Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models
- Department of Medical Biophysics, Molecular and Cellular Biology Research, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
- Correspondence to Dr Christina Hackl, Molecular & Cellular Biology Research, Sunnybrook Research Institute, S-Wing, Room 217, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada;
Contributors CH: study concept and design, acquisition, analysis and interpretation of data, statistical analysis, drafting of manuscript, obtained funding. SM: study concept and design, acquisition of data, technical support. GF: study concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript. CM: acquisition, analysis and interpretation of data, statistical analysis, critical revision of the manuscript. PX: technical support, critical revision of the manuscript. RSK: critical revision of the manuscript for important intellectual content, obtained funding and material support and study supervision.
- Revised 24 February 2012
- Accepted 25 February 2012
- Published Online First 28 April 2012
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.
Design 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).
Conclusion 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.
- orthotopic implantation
- adjuvant therapy
- abdominal surgery
- colon carcinogenesis
- colorectal carcinoma
Funding This study was supported by grants to R S Kerbel from the National Institutes of Health, USA (CA-41233), the Ontario Institute for Cancer Research, and a sponsored research agreement with GlaxoSmithKline, Philadelphia, USA. RSK holds a Tier I Canada Research Chair in Tumour Biology, Angiogenesis and Antiangiogenic Therapy. CH was supported by a Research Fellowship from the Deutsche Forschungsgemeinschaft (German Research Foundation). CM is supported by the Ontario Ministry of Research and Innovation Post-Doctoral Fellowship, the Research Excellence Fellowship for Women in Science (L'Oreal Canada and Canadian Commision for UNESCO) and the 2010 Brenda M Williams Young Investigator Award.
Competing interests RSK is a consultant to Taiho Pharmaceuticals, Japan, and GSK, USA. He receives funding from GSK to undertake studies using oral topotecan and pazopanib. CH, SM, GF, CM and PX have no competing interests.
Provenance and peer review Not commissioned; externally peer reviewed.
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