Potentiation of DNA-Damage-Induced Cytotoxicity by G2Checkpoint Abrogators
| Autor: | M Pruschy, Angela Tenzer |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
G2 Phase
Cancer Research Cell cycle checkpoint Cell Survival DNA damage Antineoplastic Agents Cell Cycle Proteins chemistry.chemical_compound Alkaloids Caffeine medicine Animals Humans Staurosporine Cell Cycle Protein Cytotoxicity Pharmacology Drug Synergism G2-M DNA damage checkpoint Cell cycle Combined Modality Therapy Cell biology chemistry Xanthines Molecular Medicine biological phenomena cell phenomena and immunity DNA DNA Damage medicine.drug |
| Zdroj: | Current Medicinal Chemistry-Anti-Cancer Agents. 3:35-46 |
| ISSN: | 1568-0118 |
| Popis: | Cell cycle checkpoints are activated in response to DNA-damage to ensure that accurate copies of the cellular genome are passed on to the next generation and to avoid replication and segregation of damaged DNA. These cellular control systems can be overcome by combining conventional DNA-damaging agents with compounds that target the cell cycle regulatory pathways, to enhance cytotoxicity. Tumor cells often comprise a corrupted G(1) cell cycle checkpoint while the G(2) cell cycle checkpoint is still intact. This review describes the concept of G(2) checkpoint abrogation with recognized (methylxanthines, UCN-01) and novel G(2) checkpoint abrogators to potentiate the cytotoxicity of DNA-damaging drugs and ionizing radiation. It illustrates the potential of G(2) checkpoint abrogators to preferentially sensitize p53-mutated, treatment resistant tumor cells for genotoxic treatment. Identification of the targets of caffeine and UCN-01 to be key-players of the G(2) checkpoint (ATM/ATR and Chk1, respectively) promoted the search for novel inhibitors of this checkpoint. Even though a direct causal link between G(2) checkpoint abrogation and chemo-/radiosensitization is difficult to prove the multitude of these novel compounds validate that inhibition of critical elements of the G(2) checkpoint (ATM/ATR-Chk1/Chk2-CDC25C-cascade) potentiates the cytotoxicity of DNA-damaging agents. |
| Databáze: | OpenAIRE |
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