Comparison of molecular markers of hypoxia and imaging with (60)Cu-ATSM in cancer of the uterine cervix.
OBJECTIVE
To determine if hypoxia-related molecular markers are associated with (60)Cu labeled diacetyl-bis (N4 -methylthiosemicarbazone); ((60)Cu-ATSM) imaging of tumor hypoxia in cervical cancer.


METHODS
Fifteen patients were enrolled in a prospective study and underwent evaluation of tumor hypoxia with positron emission tomography (PET) using (60)Cu-ATSM. (60)Cu-ATSM-PET imaging was compared with the expression of tissue molecular markers, which included vascular endothelial growth factor (VEGF), cyclo-oxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), carbonic anyhdrase IX (CA-9), and apoptotic index.


RESULTS
Six patients had hypoxic tumors determined by (60)Cu-ATSM, and nine had non-hypoxic tumors. The 4-year overall survival estimates were 75% for patients with non-hypoxic tumors and 33% for those with hypoxic tumors (p = 0.04). Overexpression of VEGF (p = 0.13), EGFR (p = 0.05), CA-9 (p = 0.02), COX-2 (p = 0.08), and the presence of apoptosis (p = 0.005) occurred in patients with hypoxic tumors. Cox proportional hazards modeling demonstrated hypoxia as determined by (60)Cu-ATSM to be a significant independent predictor of tumor recurrence (p = 0.0287).


CONCLUSIONS
(60)Cu-ATSM hypoxia was correlated with overexpression of VEGF, EGFR, COX-2, CA-9, an increase in apoptosis, and a poor outcome.
Grigsby
Perry W
PW
Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, USA. pgrigsby@wustl.edu
Malyapa
Robert S
RS
Higashikubo
Ryuji
R
Schwarz
Julie K
JK
Welch
Michael J
MJ
Huettner
Phyllis C
PC
Dehdashti
Farrokh
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D051546:Cyclooxygenase 2 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000000981:diagnostic imaging / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D009942:Organometallic Compounds; D010865:Pilot Projects; D011446:Prospective Studies; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015415:Biomarkers; D014408:Biomarkers, Tumor; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors