Head and neck cancer radiosensitization by the novel poly(ADP-ribose) polymerase inhibitor GPI-15427.
BACKGROUND
In this study, we tested the ability of a novel poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]-anthracen-3-one (GPI-15427), to enhance the effect of radiotherapy in a xenograft model of human head and neck squamous cell carcinoma (HNSCC).


METHODS
Human xenograft HNSCC tumors were established in female nude mice: animals were treated with orally administered GPI-15427 at varied doses prior to tumor irradiation. In vitro and in vivo apoptosis analyses and neutral single-cell gel electrophoresis (comet) assay were performed, with the "tail moment" calculated to evaluate DNA double-strand break damage.


RESULTS
Orally administered GPI-15427 given before radiation therapy significantly reduced tumor volume, and cells demonstrated significantly elevated mean tail moments (indicative of DNA damage) and enhanced apoptosis both in vitro and in vivo, compared with radiation-alone and control groups.


CONCLUSIONS
Use of the PARP-1 inhibitor GPI-15427 induced significant sensitization to radiotherapy, representing a promising new treatment in the management of HNSCC.
Khan
Khurram
K
Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Araki
Koji
K
Wang
Daiyou
D
Li
Guayan
G
Li
Xin
X
Zhang
Jie
J
Xu
Weizheng
W
Hoover
Randall K
RK
Lauter
Susan
S
O'Malley
Bert
B
Lapidus
Rena G
RG
Li
Daqing
D
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D020552:Comet Assay; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009930:Organic Chemicals / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C502278:GPI 15427