Celecoxib modulates the expression of cyclooxygenase-2, ki67, apoptosis-related marker, and microvessel density in human cervical cancer: a pilot study.
OBJECTIVE
We investigated whether a short treatment with the cyclooxygenase-2 (COX-2) inhibitor celecoxib could modulate Ki67 antigen and the caspase cleavage product of keratin 18, recognized as a marker of early apoptosis. The activity of celecoxib on microvessel density (MVD) and angio-power Doppler sonography-derived indices of tumor vascularization was also assessed. Serum levels of squamous cell carcinoma antigen and the proliferative potential and subsets of peripheral T cells before and after celecoxib treatment were also analyzed.


METHODS
Tumor biopsy specimens from 14 patients with cervical cancer were obtained at baseline and after 10 days of celecoxib treatment (400 mg twice daily). Tumor and stroma COX-2 expression, Ki67, apoptosis, and MVD were assessed by immunohistochemistry, whereas prostaglandin E(2) levels were measured by RIA.


RESULTS
At baseline, COX-2 integrated density values in tumor compartment ranged from 10.7 to 60.1 (median, 26.5) and were significantly higher than tumor COX-2 integrated density values after celecoxib treatment (range, 0.6-42.3; median, 12.6; P = 0.0043). The percentages of Ki67-positive tumor cells in pre-celecoxib cases ranged from 39.3 to 87.4 (median, 50.8) and were significantly higher than the percentage in the corresponding posttreatment samples (range, 27.7-83.8; median, 43.1; P = 0.0092). MVD values in pre-celecoxib biopsies ranged from 28.0 to 55.0 (median, 38.5) and were significantly higher than the corresponding values in posttreatment samples (range, 16.0-49.5; median; 27.6; P = 0.012). Also, prostaglandin E(2) levels showed a trend to be reduced after celecoxib treatment (range: 4.7-386.6 pg/mg wet tissue in pretreated cases versus 4.8-91.9 pg/mg wet tissue in posttreated cases (P = 0.092).


CONCLUSIONS
In cervical cancer, celecoxib treatment decreases tumor COX-2 expression and markers of proliferation and neoangiogenesis, while being uneffective on stroma COX-2 levels, thus suggesting that selective COX-2 inhibitors may be a promising strategy not only for chemopreventive approaches but also for therapeutic approaches in this neoplasia.
Ferrandina
Gabriella
G
Department of Gynecology/Obstetrics, Catholic University of the Sacred Heart, 00168 Rome, Italy.
Ranelletti
Franco O
FO
Legge
Francesco
F
Lauriola
Libero
L
Salutari
Vanda
V
Gessi
Marco
M
Testa
Antonia C
AC
Werner
Ulrike
U
Navarra
Pierluigi
P
Tringali
Giuseppe
G
Battaglia
Alessandra
A
Scambia
Giovanni
G
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D017209:Apoptosis; D001808:Blood Vessels / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism; D000068579:Celecoxib; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008565:Membrane Proteins; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D010865:Pilot Projects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles; D015843:Serpins / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism
D000951:Antigens, Neoplasm; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D011720:Pyrazoles; D015843:Serpins; D013449:Sulfonamides; C051072:squamous cell carcinoma-related antigen; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D015232:Dinoprostone