title: Overexpression of cyclooxygenase-2 protein and its relationship to apoptosis in cervical carcinoma treated with neoadjuvant chemotherapy.
abstract: The aims of this study were to examine the overexpression of COX-2 protein and its relationship to apoptosis in cervical carcinoma patients treated with neoadjuvant chemo-therapy (NAC), and to assess the potential role of COX-2 as a predictor of the response to NAC in a series of patients with cervical carcinoma. For immunohistochemical analysis, cervical cancer tissue samples were collected before NAC and 3 weeks after NAC using transcatheter arterial infusion of cisplatin from 40 patients who underwent surgery for advanced cervical carcinoma in stages IB, IIA and IIB and from 5 normal cervical tissues between 1991 and 2000 at the Department of Obstetrics and Gynecology, under informed consent. Patients were randomly assigned to receive one or two arterial infusions of cisplatin. COX-2 protein expression was detected by immunohistochemical staining and was classified as no expression for tumors with negative or <10%, while > or =10% positive staining was defined as overexpression. Detection of apoptosis was done by the TUNEL method. The percentage of cells with DNA fragmentation (apoptotic index, AI) was calculated before NAC and 3 weeks after NAC. The AI ratio (AI after NAC/AI before NAC) was also calculated. COX-2 expression was not detected in the normal cervix. Overexpression of COX-2 protein was detected in 18 out of 40 (45.0%) cervical cancers. A higher incidence of COX-2 protein overexpression was observed in patients with adenocarcinoma than in those with squamous cell carcinoma (p=0.1797, Fisher's exact text). The average AI value before and after NAC was 8.85 versus 11.82 respectively. In COX-2 protein-negative patients with squamous cell carcinoma, the AI ratio was 0.96+/-0.46 following one arterial infusion of cisplatin and 3.19+/-2.72 following two infusions of cisplatin. There was a significant positive correlation between apoptosis and the number of infusions of cisplatin (p=0.0098, Mann-Whitney, U-test). Our findings suggest that COX-2 protein expression could be used as a predictor of chemoresistance and that assessment of the COX-2 status could be useful to identify cervical cancer patients who may benefit from NAC.
authors.affiliation: Department of Obstetrics and Gynecology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8551, Japan. nnagai@hiroshima-u.ac.jp
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Nagai
authors.forename: Xiurong
authors.initials: X
authors.lastname: Tian
authors.forename: Keiji
authors.initials: K
authors.lastname: Mukai
authors.forename: Eiji
authors.initials: E
authors.lastname: Hirata
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Kusuda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shiroyama
authors.forename: Kazushi
authors.initials: K
authors.lastname: Shigemasa
authors.forename: Koso
authors.initials: K
authors.lastname: Ohama
mesh_terms: D017209:Apoptosis; D002945:Cisplatin / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D053938:DNA Fragmentation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*
chemical_list: D007527:Isoenzymes; D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D002945:Cisplatin