DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-l-norleucine

Hiramoto, Kazuyuki; Fujino, Tomofumi; Kikugawa, Kiyomi

doi:10.1016/0165-1161(95)00073-9

Cited by 6 publications

(4 citation statements)

References 13 publications

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“…With regard to the etiology and prediction of cancer, the technology employed should have wide application to a variety of clinical and laboratory studies in which the status of DNA structure is important. Among such possible applications are studies of the effects of DNA cleaving molecules having selective anti-cancer activity (28,29), DNA damage resulting from radiation (30), antioxidant protection against DNA oxidation (31,32), structural alterations in DNA resulting from hormones (26) and xenobiotics (27), and somatic changes in genes (33).…”

Section: Discussionmentioning

confidence: 99%

Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation

Malins

Polissar

Gunselman

1996

Proc. Natl. Acad. Sci. U.S.A.

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Wavenumber-absorbance relationships of infrared spectra of DNA analyzed by principal components analysis may be expressed as points in space. Each point represents a highly discriminating measure of DNA structure. Structural modifications of DNA, such as those induced by free radicals, alter vibrational and rotational motion and consequently change the spatial location of the points. Using this technology to analyze breast tumor DNA, we revealed a 94؇ difference in direction between the progression of normal DNA 3 primary tumor DNA and the progression of primary tumor DNA 3 metastatic tumor DNA (P < 0.001). This sharp directional change was accompanied by a substantial increase in the structural diversity of the metastatic tumor DNA (P ‫؍‬ 0.003), which, on the basis of the volume of the core cluster of points, could comprise as many as 11 ؋ 10 9 different phenotypes. This suggests that the heterogeneity and varied physiological properties known to characterize malignant tumor cell populations may at least partially arise from these diverse phenotypes. The evidence suggests that the progression to the metastatic state involves structural modifications in DNA that are markedly different from the modifications associated with the formation of the primary tumor. Overall, the findings of this and earlier studies imply that the observed DNA alterations are a pivotal factor in the etiology of breast cancer and a formidable barrier to overcome in intervention to control the disease. In terms of cancer etiology and prediction, the technology described has potentially wide application to studies in which the structural status of DNA is an important consideration.A significant body of evidence points to the involvement of the hydroxyl radical (⅐OH) in introducing mutagenic structures into DNA of the normal female breast, thus statistically increasing the probability of breast cancer (1-5). In a recent study (5), the transformation of primary breast tumors to the metastatic state was shown to involve a Ͼ2-fold increase in ⅐OH damage in DNA, as indicated by modified nucleotide base models comprising mutagenic 8-hydroxyadenine (6) and the putatively nonmutagenic ring-opened product 4,6-diamino-5-formamidopyrimidine (fapyadenine; refs. 7-11). In addition, plots of the modified nucleotide base model log 10 (fapyadenine͞8-hydroxyadenine) versus the size of metastatic and nonmetastatic breast tumors revealed that the metastatic tumor DNA had significantly greater structural diversity than the nonmetastatic tumor DNA (P ϭ 0.01; ref. 5).Principal components analysis (PCA) of data obtained by Fourier transform-infrared (FT-IR) spectroscopy yielded plots in which individual spectra were represented as points in twoor three-dimensional space. Each point was a highly discriminating representation of an individual DNA structure in that spatially and visually close points had Ͻ3% average spectral difference over the range 1750-700 cm Ϫ1 (5). The core cluster of metastatic tumor DNA points was substantially larger than the core c...

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Section: Discussionmentioning

confidence: 99%

Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation

Malins

Polissar

Gunselman

1996

Proc. Natl. Acad. Sci. U.S.A.

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“…This might be accomplished by using therapeutic agents that reduce cellular ⅐ OH concentrations or through diets rich in antioxidants (29). Alternatively, the possibility exists to increase the severity of DNA damage in tumor tissues by using DNA-cleaving molecules having selective anti-cancer activity (30,31).…”

Section: Discussionmentioning

confidence: 99%

A unified theory of carcinogenesis based on order–disorder transitions in DNA structure as studied in the human ovary and breast

