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Isolation, structure and activity of a mutagen, 2-amino-6-methyldipyrido [1, 2-a: 3', 2'-d] imidazole (Glu-P-1), were summarized. The metabolic activation, its specific reaction with DNA and biomimetic mutation of proto-ras oncogene were described.
A type II modification methylase (M BstVI) was partially purified from the thermophilic bacterium Bacillus stearothermophilus V. The methylase catalyses the transfer of methyl groups from S-adenosyl-L-methionine to unmodified double-stranded DNA. The product of methylation was identified by paper chromatography as N6-methyladenine. Since M BstVI protects DNA against cleavage by BstVI and XhoI restriction endonucleases, it follows that it methylates the adenine residue in the sequence 5'-C-T-C-G-A-G-3'.
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It was previously shown that resistance of phage Mu-1 to several restriction enzymes is due to a modification function (called mom) encoded by the phage. More recent studies emphasized that modification of Mu requires not only an active mom function, but also an active dam function supplied by the Escherichia coli host.
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Programmed cell death or apoptosis is a mechanism for the elimination of cells that occurs not only in physiological processes but also in drug-induced tumor cell death. Thus, because cisplatin, cis-diamminechloroplatinum (II), produces important damages on the DNA inducing apoptosis in several cell lines it has become a widely used antitumor drug. However, cisplatin possesses some dose-limiting toxicities mainly nephrotoxicity. Pt(IV) complexes, such as iproplatin, ormaplatin, and JM216 are a new class of platinum complexes that exhibits less toxicity than cisplatin. Some of these complexes have shown significant antitumor activity and a low cross-resistance to cisplatin. In the present paper, we have analyzed the DNA binding mode and the cytotoxicity of a novel Pt(IV)-bis (monoglutarate) complex. The data show that this novel complex produces DNA interstrand cross-links to a higher extent and with a faster kinetics than cisplatin. Also the Pt(IV)-bis (monoglutarate) complex kills glioma cells at drug concentrations significantly lower than those of cisplatin. Interestingly, this Pt(IV) complex produces in the glioma cells characteristic features of apoptosis such as 'DNA laddering' and fragmented nuclei. Moreover, the p53 protein accumulates early in glioma cells as a result of Pt(IV)-bis (monoglutarate) treatment. These data indicate that the Pt(IV)-bis (monoglutarate) complex induces apoptosis in glioma cells through a p53-dependent pathway.
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When guanosine reacts with 1,3-bis(2-chloro-2,2-dideuteroethyl)-1-nitrosourea in a mixture of pH 7.1 buffer and DMSO, the 7-chloroethylguanosine which is isolated contains two deuterium atoms located next to the guanine ring and beta to the chlorine atom as shown by electron impact mass spectrometry. It is proposed that initial attack by DNA bases occurs on the number 2 carbon of the haloethylnitrosourea with displacement of the chloride ion. In accordance with this proposed mechanism, 7-bromoethylguanosine is isolated as a major product when BCNU is reacted with guanosine in the presence of high concentrations of KBr. These results suggest that the antitumor activity of various haloethylating antitumor agents may be determined by structural changes which affect their mechanisms of reaction with DNA.
Crystal structures of N(6),N(9)-dimethyladenine and N(6)-methyladenine hydrochloride were determined from three-dimensional x-ray diffraction data. The bases assume a conformation in which the N(6)-methyl group blocks one of the hydrogen-bonding sites normally used by adenine to form Watson-Crick pairs with thymine in double-helical DNA. When in this conformation, N(6)-methyladenine residues might alter the secondary structure of DNA. thereby preventing the scission of modified DNA's by restriction enzymes.
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The polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P), the most carcinogenic PAH tested in rodent bioassays, exerts its pathobiological activity via metabolic formation of electrophilically reactive DNA-binding fjord region (+)-syn-(11S,12R,13S,14R)- or (-)-anti-(11R,12S,13S,14R)-DB[a,l]P-dihydrodiol epoxides (DB[a,l]-PDEs). DB[a,l]P is metabolized to these DB[a,l]PDEs which bind to DNA in human mammary carcinoma MCF-7 cells. The molecular response of MCF-7 cells to DNA damage caused by DB[a,l]PDEs was investigated by analyzing effects on the expression of the tumor suppressor protein p53 and one of its target gene products, the cyclin-dependent kinase inhibitor p21WAF1. Treatment of MCF-7 cells with (+)-syn- and (-)-anti-DB[a,l]PDE at a concentration range of 0.001-0.1 microM resulted in DB[a,l]PDE-DNA adduct levels between 2 and 30, and 3 and 80 pmol/mg DNA, respectively, 8 h after exposure. (-)-anti-DB[a,l]PDE exhibited a higher binding efficiency that correlated with a significantly stronger p53 response at low concentrations of the dihydrodiol epoxides. The level of p53 increased by 6-8 h after treatment. The p21WAF1 protein amount exceeded control levels by 12 h and remained elevated for 96 h. At a dose of 0.01 microM (+)-syn-DB[a,l]PDE, an increase in p21WAF1 was observed in the absence of a detectable change in p53 levels. The results indicate that the increase in p53 induced by DB[a,l]PDEs in MCF-7 cells requires an adduct level of approximately 15 pmot/mg DNA and suggest that the level of adducts rather than the specific structure of the DB[a,l]PDE-DNA adduct formed triggers the p53 response. The PAH-DNA adduct level formed may determine whether p53 and p21VAF1 pathways respond, resulting in cell-cycle arrest, or fail to respond and increase the risk of mutation induction by these DNA lesions.
