TAILIEUCHUNG - Báo cáo khoa học: Recognition of DNA modified by trans-[PtCl2NH3(4hydroxymethylpyridine)] by tumor suppressor protein p53 and character of DNA adducts of this cytotoxic complex

trans-[PtCl2NH3(4-Hydroxymethylpyridine)] (trans-PtHMP) is an analogue of clinically ineffective transplatin, which is cytotoxic in the human leuke-mia cancer cell line. As DNA is a major pharmacological target of anti-tumor platinum compounds, modifications of DNA by trans-PtHMP and recognition of these modifications by active tumor suppressor protein p53 were studied in cell-free media using the methods of molecular biology and biophysics. | ềFEBS Journal Recognition of DNA modified by trans- PtCl2NH3 4-hydroxymethylpyridine by tumor suppressor protein p53 and character of DNA adducts of this cytotoxic complex Kristyna Stehlíková1 Jana Kasparkova1 Olga Novakova1 Alberto Martinez2 Virtudes Moreno2 and Viktor Brabec1 1 Institute of Biophysics Academy of Sciences of the Czech Republic Brno Czech Republic 2 Departament de Quimica Inorganica Universitat de Barcelona Barcelona Spain Keywords antitumor conformation DNA p53 platinum drug Correspondence V. Brabec Institute of Biophysics Academy of Sciences of the Czech Republic Kralovopolska 135 CZ-61265 Brno Czech Republic Fax 420 541240499 Tel 420 541517148 E-mail brabec@ URL http labs BNAIAD The authors wish it to be known that in their opinion the first three authors should be regarded as joint first authors. Received 12 August 2005 revised 2 November 2005 accepted 14 November 2005 doi irans- PtCl2NH3 4-Hydroxymethylpyridine irans-PtHMP is an analogue of clinically ineffective transplatin which is cytotoxic in the human leukemia cancer cell line. As DNA is a major pharmacological target of antitumor platinum compounds modifications of DNA by irans-PtHMP and recognition of these modifications by active tumor suppressor protein p53 were studied in cell-free media using the methods of molecular biology and biophysics. Our results demonstrate that the replacement of the NH3 group in transplatin by the 4-hydroxymethylpyridine ligand affects the character of DNA adducts of parent transplatin. The binding of irans-PtHMP is slower although equally sequence-specific. This platinum complex also forms on double-stranded DNA stable intrastrand and interstrand crosslinks which distort DNA conformation in a unique way. The most pronounced conformational alterations are associated with a local DNA unwinding which was considerably higher than those produced by other bifunctional platinum compounds. DNA adducts of .

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