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High-Resolution Magnetic Resonance Imaging of the Efficacy of the Cytosine Analogue 1-[2-C-Cyano-2-deoxy-ß-D-arabino-pentofuranosyl]-N⁴-palmitoyl Cytosine (CS-682) in a Liver-Metastasis Athymic Nude Mouse Model¹

Departments of Pharmacology and Therapeutics [M. W., N. D. C., J. V., P. D., W. G., R. J. B] and Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Buffalo, New York 14263 [R. M., J. S.]; AntiCancer, Incorporated, San Diego, California 92111 [R. M. H.]; and Sankyo Co., Ltd., Tokyo 140-8710, Japan [T. K.]

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-ß-D-arabino-pentofuranosyl]-N⁴-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.

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