Cisplatin, cis-[PtCl2(NH3)2], is commonly utilized in various
combination chemotherapy protocols for the treatment of both ovarian and
breast cancer while the corresponding trans isomer is therapeutically inactive. This work describes efforts to elucidate the cellular mechanism of action of a novel trans-
platinum compound,
trans-(dichloroamminethiazole)platinum(II) (ATZ), which demonstrates antiproliferative and cytotoxic effects against both MCF-7 human breast and A2780 human ovarian
carcinoma cells in culture. A2780 cells were approximately twofold more sensitive to ATZ than MCF-7 cells in both cell growth and clonogenic survival assays.
Dye exclusion studies revealed a 50-70% loss in cell viability within the first 12 h of
drug treatment in both cell lines. This initial wave of cell death was succeeded by a prolonged interval of growth arrest during which a small fraction of apoptotic cells was detected. Binding of ATZ to
DNA, as estimated by atomic absorption spectroscopy, was similar for the two cell lines and was almost completely reversed 24 h after
drug removal. ATZ also induced
DNA strand breakage as well as
DNA-
protein crosslinking during the initial 12 h period when the bulk of cell death was evident. However, neither the extent of
DNA strand breakage nor that of
DNA protein crosslinking was sufficient to explain the different
drug sensitivity in the two cell lines. At 24 and 48 h after exposure of MCF-7 cells to high concentrations of ATZ, the formation of
DNA-topoisomerase I complexes is detected, coincident with a high degree of apoptosis. These studies suggest that ATZ has the capacity to interfere with
topoisomerase I in the
tumor cell, a function not evident in
cis-platinum-based drugs.