EFFECTS OF NEW TRIPHENYLETHYLENE PLATINUM(II) COMPLEXES ON THE INTERACTION WITH PHOSPHATIDYLCHOLINE LIPOSOMES

In a previous work we synthesized a class of new antineoplastic drugs by coupling a cisplatin derivative to a triphenylethylene moiety simil ar to the antiestrogen, tamoxifen. These drugs differ in the number of hydroxy functions on the triphenylethylene rings and in the length of the linking arm. To gain more insight into the cellular mechanism by which these new drugs act on cells, ne studied, using differential sca nning calorimetry, the effects of these compounds on the phase transit ion of membrane phospholipid (distearoyl phosphatidyl choline (DSPC)), and correlated these effects to drug cytotoxicity. The drugs without hydroxy function showed the highest cytotoxicity and induced little ch ange on the thermogram of DSPC, Contrarily; the drugs bearing two or t hree hydroxy groups were less toxic, but induced important modificatio ns of the thermogram. We suggest that the drugs with no hydroxy group enter the membrane, with the triphenylethylene moiety localized deep w ithin the hydrophobic core of the bilayer and do not affect the cooper ativity region (C2-C8), In contrast, drugs which bear hydroxy groups o n the triphenylethylene rings system perturb the phospholipid molecula r arrangement; this may be due either to the additional steric hindran ce of the hydroxy functions in the core of the bilayer, or to their hy drophilic effect on the polar head of the lipid. In vitro, the cytotox ic effect of these drugs seems not to be related to their affinity for the estrogen receptor. We suggest that the addition of a triphenyleth ylene moiety to the platinum(II) complexes increases the hydrophobicit y, and consequently the resulting drugs become more permeable to the m embrane, particularly the non-hydroxylated triphenylethylene derivativ es.