ring C3-C4 bond, where the spin density is distributed on both carbon atoms. Analysis of energy gaps and spin-orbit coupling elements indicates that the efficient photophysical process leading to the population of the lowest triplet state does not take place at the Franck-Condon region but along the S1 relaxation path.

Absorption↗
PubMed2002

The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis.

BACKGROUND: In the general population, squamous cell carcinomas (SCCs) of the male genitalia are rare. Ten years ago, we documented a significant dose-dependent increase in the risk of malignant genital neoplasms among men treated with psoralen plus ultraviolet A (PUVA). Since that time, fewer cohort patients have used PUVA, and genital protection among PUVA users is likely to be frequent. OBJECTIVE: Our aim was to determine the incidence and risk factors for genital neoplasms since 1989 and risk factors for these neoplasms among patients treated with PUVA. METHODS: We conducted a prospective cohort study of 892 men first treated with PUVA in 1975-1976. RESULTS: Twenty-four men (2.7%) had 51 genital neoplasms, including 10 patients with a first tumor after May 1, 1989 (the ending date for our 1990 report). Since May 1, 1989, the incidence of invasive penile and scrotal SCCs was elevated 52.6-fold (95% confidence interval, 19.3-114.6) compared with that expected for the general white population. Multivariate models revealed the highest genital tumor risk among men with high-dose exposure to both PUVA and topical tar/ultraviolet B, with an incidence rate ratio of 4.5 (95% confidence interval, 1.3-16.1) compared with the low-dose exposure group. CONCLUSION: Although use of PUVA has decreased and genital shielding in our cohort has increased, the dose-dependent increase in the risk of genital tumors in men treated with PUVA has persisted. Particularly high risks occur among those with high-dose exposures to both PUVA and topical tar/ultraviolet B.

Adult↗
PubMed2002

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions.

Nucleotide excision repair (NER) plays a central role in maintaining genomic integrity by detecting and repairing a wide variety of DNA lesions. Xeroderma pigmentosum complementation group A protein (XPA) is an essential component of the repair machinery, and it is thought to be involved in the initial step as a DNA damage recognition and/or confirmation factor. Human replication protein A (RPA) and XPA have been reported to interact to form a DNA damage recognition complex with greater specificity for damaged DNA than XPA alone. The mechanism by which these two proteins recognize such a wide array of structures resulting from different types of DNA damage is not known. One possibility is that they recognize a common feature of the lesions, such as distortions of the helical backbone. We have tested this idea by determining whether human XPA and RPA proteins can recognize the helical distortions induced by a DNA triple helix, a noncanonical DNA structure that has been shown to induce DNA repair, mutagenesis, and recombination. We measured binding of XPA and RPA, together or separately, to substrates containing triplexes with three, two, or no strands covalently linked by psoralen conjugation and photoaddition. We found that RPA alone recognizes all covalent triplex structures, but also forms multivalent nonspecific DNA aggregates at higher concentrations. XPA by itself does not recognize the substrates, but it binds them in the presence of RPA. Addition of XPA decreases the nonspecific DNA aggregate formation. These results support the hypothesis that the NER machinery is targeted to helical distortions and demonstrate that RPA can recognize damaged DNA even without XPA.

Base Sequence↗
PubMed1976

Electron microscopy of DNA crosslinked with trimethylpsoralen: test of the secondary structure of eukaryotic inverted repeat sequences.

It has been suggested that inverted repeat (palindrome) sequences, which are widespread in eukaryotic genomes, exist in two alternate configurations, a linear form and a cruciform. To investigate the relative frequency of these forms, the DNA of intact mouse tissue culture cells was covalently crosslinked with 4,5',8-trimethylpsoralen (me3-psoralen) in order to prevent rearrangement of the DNA secondary structure during DNA isolation. The distribution of me3-psoralen crosslinks was determined by electron microscopy after denaturation of the DNA in the presence of glyoxal. Because of the high frequency and the relatively uniform distribution of the me3-psoralen crosslinks, it could be concluded that almost all of the inverted repeat sequences had been crosslinked. In spite of this, no significant number of cruciforms was detected by electron microscopy. To determine whether the me3-psoralen might itself be disrupting cruciform structures, cruciforms were first produced in isolated Tetrahymena rDNA by heat treatment and then crosslinked in vitro. The crosslinking was found to stabilize rather than disrupt these cruciforms. We conclude that the inverted repeat sequences of the mouse tissue culture cells we tested are predominantly in linear forms rather than in cruciform structures inside the cell.

Base Sequence↗
PubMed1976

Psoralen-crosslinked secondary structure map of single-stranded virus DNA.

The photochemical crosslinking of DNA by 4,5',8-trimethylpsoralen (trioxsalen) has been used to freeze the secondary structures of single-stranded DNA molecules of bacteriophage fd at different ionic strengths. These secondary structures (hairpins or looped hairpins) have been visualized in the electron microscope. Most of the single-stranded circular fd DNA molecules show only one hairpin after irradiation at 15 degrees in 20 mM NaCl in the presence of trioxsalen. As the ionic strength is increased, more hairpins appear on the DNA molecules. To map these secondary structures, double-stranded supercoiled fd DNA (RFI) was cleaved with the restriction enzyme HindII, which makes only one cut on each RFI molecule. After denaturation and crosslinking of the linear single-stranded fd DNA (a mixture of viral and complementary strands), all the hairpins have been mapped on the DNA molecule with respect to this HindII site. The results show that these hairpins occur at specific sites. The most stable hairpin has been assigned to the position where the initiation site for the conversion of single-stranded fd DNA to the double-stranded covalently closed form has been mapped. The remaining hairpins map in or near regions corresponding to in vitro promoter sites on the fd DNA.

Chromosome Mapping↗
PubMed1977

Initiation of genetic exchanges in lambda phage--prophage crosses.

When Escherichia coli K-12 (lambda) lysogens were infected with lambda phages, genetic exchanges between phage and prophage occurred at low frequencies (less than 0.1% between the markers P3 and P80), but at frequencies above 1% if the infecting phages were first treated with the photosensitizing agent 4,5',8-trimethylpsoralen and 360 nm light. Exchanges were induced by psoralen damage at about the same frequency in wild-type lysogens and in those carrying recB(-), recC(-), recF(-), or lexA(-), but at an intermediate frequency in a quadruple mutant carrying recB(-)recC(-)recF(-)sbcB(-). Few if any exchanges were induced in lysogens carrying uvrA(-), uvrB(-), or recA(-). The increase in the frequency of recombination was presumably due to the psoralen damage in the phage DNA molecules and the action of host cell repair and recombination enzymes. The production of crosslinks in the phage DNA by psoralen and 360 nm light was measured by sedimentation in alkali. It showed second-order kinetics indicative of a two-photon reaction. In contrast, first-order kinetics had been reported for monoadduct formation. Second-order kinetics, similar to those for crosslink production, were found for genetic exchanges in homoimmune crosses. Presumably, crosslinks, rather than monoadducts, cause most of the exchanges. Because the uvrA(-) gene product (UV-endonuclease) was required, it is likely that recombination was initiated by DNA molecules cut at crosslinks. This system has been used to show that after the crosslinked phage duplex has been cut, one or more of the subsequent steps-homologous pairing, cutting, and joining-require the recA(+) gene product.

Coliphages↗
PubMed1978

Homology-dependent cutting in trans of DNA in extracts of Escherichia coli: an approach to the enzymology of genetic recombination.

An in vitro system is described in which the cutting of crosslinked phiX replicative form (RF) I DNA molecules by the uvr system of Escherichia coli induces the cutting of homologous undamaged DNA during incubation with crude extracts of thermally induced E. coli (lambda precA+) lysogens. This reaction, which has also been observed in intact E. coli lysogens infected with lambda phages, is dependent on the presence of functional recA+ and uvrB+ gene products. Extracts from thermally induced lambda precA+ lysogens of E. coli proved to be substantially more active than extracts from nonlysogenic cells of the same strain. The results provide preliminary evidence for an endonuclease activity that cuts intact superhelical DNA in response to interaction with homologus damaged DNA. In the present paper, we describe an in vitro system in which both the endonucleolytic cutting of DNA containing crosslinks and the induced cutting of undamaged DNA can be studied without purification of the participating enzymes. Although the information obtained is fragmentary and often puzzling, we feel that this system can contribute to an understanding of the complex mechanisms involved in repair and recombination.

Coliphages↗
PubMed1978

Topography and kinetics of genetic recombination in Escherichia coli treated with psoralen and light.

