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J. Biol. Chem., Vol. 278, Issue 48, 47516-47525, November 28, 2003

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Activation of Trans Geometry in Bifunctional Mononuclear Platinum Complexes by a Piperidine Ligand

MECHANISTIC STUDIES ON ANTITUMOR ACTION^*

Jana Kasparkova¶, Olga Novakova, Victoria Marini, Yousef Najajreh||**, Dan Gibson||**, Jose-Manuel Perez, and Viktor Brabec

From the Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic, ^||Department of Medicinal Chemistry and Natural Products, School of Pharmacy and the ^**David R. Bloom Center for Pharmacy, The Hebrew University of Jerusalem, Jerusalem 91120, Israel, and Departamento de Quimica Inorganica, Facultad de Ciencias, Universidad Autonoma de Madrid, 28049 Madrid, Spain

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.

Received for publication, May 6, 2003 , and in revised form, September 3, 2003.

^* This work was supported by Grant Agency of the Czech Republic Grant 305/02/1552A, Grant Agency of the Academy of Sciences of the Czech Republic Grant B5004301, and the Wellcome Trust (to J. K. and V. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains four additional figures.

International Scholar of Howard Hughes Medical Institute.

^¶ To whom correspondence should be addressed. Tel.: 420-541517174; Fax: 420-541240499; E-mail: jana{at}ibp.cz.

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