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Departments of Gynecology/Obstetrics [G. F., F. L., V. S., A. C. T., A. B., G. S.], Histology [F. O. R.], Pathology [L. L., M. G.], and Pharmacology [P. N., G. T.], Catholic University of the Sacred Heart, 00168 Rome, Italy, and Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich Alexander University, Erlangen, D-91051 Nuremberg, Erlangen, Germany [U. W.]
ABSTRACT
Purpose: 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.
Experimental Design: 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 E2 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 E2 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.
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