Enhanced Therapeutic Efficacy of the Nanoscale Fluoropyrimidine Polymer CF10 in a Rat Colorectal Cancer Liver Metastasis Model

Simple Summary: Liver metastases are a major cause of colorectal cancer mortality. To combat this, chemotherapy is widely used but generally does not result in long-term survival and causes serious side effects in many patients. We tested if a new polymeric chemotherapy, CF10, was more effective than the current drug, 5-FU, in a rat model of liver metastatic disease. Our studies proved that CF10 was better tolerated in rats than 5-FU, was more potent at decreasing the viability of rat colon cancer cells, and was significantly more effective than 5-FU at inhibiting cancer progression in a rat model of liver metastasis when administered at an equivalent dose. Based on these studies, we propose advancing CF10 into clinical trials and testing it for improved activity in human patients with colorectal liver metastases. Combination chemotherapy regimens that include fluoropyrimidine (FP) drugs, e.g., 5-fluorouracil (5-FU), are central to the treatment of colorectal cancer liver metastases (CRLMs), a major cause of cancer mortality. We tested a second-generation FP polymer, CF10, in a CC531/WAGRij syngeneic orthotopic rat model of liver metastasis to determine if CF10 improved response relative to 5-FU. CF10 displayed increased potency relative to 5-FU in CC531 rat colorectal cancer cells based on clonogenic assay results and caused increased apoptosis, as shown using a live/dead assay. The increased potency of CF10 to CC531 cells was associated with increased replication stress, as assessed by Western blot for biomarkers of ATR/Chk1 and ATM/Chk2 pathway activation. CF10 dosed to deliver equivalent FP content as an established dose of 5-FU in rats (50 mg/kg) did not cause weight loss in WAGRij rats even when combined with ethynyl uracil (EU), an inhibitor of dihydropyrimidine dehydrogenase, the enzyme primarily responsible for 5-FU degradation in the liver. In contrast, 5-FU caused significant weight loss that was exacerbated in combination with EU. Importantly, CF10 was significantly more effective than 5-FU at inhibiting tumor progression (similar to 90% reduction) in the CC531/WAG/Rij CRLM model. Our results reveal strong potential for CF10 to be used for CRLM treatment.