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Reduction of liver metastasis in colon cancer

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

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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 tumor growth.

Dr Christina Hackl from Canada report on the establishment of such standardized 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 cecal wall of severe combined immunodeficient mice, intrasplenically or subcutaneously.

For adjuvant therapy, cecal resections were performed 3–5 weeks after tumor cell injection.

Chemotherapy drugs tested included uracil/tegafur, folinic acid, oxaliplatin, topotecan, pazopanib and various combinations.

Subcutaneous tumors showed exaggerated sensitivity to treatment
Gut

The researchers found that subcutaneous tumors showed exaggerated sensitivity to treatment by delayed tumor growth and increased survival, but no metastatic spread.

Intrasplenic cell injection resulted in rapid and extensive but artefactual metastasis without treatment effect.

The research team found that intracecal cell injection with tumor take rates of 88–100% showed spontaneous metastases at clinically relevant rates.

Metronomic topotecan significantly polonged survival and reduced metastasis.

In the adjuvant setting, metronomic maintenance therapy prolonged survival compared with vehicle controls, control followed by topotecan or FOLFOX-like therapy.

Dr Hackl's team commented, "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."  

Gut  2013;62:259-271
21 January 2013

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