title: Optimal combination chemotherapy and chemoradiotherapy with etoposide for advanced cervical squamous cancer cells in vitro.
abstract: Patients with unresectable advanced carcinoma of the uterine cervix are usually treated with chemotherapy or chemoradiotherapy. In the present study, the optimal administration protocol for etoposide in chemotherapy and chemoradiotherapy for advanced cervical cancer patients was investigated in vitro using the radio-sensitive and anticancer drug-sensitive human cervical squamous cell carcinoma cell line ME180. Therapeutic doses of concurrent irradiation reduced the cellular etoposide sensitivity in a dose-dependent manner, while postirradiation-surviving subclones established from repeatedly irradiated ME180 cells showed significantly higher etoposide sensitivities than the non-irradiated parent cells. Of the 6 monoclonal etoposide-resistant subclones established from ME180 cells, 5 were significantly radioresistant. Although the etoposide-resistant subclones were also significantly resistant to other anticancer drugs, such as cisplatin, carboplatin, nedaplatin, pirarubicin, paclitaxel and docetaxel, they were more sensitive to 5-fluorouracil, mitomycin C and SN38 than the parent cells. Flow cytometric analyses revealed that the etoposide-resistant subclones showed significantly increased cell surface expression of CD40 compared to the parent cells, which expressed undetectable levels of CD40. However, the expression of some integrin receptor subunits, such as CD29, CD49a and CD49f, was apparently reduced in the etoposide-resistant subclones. These results indicate that etoposide should be administered to advanced cervical squamous cancer patients after the completion of radiotherapy, rather than as a concurrent chemoradiotherapy. In order to kill surviving etoposide-resistant cancer cells more effectively, 5-fluorouracil, mitomycin C and irinotecan may be candidate combination drugs for use with etoposide. Differential expression of integrin receptors and CD40 may be involved in the acquisition of etoposide resistance by cervical squamous cancer cells.
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama 641-0012, Japan. tetanaka@wakayama-med.ac.jp
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tao
authors.initials: T
authors.lastname: Bai
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
authors.forename: Naohiko
authors.initials: N
authors.lastname: Umesaki
mesh_terms: D018951:Antigens, CD20 / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019013:CD40 Antigens / Q000032:analysis; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D039423:Integrin alpha1 / Q000032:analysis; D039503:Integrin alpha6 / Q000032:analysis; D000077146:Irinotecan; D016685:Mitomycin / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D014965:X-Rays
chemical_list: D018951:Antigens, CD20; D000972:Antineoplastic Agents, Phytogenic; D019013:CD40 Antigens; D039423:Integrin alpha1; D039503:Integrin alpha6; D016685:Mitomycin; D005047:Etoposide; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin