1998 Volume 46 Issue 9 Pages 1480-1483
In a previous work we synthesized a class of new antineoplastic drugs by coupling a cisplatin derivative to a triphenylethylene moiety similar 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, we studied, using differential scanning calorimetry, the effects of these compounds on the phase transition 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 change on the thermogram of DSPC. Contrarily, the drugs bearing two or three hydroxy groups were less toxic, but induced important modifications of the thermogram.We suggest that the drugs with no hydroxy group enter the membrane, with the triphenylethylene moiety localized deep within the hydrophobic core of the bilayer and do not affect the cooperativity region (C2-C8). In contrast, drugs which bear hydroxy grops on the triphenylethylene rings system perturb the phospholipid molecular arrangement; this may be due either to the additional steric hindrance of te hydroxy functions in the core of the bilayer, or to their hydrophilic effect on the polar head of the lipid.In vitro, the cytotoxic effect of these drugs seems not to be related to their affinity for the estrogen receptor. We suggest that the addition of a triphenylethylene moiety to the platinum(II) complexes increases the hydrophobicity, and consequently the resulting drugs become more permeable to the membrane, particularly the non-hydroxylated triphenylethylene derivatives.
