Selective antimetastatic activity of cytosine analog CS-682 in a red fluorescent protein orthotopic model of pancreatic cancer

In this study we demonstrate the ability of a novel, p.o.-administered cytosine analogue, CS-682, to effectively prolong survival and inhibit metastatic growth in an imageable orthotopic mouse model of pancreatic cancer. MIA-PaCa-2-RFP pancreatic cancer cells were transduced with the Discosoma red fluorescent protein (RFP) and orthotopically implanted onto the pancreas of nude mice. Tumor RFP fluorescence facilitated real-time, sequential imaging, and quantification of primary and metastatic growth and dissemination in vivo. Mice were treated with various p.o. doses of CS-682 on a five times per week schedule until death. At a dose of 40 mg/kg, CS-682 prolonged survival compared with untreated animals (median survival 35 days versus 17 days; P = 0.0008). At nontoxic doses, CS-682 effectively suppressed the rate of primary tumor growth. CS-682 also decreased the development of malignant ascites and the formation of metastases, which were reduced significantly in number in the diaphragm, lymph nodes, liver, and kidney. Selective RFP tumor fluorescence enabled noninvasive real-time comparison between groups during treatment and facilitated identification of micrometastases in solid organs at autopsy. Thus, we have demonstrated that CS-682 is an efficacious antimetastatic agent that significantly prolongs survival in an orthotopic model of pancreatic cancer. The antimetastatic efficacy of CS-682 and its p.o. availability confer significant advantages and clinical potential to this agent for pancreatic cancer.