766. The alkylation of guanosine and guanylic acid

Brookes, P.; Lawley, P.D.

doi:10.1039/jr9610003923

Cited by 180 publications

(118 citation statements)

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“…4C), this selection was not operating. In the light of available information on methylation of nucleic acids by MNU (Brookes and Lawley, 1961;Loveless and Hampton, 1969), it might be important to look into the extent of 0-6 alkylation of guanine under these conditions, which has been suspected to be related to carcinogenesis (Loveless, 1969), considering the fact that methylation of 7(N) position of guanine had been thought to be irrelevant to mutagenesis (Loveless, 1969 (Fig. 5, 6) indicated that in the parental cell line of BSC-1 there was a gradual loss in the number of viable cells after each exposure to MNU.…”

Section: Dose Dependence In Mnu Transformationmentioning

confidence: 99%

On the Theory of Clonal Selection in Carcinogenic Transformation

Naha¹,

Ashworth²

1974

Br J Cancer

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Summary.-A temperature sensitive variant (tsl3) of African green monkey kidney cell line, carrying a temperature sensitive lesion in thymidine metabolism, was transformed by 40 ug/ml of methylnitrosourea (MNU) at the restricted temperature of 39 5°C, whereas the same cell line was not transformed by MNU at the permissive temperature of 33°C. Results presented in this paper raise the possibility that clones of cells carrying a biochemical lesion might possibly contribute to carcinogenesis with respect to certain chemical carcinogens.

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Section: Dose Dependence In Mnu Transformationmentioning

confidence: 99%

On the Theory of Clonal Selection in Carcinogenic Transformation

Naha¹,

Ashworth²

1974

Br J Cancer

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“…Radiochemical purity was determined either by paper chromatography or by thin-layer chromatography on poly(ethy1eneimine) cellulose (CELL 300/ UV254, Macherey and Nagel Co., Duren, F.R.G.) in one of two systems : (A) methanol/HCl/water 7 : 2 : 1 (system 1 of Brookes and Lawley [6]) and (B) butan-lol/water/acetic acid 25 : 25 : 6, upper phase. The chromatograms were dried for 10 min at 80 "C, sprayed with 4 % p-nitrobenzylpyridine in acetone, again 10 min at 80 "C, and sprayed with 0.25 M NaOH.…”

Section: Fig 1 Chromatographic Analysis Of Bis(2-chloroethyl)methylmentioning

confidence: 99%

The Interaction of Chromatin with Alkylating Agents

Yerushalmi

Yagil

1980

European Journal of Biochemistry

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The reaction of L5 178Y lymphoblast cell chromatin with the alkylating agent bis(2-chloroethy1)-methylamine has been studied as a function of time, pH and reagent concentration. The reaction with DNA of chromatin from which the proteins were dissociated, as well as with purified calf thymus DNA, was studied in parallel. The extent of alkylation of DNA in intact chromatin was 4-5 times as much as in parallel free DNA samples; up to 4 % of nucleotide base pairs were substituted. The extent of monofunctional substitution of the proteins was similar, on a weight basis, to that of DNA. Chromatographic analysis of the depurinated products showed that in chromatin, as in DNA, position N-7 of guanine is the major site of reaction. Up to 25 % of the reaction products were guanines cross-linked as bis(2-guanin-7-yl-ethyl)methylamine, indicating a considerable degree of DNA-DNA cross linking. Column analysis shows that up to 40% of the nuclear proteins are cross-linked to DNA at 10 mM bis(2-chloroethyl)methylamine. The increased reactivity of intact chromatin is interpreted in terms of a conformational change in the position of the DNA bases when in the organized nucleohistone complex.The nucleotide bases of the DNA moiety of chromatin are the sites of genetic specificity. Their availability in chromatin for interaction with outside molecules has been studied with a variety of reversibly associating intercalating molecules, including actinomycin D [l], quinacrine [2,3], ethidium bromide [4] and others [5].We thought it of importance to characterize reagents which interact covalently with the DNA moiety of chromatin. Covalent binding permits isolation and detailed characterization of the reacted fragments at a variety of states of nuclear activity. Bis(2-chloroethy1)methylamine (nitrogen mustard, HN2), the parent compound of the nitrogen mustards, is known to attack preferentially the nitrogen in position 7 of guanine [6-81. This position resides in the large groove of double-stranded DNA and is therefore available for interaction with regulatory proteins. Nitrogen mustard is also known for its capacity for interstrand cross-linking of DNA [9]; it can thus serve as a tool to map the proximity of DNA chains in the organized nucleohistone complex. Although considerable knowledge has accumulated regarding the action of bis- action with intact chromatin has not yet been studied.In this paper a quantitative study of the interaction of bis(2-chloroethyl)methylamine with solubilized chromatin is described. The extent of its reaction with DNA was unexpectedly found to exceed considerably the reaction with DNA free in solution. This observation is discussed in relation to present concepts of chromatin structure. MATERIALS AND METHODS ReagentBis(2-chloroethyl)methylamine (HN2, nitrogen mustard), chloride salt, was obtained from Sigma Co. (St Louis, Mo., U.S.A. ; caution : the non-protonated, alkaline form is extremely toxic; consult a safety handbook). Bis(2-chloro [ 1 ,2-14C]ethyl)methylamine was obtained from California Bionuclear ...

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“…In mammalian cells DEB is about 100 times more effective than expected from this proportionality rule. This is due to the formation of cross-links, partly involving the more reactive guanine-N-7 (20 (12).…”

Section: Linearity Of Dose Response At Low Doses?mentioning

confidence: 99%

“…In particular, the quantitative aspects of dose, dosimetry, and risk are emphasized, among other things, to show the usefulness as a This paper was presented at the 2nd International Conference on Environmental Mutagens in Human Populations held [20][21][22][23][24][25] August 1995 in Prague, Czech Republic. Manuscript received 22 November 1995; manuscript accepted 28 November 1995. Financial support from the Swedish Environmental Protection Agency, the Swedish Council for Planning and subsidiary tool of adduct monitoring in epidemiological research and cancer risk assessment.…”

Section: Introductionmentioning

confidence: 99%