Anticancer cisplatin interaction with phospholipid bilayers. A solid-state NMR study.

Cisplatin – a widely used anticancer drug. Cisplatin (cis-dichlorodiammine platinum (II), cis-DDP) is among the most widely used and broadly active cytostatic anticancer drugs. Platinum-based chemotherapy is curative for the majority of patients with adva nced testis cancer, which had no cure prior to the introduction of cisplatin chemotherapy. However, many patients become refractory to cisplatin chemotherapy, as they acquire resistance to cisplatin. The cisplatin drug enters cells/crosses the cellular m embrane (phospholipid membrane) by passive diffusion and protein mediated uptake and travels in the cytosol on the route to its anti-tumor target, the DNA. In the search for molecular mechanisms that can explain the development of cellular cisplatin resi stance and unwanted side-effects research-focus on phospholipid mechanisms now appear promising. The method best suited for clarifying molecular interaction in phospholipid membranes is solid-state NMR. Experimental protocol for the initial experiments of i) cis-DDP, ii) trans-DDP, iii) trans–[PTCl2{(E)-HN=C(OMe}2] (trans-EE) interaction study with phospholipid bilayers by solid-state NMR will focus on phospholipid headgroup specificity as well as the importance of phospholipid acyl chain unsaturation pat tern. This will be supported by our laboratory’s experience on drug interaction studies with phospholipid bilayers. In order to more precisely determine the orientation and position of i) cis-DDP, ii) trans-DDP, iii) trans–[PTCl2{(E)-HN=C(OMe}2] (trans- EE) when bound to the bilayer.. This will be achieved with the spin ½ and experimentally favorable 15N and 13C isotopes. For example, cisplatin enriched with 15N in one of its two nitrogen atoms and embedded in a phospholipid bilayer enriched with 13C in specific atomic positions will be subjected to solid state NMR recoupling experiments and experiments on oriented samples to achieve molecular structure of the phospholipid/cisplatin complex.