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The stability of DNA intrastrand cross-links of antitumor transplatin derivative containing non-bulky methylamine ligands

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Abstract

Oligonucleotides modified by clinically ineffective trans-diamminedichloridoplatinum(II) (transplatin) have been shown to be effective modulators of gene expression. This is so because in some nucleotide sequences the 1,3-GNG intrastrand adducts formed by transplatin in double-helical DNA readily rearrange into interstrand cross-links so that they can cross-link the oligonucleotides to their targets. On the other hand, in a number of other sequences these intrastrand adducts are relatively stable, which represents the major difficulty in the clinical use of the antisense transplatin-modified oligonucleotides. Therefore, we examined in this study, the stability of 1,3-GNG intrastrand adducts in double-helical DNA formed by a new antitumor derivative of transplatin, trans-[Pt(CH3NH2)2Cl2], in the sequence contexts in which transplatin formed relatively stable intrastrand cross-links which did not readily rearranged into interstrand cross-links. We have found that 1,3-GNG intrastrand adducts in double-helical DNA formed by trans-[Pt(CH3NH2)2Cl2] even in such sequences readily rearrange into interstrand cross-links. This work also suggests that an enhanced frequency of intrastrand cross-links yielded by trans-[Pt(CH3NH2)2Cl2] is a consequence of the fact that these DNA lesions considerably distort double-helical DNA in far more sequence contexts than parent transplatin. Our results suggest that trans-[Pt(CH3NH2)2Cl2]-modified oligonucleotides represent promising candidates for new agents in antisense or antigene approach.

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Abbreviations

ATP:

Adenosine triphosphate

Bp:

Base pair

CL:

Cross-link

DEPC:

Diethyl pyrocarbonate

DMS:

Dimethyl sulfate

FAAS:

Flameless atomic absorption spectroscopy

HPLC:

High-performance liquid chromatography

PAA:

Polyacrylamide

Transplatin:

trans-Diamminedichloridoplatinum(II)

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Acknowledgments

This research was supported by the Czech Science Foundation (Grants 13-08273S) and the Ministry of Education of the CR (Grant LH14317). Research of M. F. was also supported by the student project of the Palacky University in Olomouc (Grant IGAPrF 2014 029). The authors acknowledge that their participation in the EU COST Action CM1105 enabled them to exchange regularly the most recent ideas in the field of metallodrugs with several European colleagues. The authors also thank to Prof. Dan Gibson for a kind gift of trans-[Pt(CH3NH2)2Cl2].

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Authors and Affiliations

  1. Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, 77146, Olomouc, Czech Republic

    Michaela Frybortova & Viktor Brabec

  2. Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 61265, Brno, Czech Republic

    Michaela Frybortova, Olga Novakova & Viktor Brabec

Authors
  1. Michaela Frybortova
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  2. Olga Novakova
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  3. Viktor Brabec
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Correspondence to Viktor Brabec.

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Frybortova, M., Novakova, O. & Brabec, V. The stability of DNA intrastrand cross-links of antitumor transplatin derivative containing non-bulky methylamine ligands. J Biol Inorg Chem 19, 1203–1208 (2014). https://doi.org/10.1007/s00775-014-1176-8

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  • DOI: https://doi.org/10.1007/s00775-014-1176-8

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