Recombinant human DNase I for the treatment of cancer-associated thrombosis: A pre-clinical study

摘要

Cancer patients are more likely to develop thrombosis, and this co-morbidity is related to the worse prognosis of the disease. The increased formation of neutrophil extracellular traps (NETs) has been proposed as one of the mechanisms to explain cancer-associated thrombosis. In vivo, degradation of NETs with recombinant human DNase I (rhDNase I) prevents thrombus formation in mouse models. In this work, we evaluated the effect of two different chronic treatments with rhDNase I in a murine NET-dependent prothrombotic state in breast cancer model. Medium-term treatment (2.5 mg/kg rhDNase I for eight consecutive days) did not interfere with the primary growth of 4T1 tumors. On the other hand, it effectively prevented thrombus formation in the inferior vena cava stenosis model. Remarkably, medium-term treatment with rhDNase I showed minor impact in the tailbleeding model. Different from the medium-term, the long-term treatment with rhDNase I (2.5 mg/kg for 18 successive days) drastically reduced the overall survival. Remarkably, the concomitant use of Ertapenem, a carbapenem antibiotic, and rhDNase I significantly attenuated the mortality observed in the long-term treatment. Our results suggest the therapeutic potential of rhDNase I to treat cancer-associated thrombosis, although its chronic use should be carefully evaluated and potentially harmful.