Influence of methotrexate and cisplatin on tumor progression and survival in the VM mouse model of systemic metastatic cancer

We recently identified a new tumor (VM-M3), which arose spontaneously in the brain of an inbred VM mouse. When grown outside the brain, the VM-M3 tumor expresses all major biological processes of metastasis to include local invasion, intravasation, immune system survival, extravasation, and secondary tumor formation involving lung, liver, kidney, spleen and brain. The VM-M3 tumor also expresses multiple properties of macrophage-like cells similar to those described previously in numerous human metastatic cancers suggesting that the VM-M3 model will be useful for studying most types of metastatic cancer, regardless of tissue origin. VM-M3 tumor cells, expressing firefly luciferase (VM-M3/Fluc), were grown subcutaneously in the immunocompetent and syngeneic VM mouse host. The antimetastatic effects of methotrexate (MTX; 25 mg/kg) and cisplatin (10-15 mg/kg) were evaluated following i.p. injections administered once/wk for 3 weeks. Bioluminescent imaging was used to measure VM-M3/Fluc growth and metastasis. All (12/12) control mice developed systemic cancer within 21 days of subcutaneous VM-M3/Fluc implantation. Although methotrexate did not inhibit VM-M3/Fluc primary tumor growth, it reduced lung and liver metastasis by 50% and completely inhibited metastasis to kidneys, spleen and brain. Cisplatin significantly reduced primary tumor growth, blocked metastasis to lung, liver, kidneys, spleen and brain, and significantly increased survival in all treated animals. Our findings show that the response of the VM-M3/Fluc tumor to MTX and cisplatin is similar to that reported in humans with metastatic disease. These findings indicate that the VM-M3/Fluc tumor is a reliable preclinical model for evaluating antimetastatic cancer therapies and underlying control pathways.