Accumulation of novel transplatinum complexes in cisplatin and oxaliplatin resistant cell lines overcomes resistance

4109 We previously identified nine novel groups of platinum compounds based on distinctive activity profiles in the NCI 60 cell line panel (using Clustered Image Maps, the COMPARE algorithm, and other numerical methods) with characteristic chemical structures. A group of transplatin analogs of the general structure trans-[PtX2(L)(L’)] where X = Cl or OAc, L = NH3, L’= a planar, nitrogen-containing heterocycle or L = L ’ = a planar, nitrogen-containing heterocycle were further characterized. Compared to the trans-[PtCl2(L)(L’)] compounds, the trans-[PtOAc2(L)(L’)] analogs are more stable and water-soluble. When the transplanar platinum compounds were incubated with fresh plasma and subjected to ultrafiltration, 39 to 63% of the trans-[PtOAc2(L)(L’)] compounds could be recovered in the ultrafiltrate compared to only 1.8 to 4.1% of the trans-[PtCl2(L)(L’)] compounds. In addition to having a cytotoxicity profile distinct from that of cisplatin, carboplatin and oxaliplatin, all members of this class of compounds retained activity against cisplatin and oxaliplatin-resistant cell lines. A possible explanation for this persistent activity was obtained in studies examining the accumulation of platinum in the drug resistant cells lines. Platinum analogs (33 μM) were incubated for 2 h with the parental (KB) and cisplatin (KBCP20) and oxaliplatin (KBOXO80) resistant cell lines. Intracellular platinum was measured by atomic absorption spectroscopy after extraction. Compared to cisplatin and oxaliplatin whose accumulation in the drug resistant cell lines was 4.8 to 21% of that in parental KB cells (Table), the accumulation of four trans-[PtOAc2(L)(L’)] compounds was 83 to 166%. Thus these trans-[PtX2(L)(L’)] compounds have an activity profile distinct from platinum compounds currently in use, and retain activity in oxaliplatin- and cisplatin-resistant cells lines at least in part by retaining the ability to accumulate in the resistant cells at levels comparable to those in drug sensitive parental cells. 1IC50 of resistant cell line divided by IC50 of parental KB cells 2Percent of parental KB cell accumulation