title: In vivo activity of novel capecitabine regimens alone and with bevacizumab and oxaliplatin in colorectal cancer xenograft models.
abstract: Modifying the capecitabine dosing schedule from 14 days on, 7 days off (14/7) to 7 days on, 7 days off (7/7) may enable higher doses and improved antitumor efficacy in colorectal cancer xenografts. Capecitabine 14/7 (267 or 400 mg/kg) and 7/7 (467 or 700 mg/kg) schedules in doublet and triplet combinations with optimally dosed bevacizumab (5 mg/kg) and oxaliplatin (6.7 mg/kg) were studied in female athymic nude mice bearing HT29 colorectal xenografts. Additional studies of suboptimally dosed bevacizumab (2.5 mg/kg) and capecitabine 7/7 (360 mg/kg) were done in a similar Colo205 tumor xenograft model. Monotherapy and combination regimens were administered to groups of 10 animals and compared with vehicle controls. In the HT29 model, tumor growth inhibition and increase in life span (ILS) were significantly greater with capecitabine 7/7 than with 14/7 (P<0.05). The additional benefit of capecitabine 7/7 versus 14/7 was biologically significant according to National Cancer Institute criteria (>25% ILS). Adding bevacizumab to capecitabine 7/7 resulted in significantly greater survival relative to either agent alone (P<0.0001). When oxaliplatin was added, efficacy was significantly better with the triplet combination including capecitabine 7/7 (tumor growth inhibition>100% and ILS 234%) compared with 14/7 (95% and 81%, respectively). In the Colo205 model, combination therapy with capecitabine 7/7 plus bevacizumab resulted in significantly greater survival relative to either agent alone (P<0.0001). In conclusion, in athymic nude mice bearing moderately thymidine phosphorylase-expressing HT29 or Colo205 colorectal xenografts, a capecitabine 7/7 schedule permits increased drug delivery compared with traditional 14/7 regimens, greatly improving monotherapy activity without major toxicity.
authors.affiliation: Discovery Oncology R&D, Hoffmann La-Roche, Inc., 340 Kingsland Street, Building 123/2319, Nutley, NJ 07110-1199, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.forename: Ben-Quan
authors.initials: BQ
authors.lastname: Shen
authors.forename: Yu-E
authors.initials: YE
authors.lastname: Zhang
authors.forename: Joseph
authors.initials: J
authors.lastname: Kohles
authors.forename: Ute
authors.initials: U
authors.lastname: Dugan
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Zioncheck
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D000068258:Bevacizumab; D000069287:Capecitabine; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004361:Drug Tolerance; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil