Differential Induction of Chromosomal Aberrations by Topoisomerase Inhibitors in Cultured Chinese Hamster Cells.

Suzuki, Hiroshi; Nakane, Sadao

doi:10.1248/bpb.17.222

Cited by 17 publications

(8 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While the regulation of pathway choice between HRR and NHEJ by ATM is a plausible explanation for olaparib sensitivity in ATM -deficient cells 39,40 , the mechanistic underpinnings of the ATM and DNA-PKcs synthetic lethal interaction is unclear 52 . Our metaphase spread analysis data however do suggest that AZD7648 promotes DNA damage formation through a process independent of replication, as mainly chromosome breaks were detected and they generally form independently of cell cycle phase 54 . Nonetheless, the profound tumour regressions achieved in FaDu ATM KO xenografts show a clear combination benefit for DNA-PK and PARP inhibition in the ATM -null genetic background.…”

Section: Discussioncontrasting

confidence: 52%

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

et al. 2019

View full text Add to dashboard Cite

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.

show abstract

Section: Discussioncontrasting

confidence: 52%

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In in vitro genotoxicity studies, ETO was weakly positive for strain TA98 in the Ames test, induced high frequency of small and large colony mutants in the MLA test, and induced chromosomal structural aberrations in the chromosomal aberration test. 21,22 In the present experiments, the PIG-A gene mutations in TK6 cells induced by 0.055 and 0.11 μmol/L of ETO were more than twofold higher than those in negative controls under conditions without metabolic activation system and with a dose-related manner in the absence of the S9-mix (►Fig. 7), confirming the roles of ETO as a mutagen.…”

Section: Optimized Cytotoxicity Determinationsupporting

confidence: 76%

In Vitro PIG-A Gene Mutation Assay in Human B-Lymphoblastoid TK6 Cells

Zhou

Huang

et al. 2021

Pharmaceutical Fronts

View full text Add to dashboard Cite

The X-linked PIG-A gene is involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors. PIG-A mutant cells fail to synthesize GPI and to express GPI-anchored protein markers (e.g., CD59 and CD55). In recent years, in vitro PIG-A assay has been established based on the high conservation of PIG-A/Pig-a loci among different species and the large data from the in vivo system. The purpose of this study was to extend the approach for PIG-A mutation assessment to in vitro human B-lymphoblastoid TK6 cells by detecting the loss of GPI-linked CD55 and CD59 proteins. TK6 cells were treated with three mutagens 7,12-dimethylbenz[a]anthracene (DMBA), N-ethyl-N-nitrosourea (ENU), etoposide (ETO), and two nonmutagens: cadmium chloride (CdCl2) and sodium chloride (NaCl). The mutation rate of PIG-A gene within TK6 cells was determined on the 11th day with flow cytometry analysis for the negative frequencies of CD55 and CD59. The antibodies used in this production were APC mouse-anti-human CD19 antibody, PE mouse anti-human CD55 antibody, PE mouse anti-human CD59 antibody, and nucleic acid dye 7-AAD. An immunolabeling method was used to reduce the high spontaneous level of preexisting PIG-A mutant cells. Our data suggested that DMBA-, ENU-, and ETO-induced mutation frequency of PIG-A gene was increased by twofold compared with the negative control, and the effects were dose-dependent. However, CdCl2 and NaCl did not significantly increase the mutation frequency of PIG-A gene, with a high cytotoxicity at a dose of 10 mmol/L. Our study suggested that the novel in vitro PIG-A gene mutation assay within TK6 cells may represent a complement of the present in vivo Pig-a assay, and may provide guidance for their potential use in genotoxicity even in cells with a significant deficiency of GPI anchor.

show abstract

“…This drug was not mutagenic in Salmonella typhimurium and V79 Chinese hamster cells [Westendorf et al, 1984], and induced only chromatid-type aberrations in both in vitro [Suzuki and Nakane, 1994;Suzuki et al, 1995] and in vivo test systems [Nersessian et al, 1991].…”

Section: Topoisomerase II Catalytic Inhibitormentioning

confidence: 99%

“…Using the alkaline comet test, IDA was also identified as a direct inducer of DNA strand breaks, as well as damaging DNA by oxidation and methylation [Blasiak et al, 2002a,b]. In contrast to IDA, ACLA was not mutagenic in V79 Chinese hamster cells and in the Salmonella-microsome assay [Westendorf et al, 1984], being able to induce only chromatidtype aberrations in rat bone marrow and in Chinese hamster lung cells [Suzuki and Nakane, 1994;Nersessian et al, 1991].…”

Section: Introductionmentioning

confidence: 99%

Activity of topoisomerase inhibitors daunorubicin, idarubicin, and aclarubicin in the Drosophila Somatic Mutation and Recombination Test

Lehmann

Vilar

Franco

et al. 2004

Environ and Mol Mutagen

View full text Add to dashboard Cite

Anthracyclines have been widely used as anticancer drugs against different types of human cancers. The present study evaluated the mutagenic and recombinagenic properties of two anthracycline topoisomerase II (topo II) poisons, daunorubicin (DNR) and idarubicin (IDA), as well as the related topo II catalytic inhibitor aclarubicin (ACLA), using the wing Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster. The three anthracyclines were positive in this bioassay, producing mainly mitotic homologous recombination. The results for spot-size distribution and recombinagenic activity indicate that recombinational DNA damage accounts for approximately 91, 86, and 62% of DNR, IDA, and ACLA genotoxicity, respectively. Besides being a catalytic inhibitor of topo II, ACLA is also a topoisomerase I (topo I) poison. This dual topo I and II inhibitory effect, associated with its DNA-intercalating activity, could contribute to the activity of ACLA in the SMART assay.

show abstract

Differential Induction of Chromosomal Aberrations by Topoisomerase Inhibitors in Cultured Chinese Hamster Cells.

Cited by 17 publications

References 1 publication

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

In Vitro PIG-A Gene Mutation Assay in Human B-Lymphoblastoid TK6 Cells

Activity of topoisomerase inhibitors daunorubicin, idarubicin, and aclarubicin in the Drosophila Somatic Mutation and Recombination Test

Contact Info

Product

Resources

About