Environmental solar ultraviolet (UV) and visible radiations are toxic, mutagenic, and carcinogenic, however, little is known about the underlying molecular processes that cause these effects in human cells, especially in the longer wavelength regions. Our research has shown that these long-wavelength radiations induce a variety of DNA damages in mammalian cells in culture, such as DNA-to-protein crosslinks and DNA double- and single-strand backbone breaks, as well as the more completely studied DNA bipyrimidine photoproducts. Our spectral studies have shown that these DNA crosslinks and breaks are produced by different mechanisms depending upon the wavelength of the radiation used. Isolated ultraviolet A (320 nm to visible light) and visible radiations induce these DNA changes largely via indirect mechanisms involving nonDNA photosensitizers, whereas isolated ultraviolet B (280-320 nm) wavelengths induce them via direct action on DNA, which acts as the primary chromophore. Natural solar radiation therefore produces a complex mixture of DNA lesions, including direct and indirect DNA crosslinks and breaks, but the impact of these alterations upon the cell is not clear. Our research has thus far concentrated upon the quantification of the spectral efficiencies for the immediate yields of these particular DNA damages in human cells. Our proposed research will concentrate mainly upon the capability of cells to repair these DNA damages. For this work we will use the specific high- energy ultraviolet A, ultraviolet B, ultraviolet C (less than 290 nm), and visible radiations that are available in our laboratory, and human cells that are resistant or sensitive to these radiations. To gain further insight into DNA damage caused by photosensitized reactions, we also propose to study the yields and repair of these damages during irradiations in the cellular environment with experimental added photosensitizing antitumor compounds such as porphyrins or the coumarin gilvocarcin V, which are of potential value in photochemotherapy. Finally, using isolated DNA fragments, we plan to investigate site specificity for DNA damage caused by radiation in the presence of photosensitizing compounds.

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National Cancer Institute (NCI)
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Radiation Study Section (RAD)
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University of Chicago
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Chen, W; Blazek, E R; Rosenberg, I (1995) The relaxation of supercoiled DNA molecules as a biophysical dosimeter for ionizing radiations: a feasibility study. Med Phys 22:1369-75
Dudek, E J; Peak, J G; Roth, R M et al. (1993) Isolation of V79 fibroblast cell lines containing elevated metallothionein levels that have increased resistance to the cytotoxic effects of ultraviolet-A radiation. Photochem Photobiol 58:836-40
Blazek, E R; Alderfer, J L; Tabaczynski, W A et al. (1993) A 5-4 pyrimidine-pyrimidone photoproduct produced from mixtures of thymine and 4-thiouridine irradiated with 334 nm light. Photochem Photobiol 57:255-65
Blazek, E R; Peak, J G (1992) Filter elution assays for DNA damage: practical and mechanistic significance of the DNA in the filter support wash. Radiat Res 130:384-8
Churchill, M E; Peak, J G; Peak, M J (1991) Repair of near-visible- and blue-light-induced DNA single-strand breaks by the CHO cell lines AA8 and EM9. Photochem Photobiol 54:639-44
Peak, J G; Pilas, B; Dudek, E J et al. (1991) DNA breaks caused by monochromatic 365 nm ultraviolet-A radiation or hydrogen peroxide and their repair in human epithelioid and xeroderma pigmentosum cells. Photochem Photobiol 54:197-203
Churchill, M E; Peak, J G; Peak, M J (1991) Correlation between cell survival and DNA single-strand break repair proficiency in the Chinese hamster ovary cell lines AA8 and EM9 irradiated with 365-nm ultraviolet-A radiation. Photochem Photobiol 53:229-36
Peak, J G; Peak, M J (1991) Comparison of initial yields of DNA-to-protein crosslinks and single-strand breaks induced in cultured human cells by far- and near-ultraviolet light, blue light and X-rays. Mutat Res 246:187-91
Churchill, M E; Schmitz, A M; Peak, J G et al. (1990) Photosensitized damage to supercoiled plasmid DNA induced by 334-nm radiation in the presence of 2-thiouracil consists of alkali- and piperidine-labile sites as well as frank strand breaks. Photochem Photobiol 52:1017-23
Peak, M J; Jones, C A; Sedita, B A et al. (1990) Evidence that hydrogen peroxide generated by 365-nm UVA radiation is not important in mammalian cell killing. Radiat Res 123:220-3

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