Synthesis and cytotoxic activity of dextran carrying cis-dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II) complex

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Abstract
Cis-Dichloro(cyclohexane-trans-l-1,2-diamine)platinum(II) (Dach-Pt(chlorato)), is a platinum complex which is expected to exhibit higher antitumor activity than, and show no cross resistance with, cisplatin. However, its strong side-effects and low water-solubility have also been cited. We report that polymer/ antitumor drug conjugates shows reduced side-effects and high antitumor activity. In order to provide a macromolecular prodrug of Dach-Pt having reduced side-effects and high water-solubility, we synthesized polymer conjugates of Dach-Pt and dextran derivatives having carboxylic acid groups, oxidized-dextran (OX-Dex)/Dach-Pt conjugate, and carboxymethyl-dextran(CM-Dex)/Dach-Pt conjugate. The cytotoxic activities of the conjugates were investigated against p388D1 lymphocytic leukemia cells in vitro. The OX-Dex/Dach-Pt conjugate showed almost the same level of cytotoxic activity as free Dach-Pt(chlorato). Although the cytotoxic activity of free Dach-Pt(chlorato) was decreased by incubation in medium with serum, the OX-Dex/Dach-Pt conjugate kept its cytotoxic activity in higher level after 24 h incubation in medium with serum. These results suggested that the stability of Dach-Pt molecule in the medium was increased and cytotoxic activity of Dach-Pt was not decreased by fixing to OX-Dex.