title: Reduced radiosensitivity and increased CD40 expression in cyclophosphamide-resistant subclones established from human cervical squamous cell carcinoma cells.
abstract: To investigate the interaction between anticancer drug resistance and radioresistance in cervical cancer cells, 3 single cell-derived cyclophosphamide-resistant subclones were established from the drug- and radiosensitive human cervical squamous cell carcinoma cell line ME180 by chronic exposure cultures with 4-hydroxy-cyclophosphamide followed by limiting dilution. The established cyclophosphamide-resistant subclones were also radio- and multidrug-resistant to 7 other anticancer drugs. Flow cytometric analysis revealed significantly increased levels of CD40 expression on the 3 resistant subclones, whereas no CD40 expression was found on the parent ME180 cells. However, there were no changes in the expression levels of CD29, CD49a-CD49f or CD59 between the parent cells and resistant subclones. A recombinant human soluble CD40 ligand had no effect on the proliferation of the resistant subclones. Irradiation had no effect on the 4-hydroxy-cyclophosphamide sensitivity of the parent cells. These results indicate that the established cyclophosphamide-resistant subclones have impaired cell death signals, which are common to both drug- and radiation-induced apoptosis, and cyclophosphamide may not be an adequate drug for use in concurrent chemoradiotherapy. Furthermore, CD40 activation signals may be associated with the multidrug- and radioresistance in these cyclophosphamide-resistant subclones.
authors.affiliation: Department of Obstetrics and Gynecology, Wakayama Medical University, 811-1 Kimi-idera, 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: Tomoko
authors.initials: T
authors.lastname: Utsunomiya
authors.forename: Naohiko
authors.initials: N
authors.lastname: Umesaki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D019013:CD40 Antigens / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000378:metabolism; D018957:CD59 Antigens / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D005720:Gamma Rays; D006801:Humans; D039423:Integrin alpha1 / Q000096:biosynthesis; D039421:Integrin alpha2 / Q000096:biosynthesis; D039422:Integrin alpha3 / Q000096:biosynthesis; D039441:Integrin alpha4 / Q000096:biosynthesis; D039482:Integrin alpha5 / Q000096:biosynthesis; D039503:Integrin alpha6 / Q000096:biosynthesis; D019012:Integrin beta1 / Q000096:biosynthesis; D011836:Radiation Tolerance; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D019013:CD40 Antigens; D018957:CD59 Antigens; D039423:Integrin alpha1; D039421:Integrin alpha2; D039422:Integrin alpha3; D039482:Integrin alpha5; D039503:Integrin alpha6; D019012:Integrin beta1; D001761:Bleomycin; D039441:Integrin alpha4; D023201:CD40 Ligand; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide