BACKGROUND: 5-Fluoro-2'-deoxyuridine (5-FdU), a drug against gastric cancer, was covalently linked via its nucleobase with the amino-bisphosphonate alendronate (Ale), resulting in a new antimetabolite-bisphosphonate conjugate (5-FdU-Ale), designed for bone-targeting. MATERIALS AND METHODS: The cytostatic effect of 5-FdU-Ale was evaluated in vitro compared to monomers and mixtures using CASY Technologies and the human gastric adenocarcinoma cell lines 23132/87 and MKN-45, in comparison to the intestinal CCL-241 and dermal fibroblast NHDF neonatal cell lines. RESULTS: The adenocarcinoma cell lines demonstrated a slightly higher sensitivity, with respect to the cell lines CCL-241 and NHDF, to incubation with 5-FdU-Ale. In comparison to 5-FdU, 5-FU and an equimolar mixture of Ale+5-FdU and Ale+5-FU, the cytostatic activity of the 5-FdU-Ale was markedly reduced. CONCLUSION: 5-FdU-Ale was only partially or not at all metabolized to a mixture of cytostatic metabolites in vitro. Therefore an in vivo evaluation of the conjugates is indicated.
BACKGROUND:5-Fluoro-2'-deoxyuridine (5-FdU), a drug against gastric cancer, was covalently linked via its nucleobase with the amino-bisphosphonatealendronate (Ale), resulting in a new antimetabolite-bisphosphonate conjugate (5-FdU-Ale), designed for bone-targeting. MATERIALS AND METHODS: The cytostatic effect of 5-FdU-Ale was evaluated in vitro compared to monomers and mixtures using CASY Technologies and the humangastric adenocarcinoma cell lines 23132/87 and MKN-45, in comparison to the intestinal CCL-241 and dermal fibroblast NHDF neonatal cell lines. RESULTS: The adenocarcinoma cell lines demonstrated a slightly higher sensitivity, with respect to the cell lines CCL-241 and NHDF, to incubation with 5-FdU-Ale. In comparison to 5-FdU, 5-FU and an equimolar mixture of Ale+5-FdU and Ale+5-FU, the cytostatic activity of the 5-FdU-Ale was markedly reduced. CONCLUSION:5-FdU-Ale was only partially or not at all metabolized to a mixture of cytostatic metabolites in vitro. Therefore an in vivo evaluation of the conjugates is indicated.
Authors: Sarah Schott; Sonia Vallet; Robert J Tower; Seema Noor; Sanjay Tiwari; Christian Schem; Christian Busch Journal: Invest New Drugs Date: 2015-05-20 Impact factor: 3.850