Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis
| Autor: | Marie Fernet, Vincent Favaudon, Nicole Giocanti, Camille Godon, Georges Noël, Frédérique Mégnin-Chanet |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
DNA Replication
Radiation-Sensitizing Agents Cancer Research Poly ADP ribose polymerase Poly(ADP-ribose) Polymerase Inhibitors Quinolones Radiation Tolerance Poly (ADP-Ribose) Polymerase Inhibitor S Phase HeLa Mice chemistry.chemical_compound Cricetinae Neoplasms Tumor Cells Cultured Animals Humans Polymerase S phase Nucleic Acid Synthesis Inhibitors Mice Knockout biology DNA synthesis DNA biology.organism_classification Molecular biology Naphthalimides 1-Naphthylamine Oncology chemistry Cell culture biology.protein Poly(ADP-ribose) Polymerases |
| Zdroj: | Molecular Cancer Therapeutics. 5:564-574 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-05-0418 |
| Popis: | Radiosensitization caused by the poly(ADP-ribose) polymerase (PARP) inhibitor 4-amino-1,8-naphthalimide (ANI) was investigated in 10 asynchronously growing rodent (V79, CHO-Xrs6, CHO-K1, PARP-1+/+ 3T3, and PARP-1−/− 3T3) or human (HeLa, MRC5VI, IMR90, M059J, and M059K) cell lines, either repair proficient or defective in DNA-PK (CHO-Xrs6 and M059J) or PARP-1 (PARP-1−/− 3T3). Pulse exposure to ANI (1-hour contact) potentiated radiation response in rodent cells except in PARP-1−/− 3T3 fibroblasts. In contrast, ANI did not significantly enhance radiation susceptibility in asynchronously dividing human cells; yet, single-strand break rejoining was lengthened by ca. 7-fold in all but mouse PARP-1−/− 3T3s. Circumstantial evidence suggested that radiosensitization by ANI occurs in rapidly dividing cells only. Experiments using synchronized HeLa cells consistently showed that ANI-induced radiosensitization is specific of the S phase of the cell cycle and involves stalled replication forks. Under these conditions, prolonged contact with ANI ended in the formation of de novo DNA double-strand breaks hours after irradiation, evoking collision with uncontrolled replication forks of DNA lesions whose repair was impaired by inhibition of the PARP catalytic activity. The data suggest that increased response to radiotherapy by PARP inhibitors may be achieved only in rapidly growing tumors with a high S-phase content. [Mol Cancer Ther 2006;5(3):564–74] |
| Databáze: | OpenAIRE |
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