title: Therapeutic potential and molecular mechanism of a novel sulfonamide anticancer drug, indisulam (E7070) in combination with CPT-11 for cancer treatment.
abstract: OBJECTIVE
  Indisulam (N-(-3-chloro-7-indolyl)-1,4-benzenedisulfonamide; E7070) is an experimental anticancer agent. Microarray analysis indicates that indisulam downregulates several genes involved in drug resistance, and this finding led us to test the effect of combining indisulam with other anticancer drugs. We investigated the antitumor effect and mechanism of synergism when indisulam was administered in combination with CPT-11.
  
  
  METHODS
  In vitro cytotoxic activity was examined using a cell counter kit, and the combination effect was determined by isobologram analysis. The level of topoisomerase IIα was measured by Western blotting. The in vivo antitumor effect was assessed in mice inoculated with human colorectal cancer SW620 cells.
  
  
  RESULTS
  Isobologram analysis indicated that a 24-h exposure to indisulam and SN-38, an active metabolite of CPT-11, had a synergistic effect in HCT116 and SW620 cells and an additive effect in HCT15 and WiDr cells. Prolongation of exposure to 48 h resulted in a synergistic effect in HCT15 and WiDr cells. Treatment with SN-38 alone increased the amount of intracellular topoisomerase IIα in all cell lines tested. Co-treatment with indisulam suppressed the SN-38-induced upregulation of topoisomerase IIα after 24 h of exposure in HCT116 and SW620 cells and after 48 h of exposure in HCT15 and WiDr cells. This apparent association between a synergistic effect and suppression of SN-38-mediated upregulation of topoisomerase IIα suggests that indisulam enhances SN-38 cytotoxicity by suppressing topoisomerase IIα upregulation to compensate for topoisomerase I inhibition by SN-38. Synergy was also observed in xenografted tumors and was accompanied by complete suppression of topoisomerase IIα upregulation induced by CPT-11 treatment.
  
  
  CONCLUSIONS
  These observations prompted the clinical evaluation of indisulam and CPT-11 combination therapy.
authors.affiliation: Oncology PCU, Eisai Co., Ltd., Ibaraki, Japan. y2-ozawa@hhc.eisai.co.jp
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Kazutomi
authors.initials: K
authors.lastname: Kusano
authors.forename: Takashi
authors.initials: T
authors.lastname: Owa
authors.forename: Akira
authors.initials: A
authors.lastname: Yokoi
authors.forename: Makoto
authors.initials: M
authors.lastname: Asada
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshimatsu
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000187:drug effects* / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000187:drug effects* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D046228:Microarray Analysis; D013449:Sulfonamides / Q000008:administration & dosage; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; D000077146:Irinotecan; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin