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Biomedical subjects

N Müller

Publications and source records attributed to N Müller.

At least 271 records · Page 15Linked to original sources
PubMed1987

6-Methylguanine and 6-methylguanosine inhibit colony-forming ability in a malignant xeroderma pigmentosum cell line but not in other xeroderma pigmentosum and normal human fibroblast strains after treatment with 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl)-urea.

The XP cell strain XP29MA, its malignant counterpart XP29MAmal and a normal human fibroblast strain were tested for colony-forming ability after treatment with HECNU in the presence of m6G, m6Gua, and he7G. In XP29MAmal, inhibition of post-HECNU colony-forming ability was 35% when 0.25 mM of either m6G or m6Gua were present, whereas in XP29MA and the normal fibroblast strain no inhibition was detected. The he7G caused a similar but smaller inhibitory effect in XP29MAmal, but failed to do so in XP29MA. HECNU predominantly exerts its killing effect by alkylating O-6 of DNA-bound guanine and causing DNA interstrand crosslinks. Alkylation of O-6 of guanine can be repaired by 6-methylguanine-DNA methyltransferase. From our experiments we conclude that in XP29MAmal this methyltransferase was inhibited in the presence of the 6-alkylguanines, thus leaving more 2-chloroethylated sites in DNA unrepaired. This results in sensitization in terms of decreased colony-forming ability observed only in the malignant cell line.

Cell Division↗
PubMed1987

A preliminary study of MRI quantification of simulated calcified pulmonary nodules.

The potential of magnetic resonance imaging (MRI) quantification of calcium for the evaluation of pulmonary nodules was investigated in simulated nodules. Calcium salts do not contain mobile protons and thus have no signal on MR proton images. To determine whether the absence of signal from partially calcified nodules could be quantified, we studied simulated nodules containing known quantities of calcium salts. The soft tissue equivalent material was an agar-gelatin mixture (T1:1100-1500 msec; T2: 59-62 msec). In the first experiments, glass tubes were filled with the mixture, which contained suspensions of calcium carbonate (CaCO3) or silica dioxide (Si02), and were subjected to computed tomography (CT) scanning and MR imaging. In a second series of studies CaCO3 particles of various sizes (and therefore different surface-to-volume ratios) were similarly suspended and subjected to CT scanning and MR imaging. In a third series hydroxyapatite (HA) suspensions of different sizes were similarly studied. CaCO3 produced a significant reduction in MR hydrogen density and signal intensity of the agar-gelatin mixture. Reduction in T1 and T2 relaxation times was inconsistent and not related to particle size. CaCO3 produced its effect by soft-tissue displacement. HA (and Si02) caused a more marked fall in MR hydrogen density, signal intensity, and T1 and T2 relaxation times. The degree of the T1 and T2 effects was related to particle size, indicating a hydrophilic surface effect. The authors conclude that MRI quantification of calcium within pulmonary nodules (or other tissues) will be complex and will relate to the precise composition of the calcium salt and to the particle size of the aggregates.

Calcinosis↗
PubMed1987

Pulmonary lymphangitic spread of carcinoma: appearance on CT scans.

Chest computed tomography (CT), including high-resolution CT with thin (1.5-mm) sections was used to evaluate proved (pathologically or clinically) lymphangitic spread (LS) of tumor in 12 patients. These appearances were compared with thin-section scans obtained in 11 healthy subjects. Thin-section CT demonstrated findings consistent with thickening of the normal lung interstitium. In all patients, thin sections showed an increase in the number of peripheral lines (1-2 cm in length) that were diffuse in generalized disease and localized in focal disease. Normal peripheral arcades were not increased in number, but the limbs forming the arcades were thickened in all patients. A diffuse increase in linear and curvilinear structures (reticular pattern) was seen toward the center of the lung. Polygonal structures 1-2 cm in diameter were seen in seven patients with LS but not in healthy subjects. Fissures were thickened in nine patients. Selected 1.5-mm-thick CT sections are recommended through abnormal areas (seen at CT or on chest radiographs) or if these are normal at three levels (midapex, hilus, and 3 cm above the diaphragm) when scanning patients with tumors known to cause LS.

Adult↗
PubMed1987

Alkylation of 2'-deoxythymidylyl(3'----5')-2'-deoxythymidine with 2-hydroxyethylnitrosourea and stability of the resulting phosphotriester.

