Platinum (Pt)(IV) complexes are thought to function as
prodrugs for anticancer Pt(II) drugs. We studied two pairs of Pt(II)/Pt(IV) complexes to explore whether there were differences in their cytotoxic activities, their abilities to cause acquired resistance and their gene expression profiles in the resistant lines. Microtiter methods were used to evaluate the antiproliferative activity of
cisplatin,
oxoplatin, [trans-d,l-(1,2-diaminocyclo-
hexane)]dichloroplatinum(II) [
DACH-Pt(II)] and cis,trans-[trans-d,l-(1,2-diaminocyclo-
hexane)]-dichlorodihydroxoplatinum(IV) [
DACH-Pt(IV)] in a panel of 14 human
cancer cell lines.
Cisplatin and
oxoplatin showed significant similar spectra of cytotoxicity, whereas
DACH-Pt(II) and
DACH-Pt(IV) did not.
DACH-Pt(IV) required more than 24 h to reach full potency, whereas the other three Pt complexes achieved maximal activity in less than 24 h. The SISO cervical cell line was made four- to six-fold resistant to the four Pt complexes by weekly exposure to the respective agent.
Glutathione (GSH) levels increased in all resistant lines except for the
DACH-Pt(IV) resistant line. The catalytic concentrations of various redox
enzymes (GSH
transferase, GSH
peroxidase, GSH
reductase,
catalase) were all unchanged in the resistant lines relative to the native line.
Multidrug resistance protein 2 expression was detected in the
cisplatin-resistant and
oxoplatin-resistant cell lines but not in the native line. The transcription of 29,000 genes in the SISO lines resistant to either
cisplatin or
oxoplatin was studied by
DNA-microarray methods and compared with the native line. Overall changes in gene transcription were very different between the
cisplatin-resistant and
oxoplatin-resistant cell lines. Thus, Pt(IV) complexes seem to have
biological actions that distinguish them from their Pt(II) counterparts, even when they show cross-resistance.