Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells
Abstract
:1. Introduction
2. Types of DNA Damage
3. DNA Damaging Agents as Anti-Cancer Drugs
3.1. Alkylating Agents
3.2. Platinum Drugs
3.3. Antimetabolites
3.4. Topoisomerase Inhibitors
3.5. Ionising Radiation
4. The DNA Damage Response (DDR)—DNA Damage Signalling and Cell Cycle Checkpoints
5. Cell Cycle Checkpoints and Checkpoint Adaptation
6. Conclusions
Acknowledgments
Conflicts of Interest
Abbreviations
ATM | Ataxia telangiectasia mutated |
ATR | ATM and Rad3-related |
ATRIP | ATR-interacting protein |
Cdk1 | Cyclin-dependent kinase 1 |
Cdk2 | Cyclin-dependent kinase 2 |
Chk1 | Checkpoint kinase 1 |
Chk2 | Checkpoint kinase 2 |
CPT | Camptothecin |
DDR | DNA damage response |
DNA | Deoxyribonucleic acid |
dNTPs | Deoxynucleotide triphosphates |
DSBs | Double-strand breaks |
hmdUrd | 5-hydroxymethyl-2′-deoxyuridine |
MGMT | O6-methylguanine-DNA methyltransferase |
MRN | Mre11-Rad50-Nbs1 |
RFC | Replication factor C |
ROS | Reactive oxygen species |
RPA | Replication protein A |
SSBs | Single-strand breaks |
ssDNA | Single-stranded DNA |
TMZ | Temozolomide |
TopB1 | DNA topoisomerase II binding protein 1 |
Top1 | Topoisomerase I |
Top2 | Topoisomerase II |
UV | Ultraviolet |
5-FU | 5-fluorouracil |
9-1-1 | Rad9-Rad1-Hus1 |
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Agent Type | Examples of Drugs | Mechanism of Action | Type of DNA Damage |
---|---|---|---|
Alkylating agents | Nitrogen mustards Nitrosoureas Temozolomide S23906 | Base alkylation-Monofunctional DNA adducts | Block the replication machinery leading to strand breaks |
Inter, intra and DNA-protein crosslinks | Block the replication machinery leading to strand breaks | ||
Platinum drugs | Cisplatin Carboplatin Oxaliplatin | Monofunctional DNA adducts | Block the replication machinery leading to strand breaks |
Inter, intra and DNA-protein crosslinks | Block the replication machinery leading to strand breaks | ||
Antimetabolites | 5-Fluorouracil | Misincorporates into DNA | Blocks the replication machinery leading to strand breaks |
Depletes dNTPs | Blocks the replication machinery leading to strand breaks | ||
Topoisomerase poisons | Camptothecin Etoposide | Inhibit topoisomerase enzymes in complex with DNA | SSBs and DSBs |
Ionising radiation | Direct | SSBs and DSBs | |
Indirect production of ROS | DNA adducts, base oxidation, SSBs, DSBs, base deamination, DNA-protein crosslinks |
Drug | Administration | Dosage | Peak Plasma Concentration |
---|---|---|---|
Temozolomide | Oral capsule | 200 mg/m2/day for 5 days | 104 μM [45] |
150 mg/m2/day for 5 days | 66 μM [45] | ||
100 mg/m2/day for 5 days | 44 μM [45] | ||
Cisplatin (Total platinum) | Toxic concentration in blood | 16 μM [50] | |
1 h intravenous | 100 mg/m2 | 12 μM [51] | |
Rapid (4–15 min) intravenous | 100 mg/m2 | 40 μM [52] | |
Carboplatin (Total platinum) | 1 h intravenous | 400 mg/m2 | 70 μM [53] |
37 min intravenous | 350 mg/m2 | 130 μM [54] | |
Oxaliplatin (Total platinum) | 5 cycles, 2 h intravenous | 130 mg/m2 every 3 weeks | 10 μM [55] |
3 cycles, 2 h intravenous | 85 mg/m2 every 2 weeks | 6 μM [55] | |
5-Fluorouracil | 72 h intravenous | 1750 mg/m2/day | 10 μM [56] |
Camptothecin | Oral | 1.5 mg/m2/day for 5 days | 75 nM [57] |
Etoposide | Oral | 100 mg/day-8–15 days (typical dose) | 14 μM [58] |
Intravenous, 500 mg/h | 400–800 mg/m2/day for 3 days (high dose study) | 45–194 μM [59] |
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Swift, L.H.; Golsteyn, R.M. Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells. Int. J. Mol. Sci. 2014, 15, 3403-3431. https://doi.org/10.3390/ijms15033403
Swift LH, Golsteyn RM. Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells. International Journal of Molecular Sciences. 2014; 15(3):3403-3431. https://doi.org/10.3390/ijms15033403
Chicago/Turabian StyleSwift, Lucy H., and Roy M. Golsteyn. 2014. "Genotoxic Anti-Cancer Agents and Their Relationship to DNA Damage, Mitosis, and Checkpoint Adaptation in Proliferating Cancer Cells" International Journal of Molecular Sciences 15, no. 3: 3403-3431. https://doi.org/10.3390/ijms15033403