Resumen de Antitumor and antiangiogenic effects of metronomic chemotherapy in novel xenograft models for hematological malignancies and solid tumor
Antitumor and antiangiogenic effects of metronomic chemotherapy in novel xenograft models for hematological malignancies and solid tumors Immunodeficient mice have been widely used for years to generate xenograft mouse models, in order to reproduce in an accurate way the ideal model which perfectly replicates human disease. Different strains of immunodeficient mice have been developed for years to generate more efficient recipients (Shultz L.D., Nat Rev Immunol 2007). In this thesis we compared the engraftment of three different strains of NOD SCID- related immunodeficient mice (NOD SCID, NOD SCID β2 null, NOD SCID IL2rγ null), defining that NOD SCID IL2rγ null mice are the most permissive and exhibit the highest engraftment among them.
Angiogenesis is a fundamental phenomenon which supports and sustains tumor growth; for this reason circulating endothelial cells (CECs) and progenitors (EPCs) could be used as a marker of tumor growth. Indeed, the higher engraftment observed in NOD SCID IL2rγ null mice parallels to higher levels of CECs and EPCs.
The discovery of angiogenesis tumor dependence created interest in antiangiogenic treatments. Studies have shown that a daily administration in lower doses (metronomic therapy) than those commonly use with chemotherapeutics has antiangiogenic effects (Hanahan D, J Clin Invest 2000). Indeed, we observed that CECs could have a potential value as surrogate biomarkers of antiangiogenic drug response.
Starting from these evidences, we developed two novel xenograft orthotopic mouse models, one of Blastic NK lymphoma, and the other one of Hepatocellular carcinoma. Moreover, we studied the effects of metronomic antiangiogenic therapy (Lenalidomide for the Blastic NK lymphoma, and cyclophosphamide for the hepatocellular carcinoma). In both cases, treatment induces strong tumor regression, and antiangiogenic effects are confirmed by decreases levels of CECs and EPCs.
