ABSTRACT
The aim of this study was to determine the antimetastatic efficacy of the combination of 5-fluorouracil (5-FU), leucovorin (LV), and irinotecan (CPT-11) (FOLFIRI) in an orthotopic nude mouse model of GFP-HCT-116 human colon cancer-expressing green fluorescent protein (GFP). The mice were randomly divided into four groups: Group 1: saline control; Group 2: 30 mg/kg 5-FU + 90 mg/kg LV; Group 3: 5-FU + LV + 16 mg/kg CPT-11 (FOLFIRI); and Group 4: 5-FU + LV + 24 mg/kg CPT-11. 5-FU and LV were administered on days 11, 16 and 21, and CPT-11 on days 12, 18 and 22. Survival in Groups 3 and 4 was significantly longer than that in Groups 1 and 2, although no dose-dependency on CPT-11 was observed. Analysis of the primary and metastatic tumors by GFP imaging, as well as that of oncogene expression in mesentery lymph nodes, demonstrated that tumor growth and metastasis were significantly inhibited or even prevented by FOLFIRI. Pathological evaluation also demonstrated that metastasis was also inhibited by FOLFIRI. The results of the present study suggest FOLFIRI prolongs survival by inhibiting metastasis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Colonic Neoplasms/mortality , Disease Models, Animal , Animals , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Cell Line, Tumor , Colonic Neoplasms/secondary , Disease Progression , Fluorouracil/therapeutic use , Green Fluorescent Proteins/metabolism , Humans , Leucovorin/therapeutic use , Lymphatic Metastasis , Mice , Mice, Nude , Survival Rate , Treatment Outcome , Whole Body Imaging , Xenograft Model Antitumor AssaysABSTRACT
High-resolution magnetic resonance (MR) imaging techniques in a liver metastatic mouse model were used to assess CS-682, a novel 2'-deoxycytidine analogue of 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine. The efficacy of CS-682 was visualized in real time by MR imaging of initial seeding and subsequent growth of liver metastases. The relative therapeutic efficacies of CS-682 and two agents used clinically, gemcitabine [2'-deoxy-2',2'-difluorocytidine monohydrochloride (DFDC)] and 5-fluorouracil (5-FU), were compared in this model. CS-682 was found to exhibit superior efficacy by delaying the onset and inhibiting the growth of liver metastasis compared with gemcitabine, 5-FU, and control. The overall occurrence of metastases was decreased 62% by CS-682, 18% by DFDC, and 35% by 5-FU. CS-682 increased the life span of the treated animals significantly, by 28 days above the 29-day median survival without treatment, compared with 11 days by DFDC and 14 days by 5-FU. The increased survival in CS-682-treated animals correlated with the antimetastatic activity of this compound. These preclinical findings support the potential clinical utility of CS-682 in the treatment of liver metastasis.
