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. 2013 Oct 24;4:5. doi: 10.1186/2041-9414-4-5

Table 1.

Evidence linking hypoxia to tumor cell genetic instability

Author % Oxygen Cell system Assays Key findings
Rice et al. [70]
0%
AA8 (CHO)
Flow cytometry, gene copy analyses
- Anoxia induces S-phase overreplication and increases the frequency of dihydrofolate reductase gene amplification
Young et al. [71]
0% (<10 ppm)
KHT-C2-LP1 (M-fibrosarcoma),
Metastasis assay, flow cytometry
- Anoxia induces DNA overreplication and increases metastatic potential
B16F10-A1 (M-melanoma)
Reynolds et al. [61]
0% (<10 ppm)
LN12 (M-fibroblasts)
Chromosome based λ shuttle vector, PCR, DNA sequence analysis
- Anoxia induces 3–4 fold increase in supF tRNA suppressor gene mutation (transversions and deletions) frequency
Rofstad et al. [72]
0% (<10 ppm and <100 ppm)
BEX-c (H-melanoma),
Flow cytometry, Giemsa
- Anoxia followed by reoxygenation induces diplochromosomes and tetraploidization
SAX-c (H-melanoma)
Coquelle et al. [73]
0.02%
GMA32 (Chinese hamster fibroblasts)
Fluorescence in situ hybridization (FISH)
- Severe hypoxia induces fragile sites and generates homogeneously stained regions (HSRs)
Yuan et al. [74]
0% (<10 ppm)
3340 (M-fibroblast)
Host cell reactivation (HCR) assay, UV mutagenesis assay
- Anoxia induces 2-fold increase in supFG1 mutation frequency
Coquelle et al. [75]
0.02%
GMA32 (Chinese hamster fibroblasts), 112 (Chinese hamster fibroblasts)
Fluorescence in situ hybridization (FISH)
- Severe hypoxia activates fragile sites and generates double minutes and dicentric chromosomes
Mihaylova et al. [76]
0% <10 ppm
3340 (M-fibroblasts), HeLa (H-cervix adenocarcinoma), EMT6 (M-breast carcinoma)
β-galactosidase and supFG1 mutation assays
- Anoxia induces 2-fold increase in supFG1, cII and lacZ mutation frequency
Banath et al. [77]
i.p. pimonidazole
V79-VE (Chinese hamster fibroblasts),
Flow cytometry, γ-H2AX foci, HPRT mutation assay, alkaline comet assay
- Hypoxia (cells distant to the blood vessels) followed by reoxygenation does not alter mutation frequency at HPRT locus, DNA strand break rejoining or resolution of γ-H2AX foci following ionizing radiation (IR)
HCT116 (H-colon carcinoma),
SCCVII (M-squamous cell carcinoma)
Koshiji et al. [78]
1%
HCT116 (H-colon carcinoma),
β-galactosidase mutation assay, microsatellite analysis
- Hypoxia increases the frequency of microsatellite mutations
HEC59 (H-endometrial carcinoma)
Papp-Szabo et al. [59]
0%
ME (R-mammary epithelial cells),
cII mutagenicity assay
- Anoxia increases the mutation frequency by 2-fold at cII locus without affecting colonogenic survival
MFib (R-mammary fibroblasts)
Fischer et al. [79]
0%
TX3868 (H-glioblastoma)
Fluorescence in situ hybridization (FISH)
- Anoxia induces double minutes, fragile sites and anaphase-bridges and initiates gene amplification on chromosome 12q
Rodriguez-Jimenez et al. [80]
1%
C17.2 (M-multipotent neural precursor cells), M-primary neurospheres from CD31, BMMSC (H-mesenchymal stem cells), DPSC (H-mesenchymal stem cells)
Host cell reactivation (HCR) assay, microsatellite instability analysis
- Hypoxia increases mutation frequency of the β-galactosidase reporter gene and causes microsatellite instability
Keysar et al. [60]
<0.1%
AL(N) (CHO)
Complement cytotoxic assay, flow cytometry mutation assay
- Anoxia results in a significant induction of mutations especially large deletions in CD59 gene
Lee et al. [81]
3%
Primary lymphocytes from healthy donors
Sister chromatid exchange (SCE) assay, microsatellite instability assay
- Hypoxia increases SCE but does not alter microsatellite instability
Pires et al. [38]
<0.02%
RKO (H-colon carcinoma), HCT116 (H-colon carcinoma), U2OS (H-osteosarcoma), IBR3 (H-fibroblast)
DNA fiber analysis, immunofluorescence
- Anoxia blocks DNA replication at the initiation and elongation stages and compromises DNA replication restart - Acute anoxia following reoxygenation (cycling hypoxia) does not affect DNA replication restart
Kumareswaran et al.* [82] 0.2% GM05757 (H-fibroblasts) Giemsa, Multicolor fluorescence in situ hybridization (M-FISH) - Hypoxia increases the frequency of fragmented DNA, ring chromosomes, telomeric fusions, chromosomal translocations and marker chromosomes following exogenous DNA damage

CHO – Chinese hamster ovary cells; M – mouse; H – human; R – rat.

*only study investigating DNA repair under continual hypoxic conditions.