Abstract | BACKGROUND: METHODS: DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. RESULTS: A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings. CONCLUSION:
Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These characteristics could be advantageous for clinical radiotherapy since tumor cells may be exposed to low concentrations of olaparib and/or may have different levels of p53 mutation. The combination of olaparib and CPT had a stronger radiosensitizing effect, indicating that combining a PARP inihibitor with a topoiomerase I inhibitor could be promising for clinical radiosensitization.
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Authors | Katsutoshi Miura, Koh-ichi Sakata, Masanori Someya, Yoshihisa Matsumoto, Hideki Matsumoto, Akihisa Takahashi, Masato Hareyama |
Journal | Radiation oncology (London, England)
(Radiat Oncol)
Vol. 7
Pg. 62
(Apr 23 2012)
ISSN: 1748-717X [Electronic] England |
PMID | 22524618
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Phthalazines
- Piperazines
- Radiation-Sensitizing Agents
- olaparib
- Camptothecin
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Topics |
- Camptothecin
(pharmacology)
- Cell Line, Tumor
- Cell Survival
(drug effects)
- DNA Breaks, Double-Stranded
(drug effects)
- DNA Repair
(drug effects)
- Dose-Response Relationship, Drug
- Flow Cytometry
- Humans
- Phthalazines
(pharmacology)
- Piperazines
(pharmacology)
- Radiation-Sensitizing Agents
(pharmacology)
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