CARRIER-BOUND PLATINUM AND IRON COMPOUNDS WITH CARCINOSTATIC PROPERTIES

The treatment of malignancies with carcinostatic drugs per se or in co mbination with other modalities, proved its value over many decades of clinical administration. However, despite much progress in drug resea rch in recent years, complete cures by chemotherapy are still restrict ed to a small select number of cancers, whereas, in general, remission s remain incomplete or short lived, notably whenever metastatic lesion s have developed or resistance phenomena emerged. In an effort to incr ease the effectiveness of chemotherapy, several new alleys of developm ent are being pursued world-wide, and one of these, involving the bind ing of monomeric anticancer drug systems to water-soluble, biocompatib le and biodegradable polymeric carriers, is the subject of this paper. Previously developed polymer-bound cis-diaminedichloroplatinum(II) co mplexes are briefly discussed. The complex moiety is attached to the p olymeric carrier in these conjugates through metal chelation by polyme r-connected ethylene-diamine segments. Promising anti-neoplast ic acti vity is observed in tests against cultured HeLa carcinoma cells, with highest activity (IC50 15 mu g Pt/ml) shown by a polyarpartamide conju gate composing the platinum complex as a side group. Monoamine-coordin ated platinum(ll) complexes carrier-bound through primary amine termin als on short side chains are synthetically accessible by aqueous-phase platination of amine-functionalized carrier polymers. A representativ e conjugate of this class shows antiproliferative activity (against He La cells) well in the general activity range of the cis-diamineplatinu m-type polymers, suggesting that, in the polymer-attached state, plati num complex structures deviating from the familiar cis-diamineplatinum chelate pattern may well successfully compete with cisplatin-type dru g systems as cytotoxic agents. Organoiron compounds of the ferrocene t ype represent another drug system discussed in this paper. Ferrocene d erivatives have shown highly promising activity both in vitro and in v ivo, and carrier-binding of ferrocenes is seen as an efficacious means of increasing their therapeutic effectiveness. A series of water-solu ble ferrocene conjugates are presented in which 4-ferrocenylbutanoic a cid is reversibly polymer-bound by coupling with pendant amino groups. Activities against HeLa cells are in the same range as those of simil ar platinum conjugates. In view of low expected toxicities of the orga noiron polymers, as compared with the platinum compounds, this finding has significant implications for broad-based development of polymeric ferrocene conjugates. (C) 1998 John Wiley & Sons, Ltd.