The role of copper suppression as an antiangiogenic strategy in head and neck squamous cell carcinoma.
OBJECTIVE
To determine whether tetrathiomolybdate (TM), a powerful chelator of copper, is capable of lowering the body stores of copper and suppressing the growth of head and neck squamous cell carcinoma in an orthotopic murine model.


METHODS
In vivo, murine model.


METHODS
Twelve 8-week-old male C3H/HeJ mice were assigned to either a TM treatment group (n = 7) or a control group (n = 5). Serum samples were obtained from a single mouse in each group to measure the level of ceruloplasmin as a surrogate marker of total body copper on days 0, 4, and 7. Mice in both groups received a floor-of-mouth injection of 1.5 x 105 SCC VII/SF cells. After 7 to 10 days of tumor growth the treatment group received fresh water daily, to which TM was added to achieve an oral intake of 50 mg per mouse. The control group received only fresh drinking water daily. Tumor volume measurements were obtained every other day. Microvessel density counts were assessed in the tumors by Factor VIII analysis.


RESULTS
Measurable tumor growth was achieved in 100% of the mice by the tenth day. Total body copper was reduced by 28% from baseline levels in mice in the treatment group. The difference in mean tumor volume in the control group was 4.7 times greater than the TM-treated group at the completion of treatment (3004 mm3 and 633mm3, respectively). This accounted for an overall suppression rate of 79% (P =.008; two-tailed Student t test). In addition, microvessel density was reduced by 50% in the TM-treated group.


CONCLUSIONS
In this initial study, the first of its kind in head and neck squamous cell carcinoma, we have demonstrated the ability of TM to significantly suppress both the growth of squamous cell carcinoma and tumor vascularity in this orthotopic murine model, suggesting its potential for efficacy in the treatment of this disease in humans.
Cox
C
C
Department of Otolaryngology-Head and Neck Surgery, University of Michigan Health System, Ann Arbor, Michigan, USA.
Teknos
T N
TN
Barrios
M
M
Brewer
G J
GJ
Dick
R D
RD
Merajver
S D
SD
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001363:Awards and Prizes; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000517:prevention & control*; D002570:Ceruloplasmin / Q000032:analysis; D002614:Chelating Agents / Q000627:therapeutic use*; D003300:Copper / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008982:Molybdenum / Q000627:therapeutic use*; D009368:Neoplasm Transplantation
D020533:Angiogenesis Inhibitors; D002614:Chelating Agents; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate; D002570:Ceruloplasmin