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

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 tail-bleeding 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.

IL-1ß Blockade Attenuates Thrombosis in a Neutrophil Extracellular Trap-Dependent Breast Cancer Model.

Cancer patients are at increased risk of developing thrombosis, comorbidity that has been associated with increased neutrophil counts and the formation of neutrophil extracellular traps (NETs). Interleukin-1ß (IL-1ß) modulates the expression of granulocyte colony-stimulating factor (G-CSF), a cytokine that promotes cancer-associated neutrophilia and NET generation. Herein, we combined a murine breast cancer model with a flow-restriction thrombosis model to evaluate whether the IL-1ß blockade could interfere with cancer-associated thrombosis. Mice bearing metastatic 4T1 tumors exhibited high neutrophil counts as well as elevated expression of G-CSF and IL-1ß in their tumors. On the other hand, mice bearing non-metastatic 67NR tumors showed no elevation in neutrophil counts and displayed low expression levels of G-CSF and IL-1ß in their tumors. 4T1 tumor-bearing mice but not 67NR tumor-bearing mice exhibited a NET-dependent prothrombotic state. Pharmacological blockade of IL-1 receptor (IL-1R) decreased the primary growth of 4T1 tumors and reduced the systemic levels of myeloperoxidase, cell-free DNA (cfDNA) and G-CSF, without interfering with the neutrophil counts. Most remarkably, the blockade of IL-1R abolished the prothrombotic state observed in 4T1 tumor-bearing mice. Overall, our results demonstrate that IL-1ß might be a feasible target to attenuate cancer-associated thrombosis, particularly in cancer types that rely on increased G-CSF production and involvement of NET formation.