Abstract Archives of the RSNA, 2008
Modulation of Radiation Response of Head and Neck Cancer Cells with Poly (ADP-Ribose) Polymerase Inhibitor-ABT888
Presented on December 1, 2008
Presented as part of LL-RO-D: Radiation Oncology and Radiobiology
James Clarke MD, Presenter: Nothing to Disclose
John Christopher Grecula MD, Abstract Co-Author: Nothing to Disclose
william Hall BS, Abstract Co-Author: Nothing to Disclose
Greg Otterson MD, Abstract Co-Author: Nothing to Disclose
Jian Z. Wang PhD, Abstract Co-Author: Nothing to Disclose
Li Wang PhD, Abstract Co-Author: Nothing to Disclose
James Lang PhD, Abstract Co-Author: Nothing to Disclose
Simon Shek-Man Lo MD, Abstract Co-Author: Nothing to Disclose
Nina A. Mayr MD, Abstract Co-Author: Nothing to Disclose
Miguel Villalona-Calero MD, Abstract Co-Author: Nothing to Disclose
Amit Agrawal MD, Abstract Co-Author: Nothing to Disclose
et al, Abstract Co-Author: Nothing to Disclose
Cellular DNA repair mechanisms play a critical role in maintaining the genomic stability. The family of poly(ADP-ribose) polymerase (PARP) enzymes have been implicated in many important cellular processes including repairing DNA damage caused by various injury factors such as chemotherapy or radiation. The DNA repair process involves a rapid activation of PARPs by DNA strand breaks, poly(ADP-ribose)lation of PARPs as well as histone and other nuclear kinases, and recruitment of repair enzymes. Therefore, using PARP inhibitors to potentiate the tumor killing effects of standard anticancer therapy has drawn a great interest.
ABT-888 is a potent inhibitor of PARP-1 and 2 enzymes. Although as single agent, it has no anti-proliferative effect, it has been shown that ABT-888 augmented the antitumor activity of DNA-damage drugs such as cisplatin, irinotecan, & alkylating agents in various human tumors in preclinical studies. We hypothesize that the PARP inhibitor ABT-888 through its anti-DNA repair mechanism would enhance the killing effect of ionizing radiation in 2 head & neck cancer cell lines (H & N).
Two cell lines of Tongue cancer -SCC4 and SCC15, were treated with ABT-888 (5 µmol/L) just before irradiation. Cells were irradiated with 0, 2, 4, or 6 Gy utilizing a Cs-137 cell irradiator. Clonogenic survival assays were used to evaluate the radiosensitizing effect of ABT-888 on the two cell lines. Western blotting of PAR was performed to explore the effects of PAR-1 inhibition on irradiated cancer cells.
The combination of ABT-888 and radiation, compared with radiation alone, showed significant enhancement on radiation-induced clonogenic inhibition of SCC4 and SCC15. Clonogenic survival was dose dependent. A decrease in PAR proteins on cancer cell lines in vitro treated with either ABT-888 alone or in combination with Irradiation was observed by immunoblot analysis, indicating the ability of ABT-888 to inhibit PARP activity and contributing to the mechanism of increased cell death.
Conclusion: Invitro, ABT-888 sensitizes head & neck cancer cell lines to radiation
*Supported in part by NCI N01-CM-62207, NCI 5 P30 CA016058, and the George Condos Memorial Fund
ABT-888 is an active radiosensiter in head & neck cancer cell lines and should be tested invivo and in clinical trials.
et al, ,
Modulation of Radiation Response of Head and Neck Cancer Cells with Poly (ADP-Ribose) Polymerase Inhibitor-ABT888. Radiological Society of North America 2008 Scientific Assembly and Annual Meeting, February 18 - February 20, 2008 ,Chicago IL. http://archive.rsna.org/2008/6022262.html