Adjuvant treatment with the
cytosine analogue 1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-N(4)-palmitoylcytosine (CS-682) results in a highly significant increase in survival in the aggressive orthotopic MIA-PaCa-2 human
pancreatic cancer mouse model. Seven days after implantation, mice were randomized into eight groups, depending on whether they were to be treated by
tumor resection, 5 weeks of
CS-682 chemotherapy at 40-60 mg/kg once daily, or both. Throughout the course of treatment, noninvasive optical whole-body imaging based on brilliant
red fluorescent protein expression of the
tumor permitted visualization and quantification of primary, metastatic, and recurrent disease. Total
tumor burden negatively correlated with survival. Untreated mice died of disseminated disease with a median survival of 26 days. Surgical resection alone conferred a small but significant survival advantage (median survival, 28 days, P = 0.03). Primary
CS-682 treatment at all doses also significantly prolonged survival compared with untreated animals (P < 0.05) and was more effective than surgery alone at doses of 50 and 60 mg/kg (median survival, 34 days, P = 0.045, and 38.5 days, P = 0.03, respectively). Maximal survival (median, 48 days, with 30% of animals surviving longer than 60 days) was achieved by adjuvant
CS-682 (50 mg/kg), given after surgical resection of the primary pancreatic
tumor (P = 0.004 compared with surgery alone). The results demonstrate that adjuvant
oral administration of
CS-682 for
pancreatic cancer is highly effective with acceptable toxicity, suggesting its potential for cure of this disease in appropriate combinations.