TRANSPORT OF N7-PLATINATED PURINES ACROSS HELA CELLS PLASMA MEMBRANE

Cisplatin, cis-diamminedichloroplatinum(II), is an effective antitumor drug known to exert its action by binding to the N7 of purine bases in nuclear DNA, consequently impairing replication, transcription and repair processes. Recently we have demonstrated, by the model complex [Pt(dien)(N7-5'-dGTP)] (dien = diethylenetriamine) the possible existence of an alternative mechanism for cisplatin antitumor activity, in which the metal is bonded to free purine bases, before incorporation in the newly synthesized DNA. This evidence suggests a new possible approach for the development of N7-platinated purines, as new antitumor drugs, for the treatment of cancer diseases. However, it is known that the efficacy of a new drug it is strictly related upon the transport across the cells plasma membrane barrier which strongly condition the drug pharmacokinetic and the targeted cells bioavailability. In particular in this study, we tested the possibility that N7-platinated purines could be transported into cells. At this scope we synthesized model Pt(II) coordination compounds, of the type [Pt(dien)(N7-G)] (G = Guanine derivative) and analysed the uptake of each single platinated nucleoside/nucleotide into Hela cells, by measuring Pt accumulation, by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). The quantitative analysis of Pt has provided a strong evidence for transport of the N7 platinated nucleoside [Pt(dien)(N7-dGuo)] into Hela cells (see figure). Moreover, the observed intracellular Pt accumulation was strictly sodiumdependent suggesting a carrier-mediated uptake for the [Pt(dien)(N7-dGuo)]. Overall, these results suggest that N7-platination does not compromise cellular uptake of nucleosides and may have important implications in the development of new potential nucleoside analogues in cancer treatment.