The toxicity of the new derivative of
transplatin, namely trans-[PtCl2(DEA)(NH3)] (DEA =
diethylamine), in which only one NH3 group was replaced by a small, non-bulky DEA
ligand, in the
cisplatin sensitive and resistant tumor cell lines was examined. The results indicate that this very small modification of the
transplatin molecule results in a considerable enhancement of toxicity in the
cancer cells. Thus, this finding is consistent with the thesis that the trans geometry in Pt(II)-dichlorido compounds can also be effectively activated by the replacement of only one NH3
ligand in
transplatin by the non-bulky
ligand, such as the short aliphatic
amine, (C2H5)2NH. We also demonstrate that trans-[PtCl2(DEA)(NH3)], in contrast to
transplatin, can be grouped with the coordination compounds exhibiting antitumor activity and capable of inducing lysis in lysogenic bacteria. Thus, these results afford, for the first time, experimental support for the view that
DNA is the potential cellular target also for antitumor derivatives of
transplatin.
DNA binding mode of trans-[PtCl2(DEA)(NH3)] in cell-free media was examined as well. The results show that the small aliphatic DEA
ligand has significant consequences for the
DNA conformational changes. Unlike 'classical'
transplatin, modification of
DNA with trans-[PtCl2(DEA)(NH3)] leads to mainly bifunctional cross-links. The extent and destabilization of the double-helical structure of
DNA by this new trans-
platinum complex are similar to those induced by
cisplatin. As a consequence the lesions effectively inhibit transcription of template
DNA similarly to the lesions of
cisplatin, but markedly more than the lesions of
transplatin. The stronger inhibition of
DNA transcription by the adducts of trans-[PtCl2(DEA)(NH3)] in comparison with the adducts of
transplatin adds a new dimension to the impact of the activated trans geometry in
platinum compounds on biological processes, possibly including
DNA transcription.