title: CPT-11 may provide therapeutic efficacy for esophageal squamous cell cancer and the effects correlate with the level of DNA topoisomerase I protein.
abstract: CPT-11 is a potent anti-cancer drug and a specific inhibitor of DNA topoisomerase I (Topo I). In this study, we aim to evaluate the effects of CPT-11 on esophageal squamous cell cancers (ESCC) and to determine the correlation between the effects and the levels of Topo I expression. We examined the growth-inhibitory effect caused by SN-38, an active metabolite of CPT-11, in 14 human ESCC cell lines established from 10 primary and 4 metastatic lesions. CPT-11 was considered effective against 5 cell lines from primary lesions and one from metastatic lesions, and thus may show therapeutic efficacy against both primary and metastatic ESCC tumors. Although Topo I mRNA levels in these 14 ESCC cell lines, as quantitated by northern blot analysis, showed no correlation with the IC(50) values, Topo I protein levels, as quantitated by western blot analysis, showed an inverse correlation with the IC(50) values. Topo I protein levels could be an indicator of sensitivity to CPT-11. We also determined Topo I protein levels in 40 ESCC tumors and matched normal mucosae. Thirty-four tumors showed 1.2 - 22.3-fold increases in Topo I levels. Two patients receiving pre-operative chemotherapy and one receiving radiotherapy exhibited increased Topo I protein levels in their tumor lesions. It appeared that CPT-11 could provide selective therapeutic efficacy against ESCC tumors. CPT-11 may be effective for the treatment of metastatic ESCC tumors and as a second-line anti-cancer drug for ESCC.
authors.affiliation: Department of Surgery, Tokyo Medical and Dental University, Bunkyou-ku, Tokyo 113-8519, Japan. yasu.nakajima.srg1@tmd.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Nakajima
authors.forename: S
authors.initials: S
authors.lastname: Miyake
authors.forename: K
authors.initials: K
authors.lastname: Nagai
authors.forename: T
authors.initials: T
authors.lastname: Kawano
authors.forename: T
authors.initials: T
authors.lastname: Iwai
mesh_terms: D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D000077146:Irinotecan; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin