DNA strand scission activity of metalloporphyrins.
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Biomedical subjects
Publications and source records attributed to R J Fiel.
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The photosensitizing effects of hematoporphyrin derivative, meso-tetra(p-sulfonatophenyl)porphine, meso-tetra(p-carboxyphenyl)porphine, and meso-tetra(4-N-methylpyridyl)-porphine on ColE1 supercoiled DNA were studied using agarose gel electrophoresis. Photoinduced single- and double-strand breaks were observed to form under neutral conditions. Singlet oxygen was shown to predominate in the mechanism of the induction of these lesions in the case of hematoporphyrin derivative, meso-tetra(p-sulfonatophenyl)porphine, and meso-tetra(p-carboxyphenyl)porphine and to play a significant role in the case of meso-tetra(4-N-methylpyridyl)porphine. The results suggest the possibility that the risk of photodynamic carcinogenesis may accompany photochemotherapy and fluorescence endoscopic procedures involving porphyrin photosensitizers.
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The porphyrin photosensitizer, meso-Tetra (4-N-methyl-pyridyl) porphine tetraperchlorate is shown to unwind supercoiled ColEI DNA at a somewhat lower concentration than ethidium bromide. In contrast to this, the Fe(III) chelate of T4MPyP cannot unwind supercoiled DNA. It is concluded that these results corroborate our previous findings that, despite its large bulk, T4MPyP is fully capable of intercalating in DNA.
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The porphyrin photosensitizer, meso-Tetra (4-N-methylpyridyl) porphine tetraperchlorate binds to calf thymus DNA by intercalation and by external electrostatic association. This was concluded from the results of measruements involving Scatchard analysis, viscometry, thermal denaturation, and circular dichroism.
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Visible light (6328A) was shown to inactivate RNA-dependent DNA polymerase activity of Moloney mouse leukemia virus, in the presence of hematoporphyrin. The same treatment on exogenous, template-initiation complex had no effect on enzyme activity. It was suggested that this enzyme may be the target of photodynamic inactivation of this and related viruses.
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The degree of inhibition of mammalian DNA-dependent RNA polymerases I and II and Moloney leukemia virus RNA-dependent DNA polymerase by pyran copolymer was dependent on the concentration of the divalent cation cofactor in the reaction mixture. Inhibition was completely blocked by an excess of divalent cations. It was concluded that pyran inhibited these enzymes by complexing with the essential divalent cation cofactor.
Differences noted in enzyme II directed RNA synthesis under varying salt conditions in nuclei isolated from uninfected and Friend virus (FV)-infected spleen cells, have been attributed to chromosomal modifications (Babcock and Rich 1973). This investigation was undertaken to determine if compositional changes occur in the chromatin of FV-infected spleens, which correlate with an altered rate of synthesis by enzyme II. A quantitative study of the chromatin constituents at various times after infection indicated that they vary in the same temporal manner as the rate of RNA synthesis in isolated nuclei. Relative to DNA, RNA, histone, and nonhistone protein reached a maximum at 14 days postinfection. This was followed by a gradual decrease during the remainder of the infection. Chromatin endogenous DNA-dependent RNA polymerase activity varied in the same manner, suggesting that RNA synthesis directed by enzyme II is modulated by chromosomal proteins.
The effect on mitosis of a human hematopoietic cell line RPMI-1788 treated with a metal chelate (Zn++) of meso-tetra (p-carboxyphenyl) porphine (Zn-TCPP) alone at various concentrations or in combination with gamma-irradiation at various doses were studied. The results showed that both Zn-TCPP and radiation were effective in interfering with normal mitosis and that the effect of radiation was relatively more effective. Data also suggest interacting effects between Zn-TCPP and gamma-irradiation. At low doses of radiation, Zn-TCPP potentiated the effect of radiation. The reverse seemed to be true at a high dose of radiation. The effects of two porphyrins (Zn-TCPP and hematoporphyrin) and radiation on chromosomes were also studied. Chromosomal aberrations characteristic of radiation were observed. The porphyrins were found not to be effective chromosome-breaking agents under the experimental conditions tested.
The radiation modifying effects of a series of the metal chelates of meso-tetra(p-carboxyphenyl) porphine has been investigated using a human lymphoid cell line, RPMI 1788. These studies revealed that Ni and Zn porphyrins were effective radiation sensitizers at concentrations as low as 10-9M. Further studies with Zn porphyrin showed it to be almost equally effective when added immediately after irradiation and partially effective when added up to 90 minutes post irradiation, suggesting that it may be acting by interfering with a repair mechanism.
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