Malins

Polissar

Schaefer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Fourier transform-infrared͞statistics models demonstrate that the malignant transformation of morphologically normal human ovarian and breast tissues involves the creation of a high degree of structural modification (disorder) in DNA, before restoration of order in distant metastases. Order-disorder transitions were revealed by methods including principal components analysis of infrared spectra in which DNA samples were represented by points in two-dimensional space. Differences between the geometric sizes of clusters of points and between their locations revealed the magnitude of the order-disorder transitions. Infrared spectra provided evidence for the types of structural changes involved. Normal ovarian DNAs formed a tight cluster comparable to that of normal human blood leukocytes. The DNAs of ovarian primary carcinomas, including those that had given rise to metastases, had a high degree of disorder, whereas the DNAs of distant metastases from ovarian carcinomas were relatively ordered. However, the spectra of the metastases were more diverse than those of normal ovarian DNAs in regions assigned to base vibrations, implying increased genetic changes. DNAs of normal female breasts were substantially disordered (e.g., compared with the human blood leukocytes) as were those of the primary carcinomas, whether or not they had metastasized. The DNAs of distant breast cancer metastases were relatively ordered. These findings evoke a unified theory of carcinogenesis in which the creation of disorder in the DNA structure is an obligatory process followed by the selection of ordered, mutated DNA forms that ultimately give rise to metastases.The hydroxyl radical ( ⅐ OH) is a highly reactive chemical species that is known to alter the structure of DNA in human tissues (1-4). In hormone responsive tissues (e.g., the human breast), this radical is believed to be produced via the metal (e.g., Fe 2ϩ )-catalyzed decomposition of H 2 O 2 , which may arise from redox cycling of catecholestrogen metabolites (5) and xenobiotics (e.g., aromatic hydrocarbons) (6, 7). The ⅐ OH-induced modification of DNA involves the nucleotide base and phosphodiester-deoxyribose structures (3,8). The reaction rate with the bases has been estimated to be approximately four times that occurring with deoxyribose (8). The base reactions produce mutagenic derivatives, such as 8-hydroxyguanine (8-OH-Gua) and 8-hydroxyadenine (8-OH-Ade), together with the putatively nonmutagenic ring-opened structures 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-G) and 4,6-diamino-5-formamidopyrimidine (Fapy-A) (2, 9). The ⅐ OH also abstracts hydrogen atoms from the furanose ring of deoxyribose (8), which produces a variety of hydroxy derivatives that lead to strand breaks and the loss of phosphoric acid (8). Accordingly, the attack of the ⅐ OH creates substantial disorder likely reflected in the formation of potentially billions of new DNA structures (10), some of which may give rise to altered protein expression and function.Fourier transform-infrared (FT...

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“…The antibiotic 6-diazo-5-oxo-L-norleucine utilizes a terminal diazo unit to generate unimolecular diradical intermediates following thermal incubation and loss of N 2 . 1 The kinamycin antibiotics also possess the reactive terminal diazo unit, 2 and UV photolysis of kinamycin analogs is thought to generate diradical intermediates that effect DNA cleavage. 3 Bioorganic chemists have incorporated this strategy into the design of synthetic photonucleases by preparing diazene and benzotriazole agents that produce diradical intermediates capable of cleaving DNA upon UV excitation.…”

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confidence: 99%

“…The energy required to photochemically produce a Fe 2+ -L °+ state can be estimated by the sum of the redox potentials for the free ligand and the metal center, where DE = 2E ox (1) + E red (2). The cyclic voltammogram (CV) of 1 demonstrates an irreversible oxidation wave at a peak potential of +1.7 V vs. Ag/AgCl [E ox (1)], derived from rapid denitrogenation. [8][9][10] The CV of 2 exhibits a reversible Fe(III)/(II) redox couple with a half potential of 20.3 V vs. Ag/ AgCl [E red (2)].…”

mentioning

confidence: 99%

Photoactivated DNA cleavage via charge transfer promoted N2 release from tris[3-hydroxy-1,2,3-benzotriazine-4(3H)-one]iron(III)

et al. 2000

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DNA strand cleavage by tumor-inhibiting antibiotic 6-diazo-5-oxo-l-norleucine

Cited by 6 publications

References 13 publications

Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation

Tumor progression to the metastatic state involves structural modifications in DNA markedly different from those associated with primary tumor formation

A unified theory of carcinogenesis based on order–disorder transitions in DNA structure as studied in the human ovary and breast

Photoactivated DNA cleavage via charge transfer promoted N2 release from tris[3-hydroxy-1,2,3-benzotriazine-4(3H)-one]iron(III)

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