Efficacy of combining GMX1777 with radiation therapy for human head and neck carcinoma.
OBJECTIVE
Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD(+) biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy.


METHODS
Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated.


RESULTS
IC(50) values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD(+) followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. [(18)F]FDG-positron emission tomography/computed tomography images showed reduction in [(18)F]FDG uptake after GMX1777 administration, showing decreased glucose metabolism in vivo.


CONCLUSIONS
Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients.
Kato
Hisayuki
H
Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Ito
Emma
E
Shi
Wei
W
Alajez
Nehad M
NM
Yue
Shijun
S
Lee
Carolina
C
Chan
Norman
N
Bhogal
Nirmal
N
Coackley
Carla L
CL
Vines
Doug
D
Green
David
D
Waldron
John
J
Gullane
Patrick
P
Bristow
Rob
R
Liu
Fei-Fei
FF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006146:Guanidines / Q000008:administration & dosage* / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000532:radiotherapy*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
C541789:1-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxycarbonyloxymethyl)-4-(N'-cyano-N''-(6-(4-chlorophenoxy)hexyl)-N-guanidino)pyridinium; D004791:Enzyme Inhibitors; D006146:Guanidines; D009243:NAD; D000255:Adenosine Triphosphate; D054409:Nicotinamide Phosphoribosyltransferase