Abstract
Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is rapidly and directly activated by single-strand breaks and is required for efficient base excision repair. These properties indicate that inhibition of PARP-1 might enhance the cellular response to low doses of radiation. We tested the effect of chemical inhibition of PARP-1 on low-dose clonogenic survival in a number of cell lines and the low-dose radiation response of a PARP-1 knockout murine cell line. Methods and Materials: Clonogenic cell survival of V79-379A and CHO-K1 hamster fibroblasts, T98G and U373-MG human glioma cells, and 3T3 mouse embryo fibroblast PARP-1 knockout cells was measured using a precise flow cytometry-based plating assay. Chemical inhibitors of PARP enzymes were tested for their effect on clonogenic survival after a range of ionizing radiation doses. Results: Chemical inhibition of PARP activity induced marked radiosensitization of V79, CHO, and exponentially growing T98G cells in the 0.05-0.3-Gy range. This effect was not seen in U373 cells or in confluent T98G populations. Low-dose radiosensitization was not apparent in PARP-1 knockout cells. Conclusion: Low-dose radiosensitization of actively dividing tumor cells by PARP-1 inhibitors suggests that they may have a role in enhancing the efficacy of ultrafractionated or low-dose-rate radiotherapy regimens. We hypothesize that PARP-2 compensates for the absence of PARP-1 in the knockout cell line.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 410-419 |
| Number of pages | 10 |
| Journal | International Journal of Radiation Oncology Biology Physics |
| Volume | 58 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 1 2004 |
| Externally published | Yes |
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Keywords
- DNA repair
- Low-dose hypersensitivity
- Low-dose radiation
- PARP inhibitors
- Poly(ADP-ribose) polymerase-1
- Poly(ADP-ribose) polymerase-2
ASJC Scopus subject areas
- Radiation
- Oncology
- Radiology Nuclear Medicine and imaging
- Cancer Research
Cite this
PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. / Chalmers, Anthony; Johnston, Peter; Woodcock, Mick; Joiner, Michael; Marples, Brian.
In: International Journal of Radiation Oncology Biology Physics, Vol. 58, No. 2, 01.01.2004, p. 410-419.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation
AU - Chalmers, Anthony
AU - Johnston, Peter
AU - Woodcock, Mick
AU - Joiner, Michael
AU - Marples, Brian
PY - 2004/1/1
Y1 - 2004/1/1
N2 - Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is rapidly and directly activated by single-strand breaks and is required for efficient base excision repair. These properties indicate that inhibition of PARP-1 might enhance the cellular response to low doses of radiation. We tested the effect of chemical inhibition of PARP-1 on low-dose clonogenic survival in a number of cell lines and the low-dose radiation response of a PARP-1 knockout murine cell line. Methods and Materials: Clonogenic cell survival of V79-379A and CHO-K1 hamster fibroblasts, T98G and U373-MG human glioma cells, and 3T3 mouse embryo fibroblast PARP-1 knockout cells was measured using a precise flow cytometry-based plating assay. Chemical inhibitors of PARP enzymes were tested for their effect on clonogenic survival after a range of ionizing radiation doses. Results: Chemical inhibition of PARP activity induced marked radiosensitization of V79, CHO, and exponentially growing T98G cells in the 0.05-0.3-Gy range. This effect was not seen in U373 cells or in confluent T98G populations. Low-dose radiosensitization was not apparent in PARP-1 knockout cells. Conclusion: Low-dose radiosensitization of actively dividing tumor cells by PARP-1 inhibitors suggests that they may have a role in enhancing the efficacy of ultrafractionated or low-dose-rate radiotherapy regimens. We hypothesize that PARP-2 compensates for the absence of PARP-1 in the knockout cell line.
AB - Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is rapidly and directly activated by single-strand breaks and is required for efficient base excision repair. These properties indicate that inhibition of PARP-1 might enhance the cellular response to low doses of radiation. We tested the effect of chemical inhibition of PARP-1 on low-dose clonogenic survival in a number of cell lines and the low-dose radiation response of a PARP-1 knockout murine cell line. Methods and Materials: Clonogenic cell survival of V79-379A and CHO-K1 hamster fibroblasts, T98G and U373-MG human glioma cells, and 3T3 mouse embryo fibroblast PARP-1 knockout cells was measured using a precise flow cytometry-based plating assay. Chemical inhibitors of PARP enzymes were tested for their effect on clonogenic survival after a range of ionizing radiation doses. Results: Chemical inhibition of PARP activity induced marked radiosensitization of V79, CHO, and exponentially growing T98G cells in the 0.05-0.3-Gy range. This effect was not seen in U373 cells or in confluent T98G populations. Low-dose radiosensitization was not apparent in PARP-1 knockout cells. Conclusion: Low-dose radiosensitization of actively dividing tumor cells by PARP-1 inhibitors suggests that they may have a role in enhancing the efficacy of ultrafractionated or low-dose-rate radiotherapy regimens. We hypothesize that PARP-2 compensates for the absence of PARP-1 in the knockout cell line.
KW - DNA repair
KW - Low-dose hypersensitivity
KW - Low-dose radiation
KW - PARP inhibitors
KW - Poly(ADP-ribose) polymerase-1
KW - Poly(ADP-ribose) polymerase-2
UR - http://www.scopus.com/inward/record.url?scp=0942300650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0942300650&partnerID=8YFLogxK
U2 - 10.1016/j.ijrobp.2003.09.053
DO - 10.1016/j.ijrobp.2003.09.053
M3 - Article
VL - 58
SP - 410
EP - 419
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
SN - 0360-3016
IS - 2
ER -