SYNTHESIS AND CYTOTOXIC ACTIVITY OF DEXTRAN-IMMOBILIZING PLATINUM(II)COMPLEX THROUGH CHELATE-TYPE COORDINATION BOND

trans-l-1,2-diamine)platinum(II):Dach-Pt(chlorato) is a platinum compl ex which is expected to exhibit higher antitumor activity than cisplat in and which shows no cross-resistance with cisplatin. However, its st rong side-effects and low water solubility have been noted. We have re ported that polymer/antitumor drug conjugates show reduced side-effect s and high antitumor activity. In order to provide a macromolecular pr odrug of Dach-Pt having reduced side-effects and high water solubility , we synthesized dextran derivatives containing dicarboxylic acid grou ps to immobilize Dach-Pt via a chelate-type co ordination bo nd, dicar boxymethyl-dextran(DCM-Dex)/Dach-Pt conjugate. We investigated the rel ease behavior of the platinum complex from the carrier polymer and the cytotoxic activity of the conjugate against p388D(1) lymphocytic leuk emia cells in vitro compared with the carboxymethyl-dextran (CM-Dex)/D ach-Pt conjugate. The DCM-Dex/Dach-Pt conjugate showed almost the same level of cytotoxic activity as free Dach-Pt(chlorato) or Dach-Pt(malo nato). Although the cytotoxic activity of free Dach-Pt(chlorato) was d ecreased by incubation in a medium with serum, the DCM-dextran/Dach-Pt conjugate kept its higher level of cytotoxic activity after incubatio n in a medium with serum. These results suggested that the stability o f the Dach-Pt moiety in the medium was increased and cytotoxic activit y of Dach-Pt was not decreased by fixation to dextran through a chelat e-type coordination bond.