Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models

Abstract

ObjectiveAdvanced 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.DesignHuman 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.ResultsSubcutaneous 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).ConclusionThe 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.

Tumor-environment biomimetics delay peritoneal metastasis formation by deceiving and redirecting disseminated cancer cells

“…SK-OV-3 is a human ovarian cancer cell line (ATCC number: HTB-77). HT29hCG-Luc is a human colon cancer cell line (ATCC number: HTB-38) kindly provided by Dr. C. Hackl [15]. MSTO-211h is a human mesothelioma cancer cell line (ATCC number: CRL-2081).…”

Models in Translational Oncology: A Public Resource Database for Preclinical Cancer Research

“…It is worth to mention that the overwhelming number of ectopic transplantation models do not mimic the human counterpart with respect to tumor vascularization, tumor microenvironment, metastatic spread to the relevant distant sites, or responsiveness toward chemotherapeutics and other drugs (37). Cell transplantation into the organ of origin, the orthotopic transplantation, is rarely done, although it resembles much better the human situation with respect to the tumor microenvironment or cancer metastasis However, depending on the context, this assay needs advanced technical skills (38).…”

Metronomic topotecan for colorectal cancer: a promising new option

“…This emerging approach has been extensively evaluated in clinical trials and animal models 1. Hackl et al 2 report for the first time that metronomic oral topotecan therapy in adjuvant and metastatic settings prolongs survival and reduces liver metastasis in mouse models of metastatic CRC. Their findings provide a rational for clinical trials of metronomic oral topotecan in CRC at stage III and metastatic CRC as well.…”

“…However, the efficacy of metronomic oral topotecan is not known in CRC. In this issue of Gut , Hackl et al 2 examined the effects of metronomic oral topotecan plus pazopanib and/or tegafur-uracil in mouse metastatic models of CRC and found that metronomic oral topotecan significantly prolonged survival by inhibiting primary tumours and liver metastasis.…”

“…In transplantation models, liver and lung metastasis in the immunocompromised or syngeneic mouse can be induced by orthotopic intracaecal, intrasplenic and intravenous injection of human or mouse colon carcinoma cells. The study reported in this issue of Gut provides the first evidence directly comparing the frequency of metastasis and efficiency of FOLFOX-like treatment in different models, such as subcutaneous injection, intrasplenic injection with or without splenectomy, intracaecal cell injection, and caecal tumour fragment implantation 2. FOLFOX is a chemotherapy regimen that includes folinic acid, 5-FU and oxaliplatin.…”