DNA Interactions of Antitumor Cisplatin Analogs Containing Enantiomeric Amine Ligands

Malina, Jaroslav; Hofr, Ctirad; Maresca, Luciana; Natile, Giovanni; Brabec, Viktor

doi:10.1016/s0006-3495(00)76748-8

Cited by 59 publications

(71 citation statements)

References 69 publications

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“…They react preferentially with single-stranded DNA and distorted double-stranded DNA (34,35). We used for this analysis exactly the same methodology described in detail in our recent papers dealing with DNA adducts of various antitumor platinum drugs (21,31,34,36,37). Therefore, these experiments are only described in more detail in the Supporting material (see "Chemical Probes" and Fig.…”

Section: Cellular Platinummentioning

confidence: 99%

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

Kašpárková

Nováková

Marini

et al. 2003

Journal of Biological Chemistry

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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-(PtCl 2 (NH 3 )(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-(PtCl 2 (NH 3 )(piperidine)) could persist for a sufficiently long time, potentiating its toxicity toward tumor cells. trans-(PtCl 2 (NH 3 )(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-(PtCl 2 (NH 3 )(piperidine)). Hence, the role of structurally unique intrastrand cross-links in the antitumor effects of transplatin analogues in which one ammine group is replaced by a heterocyclic ligand may predominate.The more widespread clinical applicability of cis-diamminedichloroplatinum(II) (cisplatin) 1 (Fig. 1A) and its analogue cis-diamminecyclobutanedicarboxylatoplatinum(II) is limited to a relatively narrow range of tumors (1-3); some tumors have natural resistance to these platinum drugs, whereas others develop resistance after the initial treatment.Cisplatin also has limited solubility in aqueous solution and is administered intravenously. There are also significant problems in terms of inducing severe side effects (especially kidney damage and vomiting/nausea). The drawbacks coupled with cisplatin and cis-diamminecyclobutanedicarboxylatoplatinum(II) toxicity have been the impetus for the development of improved platinum drugs. The paradigm for structure-pharmacological activity relationship of platinum complexes is that the trans isomer of cisplatin (transplatin) (Fig. 1A) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit an enhanced cytotoxicity in tumor cell lines, such that cytotoxicity is equivalent or even better than that of the analogous cis isomers and, indeed, cisplatin itself (for reviews, see Refs. 4 -6). Examples of such new antitumor transplatinum compounds are (i) analogues containing planar amine ligand of ...

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Section: Cellular Platinummentioning

confidence: 99%

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

Kašpárková

Nováková

Marini

et al. 2003

Journal of Biological Chemistry

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“…Hence, studies have mainly focused on DNA modifications and biological properties of enantiomeric DACH and closely related DAB complexes (43)(44)(45)(46)(47).…”

Section: Chiral Discrimination In Platinum Anticancer Drugsmentioning

confidence: 99%

Chiral discrimination in platinum anticancer drugs.

Benedetti

Malina

Kašpárková

et al. 2002

Environ Health Perspect

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In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

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“…Whereas the thermal and thermodynamic properties of DNA duplexes containing intrastrand cross-link of cisplatin or its analogues have already been studied in detail (15,21,22), no attention has been paid to thermal stability and energetics of DNA interstrand cross-links of platinum drugs. It is so despite the fact that DNA interstrand cross-links of platinum complexes could play a very significant role in the biological activity of these compounds because these covalent cross-links preventing separation of the two strands of DNA could block DNA replication markedly more efficiently than intrastrand adducts (23).…”

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Thermal and Thermodynamic Properties of Duplex DNA Containing Site-specific Interstrand Cross-link of Antitumor Cisplatin or Its Clinically Ineffective Trans Isomer

Hofr¹,

Brabec

2001

Journal of Biological Chemistry

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The effect of the single, site-specific interstrand crosslink formed by cisplatin or transplatin on the thermal stability and energetics of a 20-base pair DNA duplex is reported. The cross-linked or unplatinated 20-base pair duplexes were investigated with the aid of differential scanning calorimetry, temperature-dependent UV absorption, and circular dichroism. The cross-link of both platinum isomers increases the thermal stability of the modified duplexes by changing the molecularity of denaturation. The structural perturbation resulting from the interstrand cross-link of cisplatin increases entropy of the duplex and in this way entropically stabilizes the duplex. This entropic cross-link-induced stabilization of the duplex is partially but not completely compensated by the enthalpic destabilization of the duplex. The net result of these enthalpic and entropic effects is that the structural perturbation resulting from the formation of the interstrand cross-link by cisplatin induces a decrease in duplex thermodynamic stability, with this destabilization being enthalpic in origin. By contrast, the interstrand cross-link of transplatin is enthalpically almost neutral with the cross-link-induced destabilization entirely entropic in origin. These differences are consistent with distinct conformational distortions induced by the interstrand cross-links of the two isomers. Importantly, for the duplex cross-linked by cisplatin relative to that cross-linked by transplatin, the compensating enthalpic and entropic effects almost completely offset the difference in cross-link-induced energetic destabilization. It has been proposed that the results of the present work further support the view that the impact of the interstrand cross-links of cisplatin and transplatin on DNA is different for each and might also be associated with the distinctly different antitumor effects of these platinum compounds.The thermal and thermodynamic stability of DNA play an important role in many biological processes. In addition, agents of biological significance that modify DNA may also affect its thermal and thermodynamic stability, which may be associated with the mechanism underlying biological activity of such agents. Thus, the studies of thermal and thermodynamic stability of DNA modified by various agents are of great interest.It is well established that platinum coordination complexes exhibit antitumor effects (1-4). The success of platinum complexes in killing tumor cells results from their ability to form on DNA various types of covalent adducts that are capable of terminating DNA synthesis (5, 6) and the cellular processes triggered by the presence of those adducts on DNA (7). The first platinum complex introduced in the clinic is cis-diamminedichloroplatinum(II) (cisplatin) 1 (1). Although the antitumor effects of cisplatin were discovered more than 30 years ago, the mechanism of its antitumor activity has not yet been fully understood. It has been shown (8, 9) that this bifunctional platinum complex mainly forms intrastrand cross-l...

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DNA Interactions of Antitumor Cisplatin Analogs Containing Enantiomeric Amine Ligands

Cited by 59 publications

References 69 publications

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

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

Chiral discrimination in platinum anticancer drugs.

Thermal and Thermodynamic Properties of Duplex DNA Containing Site-specific Interstrand Cross-link of Antitumor Cisplatin or Its Clinically Ineffective Trans Isomer

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