A paradigm for the structure-pharmacological activity relationship of bifunctional
platinum antitumor drugs is that the trans isomer of antitumor
cisplatin (
transplatin) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit cytotoxicity in
tumor cells that is even better than that of the analogous cis isomers. We reported recently (Kasparkova, J., Marini, V., Najajreh, Y., Gibson, D., and Brabec, V. (2003) Biochemistry 42, 6321-6332) that the replacement of one ammine
ligand by the heterocyclic
ligand, such as
piperidine,
piperazine, or 4-picoline in the molecule of
transplatin resulted in a radical enhancement of its cytotoxicity. We examined
oligodeoxyribonucleotide duplexes bearing a site-specific cross-link of the
transplatin analogue containing the
piperidine ligand by biochemical methods. The results indicate that in contrast to
transplatin, trans-(PtCl2(NH3)(piperidine)) forms stable 1,3-intrastrand cross-links in double-helical
DNA that distort
DNA and are not readily removed from
DNA by nucleotide excision repair system. Hence, the intrastrand cross-links of trans-(PtCl2(NH3)(piperidine)) could persist for a sufficiently long time, potentiating its toxicity toward
tumor cells. trans-(PtCl2(NH3)(piperidine)) also forms in
DNA minor interstrand cross-links that are similar to those of
transplatin so that these adducts appear less likely candidates for genotoxic lesion responsible for antitumor effects of trans-(PtCl2(NH3)(piperidine)). Hence, the role of structurally unique intrastrand cross-links in the anti-
tumor effects of
transplatin analogues in which one ammine group is replaced by a heterocyclic
ligand may predominate.