High-resolution magnetic resonance imaging of the efficacy of the cytosine analogue 1-[2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl]-N(4)-palmitoyl cytosine (CS-682) in a liver-metastasis athymic nude mouse model.
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.
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Ming
M
Wu
Richard
R
Mazurchuk
Neeta D
ND
Chaudhary
Joseph
J
Spernyak
Jean
J
Veith
Paula
P
Pera
William
W
Greco
Robert M
RM
Hoffman
Tomowo
T
Kobayashi
Ralph J
RJ
Bernacki
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001087:Arabinonucleosides / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D003841:Deoxycytidine; D003596:Cytosine; D005472:Fluorouracil; C117959:sapacitabine; D000093542:Gemcitabine