title: Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models.
abstract: OBJECTIVE
  Advanced and recurrent diseases are the major causes of death in colon cancer. No standard preclinical model addresses advanced disease and spontaneous metastasis after orthotopic tumour growth. In this study, the authors report the establishment of such standardised orthotopic mouse models of colon cancer and their use in evaluating metronomic topotecan alone or in combination with standard chemotherapy.
  
  
  METHODS
  Human colon cancer cell lines, transfected with human chorionic gonadotropin and luciferase, were injected orthotopically into the caecal wall of severe combined immunodeficient mice, intrasplenically or subcutaneously. For adjuvant therapy, caecal resections were performed 3-5 weeks after tumour cell injection. Chemotherapy drugs tested included uracil/tegafur, folinic acid, oxaliplatin, topotecan, pazopanib and various combinations.
  
  
  RESULTS
  Subcutaneous tumours showed exaggerated sensitivity to treatment by delayed tumour growth (p=0.002) and increased survival (p=0.0064), but no metastatic spread. Intrasplenic cell injection resulted in rapid and extensive but artefactual metastasis without treatment effect. Intracaecal cell injection with tumour take rates of 87.5-100% showed spontaneous metastases at clinically relevant rates. Metronomic topotecan significantly polonged survival and reduced metastasis. In the adjuvant setting, metronomic maintenance therapy (after FOLFOX-like induction) prolonged survival compared with vehicle controls (p=0.0003), control followed by topotecan (p=0.0161) or FOLFOX-like therapy (p=0.0003).
  
  
  CONCLUSIONS
  The refined orthotopic implantation technique proved to be a clinically relevant model for metastasis and therapy studies. Furthermore, metronomic therapy with oral topotecan may be promising to consider for clinical trials of metastatic colon cancer and long-term adjuvant maintenance therapy of colon cancer.
authors.affiliation: Department of Medical Biophysics, Molecular and Cellular Biology Research, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada. christinahackl@gmx.de
authors.forename: Christina
authors.initials: C
authors.lastname: Hackl
authors.forename: Shan
authors.initials: S
authors.lastname: Man
authors.forename: Giulio
authors.initials: G
authors.lastname: Francia
authors.forename: Chloe
authors.initials: C
authors.lastname: Milsom
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kerbel
mesh_terms: D059250:Administration, Metronomic; D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections / Q000379:methods; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D015996:Survival Rate; D019772:Topotecan / Q000008:administration & dosage
chemical_list: D009944:Organoplatinum Compounds; D019772:Topotecan; D002955:Leucovorin; D005472:Fluorouracil