DIFFERENTIAL CYTOTOXICITY OF METAL CHELATING-AGENTS IN CISPLATIN SENSITIVE AND RESISTANT HUMAN OVARIAN-CANCER CELLS

The efficacy of cisplatin use in the treatment of certain human tumors is reduced because of acquired cellular resistance to cisplatin. Cellular resistance to cisplatin is related to the content of cellular metallothionein. Synthetic metal chelating agents might influence cisplatin resistance through compromising the structure of MT by the competition for metal ions by (a) the chelating agents, (b) MT, and/or (c) cisplatin. This in vitro investigation was undertaken to study the differential cytotoxicity of certain synthetic metal chelating agents in human ovarian cancer cell lines that were sensitive and resistant to cisplatin. Standard cytotoxicity assays were conducted using the neutral red procedure. The cisplatin sensitive cell line showed resistance to ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), and nitrilotriacetic acid (NTA) in an order which closely resembled the order of the metal formation constants of the three chelates. The cisplatin resistant cell line showed resistance to DTPA, EDTA, and NTA in an order that followed their metal formation constants. N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) exhibited the same cytotoxicity for both the cisplatin sensitive and resistant cells. Since chelating agents might play a role in the cellular resistance to cisplatin, these results provide important baseline cytotoxicity data and show that, in general, cytotoxic resistance to the chelating agents used followed a pattern similar to cellular cisplatin resistance.