Genetic exchanges appear to be involved in repair of cross-linked DNA. Kinetics for completion of repair and strand rejoining controlled by the recA(+) gene were examined in Escherichia coli treated with psoralen and light. The results suggest the following model for genetic recombination. After cross-linking treatment, cells in a population initiate repair in near synchrony. Removal of DNA cross-links, preparation of substrate for recombination, and initiation of the first recA-dependent event are completed in less than 1 min. Recombination events occur singly in each cell or chromosome, and require 2.3 +/- 0.4 min at 32 degrees for the recA(+)-dependent step. After completion of the first event, subsequent recombination events occur in a sequential or progressive fashion around the chromosome or in clusters which may consist of one or more domains of the folded chromosome. The time required to proceed to successive sites is either a constant, independent of the distance on the chromosome, or is quite small compared to 2.3 min. DNA substrate for recombination decays with approximate first-order kinetics and the rate is dependent on the number of unrepaired sites. Cell survival can be expressed as a competition between completion of all repair events and the simultaneous decay of chromosomes to forms not reparable by recombination.Equations relating kinetics for completion of repair, the size distribution of DNA molecules, and cell survival are derived for the above model, using as parameters only rate constants for recombination and decay of substrate, and number of events per chromosome. An excellent correlation is found between experimentally determined and theoretical values.

DNA Repair↗
PubMed1986

Action mechanism of ABC excision nuclease on a DNA substrate containing a psoralen crosslink at a defined position.

Many carcinogenic as well as chemotherapeutic agents cause covalent linkages between complementary strands of DNA. If unrepaired, DNA crosslinks are blocks to DNA replication and transcription and therefore represent potentially lethal lesions to the cell. Genetic studies of Escherichia coli have demonstrated that the repair enzyme ABC excision nuclease, coded for by the three unlinked genes, uvrA, uvrB, and uvrC, plays a crucial role in DNA crosslink repair. To study the molecular events of ABC excision nuclease-mediated crosslink repair, we have engineered a DNA fragment with a psoralen-DNA interstrand crosslink at a defined position, digested this substrate with pure enzyme, and analyzed the reaction products on DNA sequencing gels. We find that the excision nuclease cuts only one of the two strands involved in the crosslink, incises the crosslink by hydrolyzing the ninth phosphodiester bond 5' and the third phosphodiester bond 3' to the furan-side thymine of the crosslink, and does not produce double-strand breaks at any significant level. Based on these data, we present a model by which ABC excision nuclease initiates crosslink repair in vivo.

DNA↗
PubMed1986

Use of nonisotopic M13 probes for genetic analysis: application to HLA class II loci.

Previously, DNA polymorphisms in the HLA gene cluster have been analyzed using radioactive probes in Southern blot experiments; the restriction fragment length polymorphisms (RFLPs) revealed by this analysis are capable of subdividing HLA serological types. Here, we report the use of DNA probes labeled with biotinylated psoralen to provide nonisotopic detection of HLA class II RFLP patterns. These biotinylated probes contain cDNA sequences encoding the alpha and beta chains of DP, DQ, and DR HLA class II genes as inserts in M13 vectors. The recombinant M13 molecules are partially double-stranded with single-stranded HLA cDNA regions and contain biotinylated psoralen covalently linked to duplex DNA by UV irradiation. Following hybridization, the presence of biotinylated probe bound to target DNA is detected using a streptavidin-horseradish peroxidase conjugate, which converts the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue precipitate in less than 1 hr. The probe and detection system described here can detect single-copy genes in less than 0.5 microgram of total human DNA on Southern blots and generates the same specific RFLP patterns as do probes labeled with 32P by nick-translation. These biotinylated HLA class II probes have been applied to tissue typing for bone marrow transplantation and the study of insulin-dependent diabetes susceptibility, revealing in each case relevant polymorphisms not detected by serologic typing.

Biotin↗
PubMed1991

Gene- and strand-specific repair in vitro: partial purification of a transcription-repair coupling factor.

In eukaryotic and prokaryotic cells, activity transcribed genes and, in some instances, the template strand of these genes have been found to be repaired 2-10 times more rapidly than nontranscribed genes or the coding strand of transcribed genes. We demonstrate here gene- and template strand-specific repair synthesis in vitro by using an Escherichia coli cell-free extract and a plasmid carrying a gene with the strong tac promoter. Strand-specific repair of UV, 4'-hydroxymethyl1-4,5',8-trimethylpsoralen, and cis-dicholorodiammine platinum(II) damage was dependent upon transcription and a functional nucleotide excision repair system and was stimulated by 6% (wt/vol) polyethylene glycol. A defined system consisting of the transcription and repair proteins in highly purified form did not perform strand-specific repair; however, active fractions of extract conferred strand specificity to the defined system. Transcription-repair coupling activity was partially purified from extract by successive DEAE-agarose and gel filtration chromatography. The coupling factor is heat-labile, with an estimated Mr of 100,000.

Bacterial Proteins↗