DNA repair, DNA synthesis and cell cycle delay in human lymphoblastoid cells differentially sensitive to the cytotoxic effects of nitrogen mustard

Dean, S.W.; Fox, Margaret

doi:10.1016/0167-8817(84)90067-1

Cited by 8 publications

(1 citation statement)

References 39 publications

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“…Several models of SCE formation have been proposed in which delayed progression through S-phase is an integral component of the pathway [Ishii and Bender, 1980;Painter, 19801. In studies which have addressed the mechanism of toxicity in mammalian cells, inhibition of DNA synthesis has been considered an important factor in cell death [Graham and Fox, 1983;Dean and Fox, 1984;Treon and Bartholomew, 19851. However, the results of recent studies indicate that while inhibition of DNA synthesis may occur as a result of carcinogen exposure, cellular toxicity may be more closely related to an arrest in the G, phase of the cell cycle [Sorenson and Eastman, 1988a,b;Black et al, 1989;Rowley and Kort, 19891. In order to provide insight into these relationships, P3 cells were exposed to EMS and MMS, the induction of SCE and the reduction in relative cloning ability were measured, and the degree of correlation between the two responses was determined.…”

Section: Introductionmentioning

confidence: 99%

Flow cytometric evaluation of cell‐cycle progression in ethyl methanesulfonate and methyl methanesulfonate‐exposed P3 Cells: Relationship to the induction of sister‐chromatid exchanges and cellular toxicity

Morris

Domon

McGarrity

et al. 1991

Environ and Mol Mutagen

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In order to determine the relationships among the reduction in relative cloning efficiency (RCE), sister-chromatid exchange (SCE) formation, and interference with progression through the cell-cycle, human teratocarcinoma-derived (P3) cells were exposed to either ethyl methanesulfonate or to methyl methanesulfonate. The relationship between SCE and toxicity was quantified, the progression through the cell-cycle was evaluated with flow cytometric methods, and the effects of these chemicals on cell growth and average generation time (AGT) were determined. A strong correlation existed between RCE and SCE (r = -0.978, p less than .001) which was accompanied by an inhibition of growth as evidenced by a significant (p less than .0001) negative linear effect of concentration on the relative cell count from 24 to 72 hours after exposure and by a concentration-dependent increase (p less than .0001) in the AGT. Delays in the transit through S-phase were evident 4 hours after exposure to toxic concentrations of either carcinogen and by 8 to 12 hours post-exposure at the lower concentrations. Increases in the percentage of nuclei in G2 + M, indicative of G2 arrest, occurred from 12 to 24 hours after exposure. One interpretation of these results is that those effects of EMS and MMS exposure which result in S-phase delay and G2 arrest may be those elements common to the induction of SCE and cellular toxicity.

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Section: Introductionmentioning

confidence: 99%

Flow cytometric evaluation of cell‐cycle progression in ethyl methanesulfonate and methyl methanesulfonate‐exposed P3 Cells: Relationship to the induction of sister‐chromatid exchanges and cellular toxicity

Morris

Domon

McGarrity

et al. 1991

Environ and Mol Mutagen

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Effects of 4‐hydroperoxycyclophosphamide (4‐OOH‐CP) and 4‐hydroperoxydechlorocyclophosphamide (4‐OOH‐deCICP) on the cell cycle of post implantation rat embryos

Little

Mirkes

1992

Teratology

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In this study, we used preactivated forms of cyclophosphamide (CP) and dechlorocyclophosphamide (deClCP) to examine the effects of phosphoramide mustard (PM) and acrolein, respectively, on the cell cycle of postimplantation rat embryos. The percentage distribution of cells in the G1/G0, S, and G2/M phases of the cell cycle was determined by flow-cytometric analysis. At embryotoxic concentrations, 4-OOH-CP (PM) induced major cell cycle perturbations whereas 4-OOH-deClCP (acrolein) caused no major perturbation of the cell cycle. These data support the hypothesis that the mechanism of the embryotoxic action of PM involves alkylation of DNA, whereas the mechanism of action of acrolein does not. The primary effect of PM on the cell cycle was an initial delay in the S phase followed by a G2/M arrest. At low embryotoxic concentrations of 4-OOH-CP, there was apparent reversal of the G2/M arrest; at higher embryotoxic concentrations there was little recovery from the G2/M arrest. The high level of cell death found at higher drug concentrations suggests that prolonged G2/M arrest leads to cell death. Using radiolabeled CP and cell sorting, it was determined that PM predominantly alkylated DNA in the S phase of the cell cycle. Overall, the data from this study support the hypothesis that DNA cross-links, induced by the alkylation of DNA by PM, induce cell cycle perturbations. Furthermore, these cell cycle alterations may be one of the early steps in the mechanism leading to the embryotoxicity of PM.

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Drug resistance and DNA repair

Fox

Roberts

1987

Cancer Metast Rev

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DNA repair confers resistance to anticancer drugs which kill cells by reacting with DNA. A review of our current information on the topic will be presented here. Our understanding of the molecular biology of repair of 0(6)-alkylguanine adducts in DNA has advanced as a result of the molecular cloning of the E. coli ada gene but the precise role of this lesion in the cytotoxic effects of alkylating agents in mammalian cells is not completely understood. Less progress has been made in understanding the enzymology and molecular biology of DNA cross-link repair even though such lesions are important for the cytotoxic effects of the widely used bifunctional alkylating agents and platinum compounds. It is evident that drug sensitive or resistant phenotypes are as highly complex as are the effects of DNA damage on cell metabolism and various aspects of these effects are discussed. Few clear correlations have been made between quantitative differences in DNA repair capacity and cellular sensitivity but assays which were developed to measure fidelity and intragenomic heterogeneity in DNA repair are beginning to be applied. Such studies may reveal subtle differences between sensitive and resistant cell lines. The molecular cloning of human DNA repair genes by transfection into drug sensitive rodent cells has been attempted. Some success has been achieved in this area but the functions of the cloned genes have yet to be identified.

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DNA repair, DNA synthesis and cell cycle delay in human lymphoblastoid cells differentially sensitive to the cytotoxic effects of nitrogen mustard

Cited by 8 publications

References 39 publications

Flow cytometric evaluation of cell‐cycle progression in ethyl methanesulfonate and methyl methanesulfonate‐exposed P3 Cells: Relationship to the induction of sister‐chromatid exchanges and cellular toxicity

Flow cytometric evaluation of cell‐cycle progression in ethyl methanesulfonate and methyl methanesulfonate‐exposed P3 Cells: Relationship to the induction of sister‐chromatid exchanges and cellular toxicity

Effects of 4‐hydroperoxycyclophosphamide (4‐OOH‐CP) and 4‐hydroperoxydechlorocyclophosphamide (4‐OOH‐deCICP) on the cell cycle of post implantation rat embryos

Drug resistance and DNA repair

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