Previously, we reported that when Salmonella typhimurium and Escherichia coli were treated with N-nitrosodimethylamine (NDMA) under irradiation with ultraviolet-A (UVA), mutagenesis of the bacteria took place without externally added activation enzymes. We also observed the formation of O(6)-methylguanine (O(6)-meG), N(7)-methylguanine (N(7)-meG) and 7,8-dihydro-8-oxodeoxyguanosine (8-oxodG) in calf thymus DNA treated with NDMA plus UVA. In this study, we observed the mutagenicity of NDMA under irradiation of natural sunlight in S. typhimurium. Furthermore, we detected the formation of O(6)-meG, N(7)-meG and 8-oxodG in calf thymus DNA treated with NDMA plus simulated sunlight. Regarding the mutagenesis of S. typhimurium by NDMA plus UVA, we have now identified and quantified O(6)-meG formed in the genomic DNA of the bacteria under conditions of the mutagenesis.
Oral administration of hydroquinone (HQ) to male Fischer 344 (F344) rats results in dose-related kidney toxicity beginning with mild enzymuria by 1 week, significant cell proliferation by 6 weeks, and nephropathy and an increase in the incidence of renal tubule adenomas after 2 years. Female F344 rats, B6C3F1 mice, Sprague-Dawley rats, dogs, and humans are resistant to the renal toxicity of HQ associated with repeated exposure. To determine the potential of HQ to induce covalent DNA adducts in the kidney, male and female F344 rats were given 0, 2.5, 25, or 50 mg/kg HQ by gavage for 6 weeks, and nuclear DNA isolated from kidneys was analyzed by the 32P-postlabeling assay. At 50 mg/kg, males, but not females, showed an increase in the rate of excretion of N-acetyl-beta-D-glucosaminidase, indicative of proximal tubular damage. Analysis of nuclear DNA preparations by the postlabeling assay showed that HQ does not produce covalent DNA adducts in the kidneys of male and female rats. The assay's lower limit of detection is 1 adduct in 10(9) to 10(10) DNA nucleotides. No treatment-related increases in background radioactivity levels on the chromatograms were seen at locations corresponding to the major in vitro adducts of HQ and p-benzoquinone. HQ treatment, however, resulted in the reduction of the levels of certain endogenous adducts (I-compounds), the biological significance of which is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)
In the present paper, we show that the reaction of the antipyranosomatid berenil drug with K2PtCl4 resulted in the synthesis of a covalent (Pt(II)-berenil compound of formula [Pt2Cl4(berenil)2]Cl4.4H2O as shown by IR, 1H, 13C, and 195Pt-NMR. The Pt-berenil compound was tested for in vitro antitumor activity against HL-60 and U-937 human leukemic cells. The results show that the LC70 values of the Pt-berenil are about two-fold lower than those of cis-DDP in both HL-60 and U-937 cell lines. Melting data of Pt-berenil:DNA and berenil:DNA complexes indicate that the platinated compound produces on a DNA secondary structure higher compaction than the berenil ligand. The mobility in agarose gels and the circular dichroism spectra of the compounds:DNA complexes revealed, moreover, that both induce drastic changes on a DNA secondary and tertiary structure. The total reflection X-ray fluorescence data showed, in additIon that DNA platination in Pt-berenil:DNA complexes occurs within minutes after addition of the drug, in contrast to what that observed in cis-DDP:DNA complexes. On the basis of these results, we propose that in Pt-berenil, the berenil ligand acts as a carrier of the active cis-P(II) centers towards DNA.
In contrast to Escherichia coli and Salmonella typhimurium, Bacillus subtilis could convert ethionine to S-adenosylethionine (SAE), as can Saccharomyces cerevisiae. This conversion was essential for growth inhibition by ethionine because metE mutants which were deficient in S-adenosylmethionine synthetase activity, were resistant to 10 mM ethionine and converted only a small amount of ethionine to SAE. Another mutation (ethA1) produced partial resistance to ethionine (2 mM) and enabled continual sporulation in glucose medium containing 4 mM DL-ethionine. This sporulation induction probably resulted from the effect of SAE, since it was abolished by the addition of a metE1 mutation. The induction of sporulation was not simply controlled by the ratio of SAE to S-adenosylmethionine, but apparently depended on another effect of the ethA1 mutation, which could be demonstrated by comparing the restriction of clear plaque mutants of bacteriophage phi 105 grown in an ethA1 strain with the restriction of those grown in the standard strain. The phages grown in the ethA1 strain showed increased protection against BsuR restriction. We propose that SAE induces sporulation through the inhibition of a key methylation reaction.