One of the main targets of RNA and DNA alkylation is the phosphate group. In contrast to RNA phosphotriesters, DNA phosphotriesters are relatively stable. Introduction of 2-hydroxyethyl phosphotriesters into DNA, however, has been reported to decrease its stability towards hydrolytic cleavage considerably. 2-Chloroethylnitrosoureas (CNUs) have been found to form predominantly 2-hydroxyethyl adducts of DNA. In the present study, we have determined the stability of 2'-deoxythymidylyl-(3'----5')-2'-deoxythymidine (dTpdT) after alkylation with various nitrosoureas, including N-methyl-N-nitrosourea (MNU) and 2-hydroxyethylnitrosourea (HENU) at alkaline and neutral pH (at 37 degrees C). The half-lives (t1/2) at pH 12.5 were, for example, 2.8 h for di(2'-deoxythymidine)methylphosphotriester [dTp(me)dT] but less than 1 min for di(2'-deoxythymidine) (2-hydroxyethyl)-phosphotriester [dTp(he)dT]. At pH 7.0, dTp(me)dT was stable for more than three days, whereas the t1/2 for dTp(he)dT was only 1.0 h at pH 7.0 (27 min at pH 9.0). The marked lability of dTp(he)dT, in comparison to other phosphotriester analogues, can be explained by intermediate formation of a dioxaphospholane ring resulting in triester bond breakage. Our data strongly support the hypothesis that a great proportion of DNA single-strand breaks induced in DNA by HENU or CNUs can be attributed to intermediate formation of 2-hydroxyethyl phosphotriesters.

Alkylation↗
PubMed1986

Studies on the stability of trialkyl phosphates and di-(2'deoxythymidine) phosphotriesters in alkaline and neutral solution. A model study for hydrolysis of phosphotriesters in DNA and on the influence of a beta hydroxyethyl ester group.

Various trialkyl phosphates were investigated as model compounds for DNA-phosphotriesters for their stability in neutral or alkaline conditions. The results show that phosphotriesters were highly stable even at strongly alkaline pH, with the exception of diethyl 2-hydroxyethyl phosphate (DHP). The extreme instability of the latter was found to be due to the 2-hydroxy function. In accordance with earlier interpretations the 2-hydroxyethyl group is proposed to participate in the formation of a highly reactive dioxaphospholane ring intermediate which decays rapidly by hydrolysis. Alkylation of 3'- and 5'-deoxythymidine monophosphates with methyl- or hydroxyethylnitrosourea (MNU, HENU) results in practically exclusive phosphate alkylation. In analogy with the model phosphotriesters, di(2'-deoxythymidine) phosphotriesters generated after reaction with MNU or HENU showed extreme dependence of their stabilities on the nature of the alkyl group transferred to phosphate. Whereas the methyl phosphotriester was highly stable, the corresponding hydroxyethyl analogue showed half lives of decay of less than 1 min (pH 12.5), 27 min (pH 9.1) and 60 min (pH 7). Thus the introduction of a 2-hydroxyethyl function into phosphate strongly decreases the stability of the phosphate link of DNA, resulting in DNA single strand breaks, in analogy to RNA phosphotriesters which have been found earlier to be highly unstable because of the presence of the ribose 2'-OH-group.

Alkylation↗
PubMed1986

DNA adducts and DNA damage by antineoplastic and carcinogenic N-nitrosocompounds.

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds as well as by carcinogenic 2-hydroxyalkylnitrosamines are discussed. CNUs are monofunctional and bifunctional alkylating agents that form, in a quantitatively minor reaction, DNA-DNA crosslinks (XL). In vitro, by far the most abundant alkylation products of DNA are those resulting from 2-hydroxyethylation. The reaction sequence responsible for 2-hydroxyethylation comprises intermediate oxazolidine ring closure followed by generation of 2-hydroxyethylnitrosourea and ethylene oxide. Oxadiazolium intermediates have not been found to play a role. In contrast to the in vitro experiments, in vivo 2-hydroxyethyl adducts are formed to a much lesser extent und 2-chloroethyl adducts are predominant in rat kidney DNA. 2-Hydroxyethylation of phosphate groups introduces extreme instability into the sugar-phosphate backbone since the resulting phosphotriester rapidly breaks down through a dioxaphospholane ring intermediate. Measurements of DNA XL in target tumor tissue and in bone marrow provides a sensitive tool for evaluation in bone marrow provides a sensitive tool for evaluation of hormone-linked cytotoxic agents. The potent environmental carcinogen N-nitrosodiethanolamine (NDELA) has been found to be activated in the rat liver by a two-step metabolic transformation sequence involving alcohol dehydrogenase and, subsequently, sulfotransferase. Evidence for this mechanism is provided by measuring DNA single strand breaks in rat liver DNA and by studying the effect of various enzyme inhibitors on the extent of DNA damage induced in vivo by NDELA and its metabolites.

Alkylation↗