Interaction of 11 cisplatin analogues with DNA: characteristic pattern of damage with monofunctional analogues

Abstract

In this paper the sequence specificity of DNA damage has been determined for 11 cisplatin analogues. A number of the analogues used in this study have been included in clinical trials. A Taq DNA polymerase linear amplification technique was utilised to ascertain the sequence selectivity of cisplatin analogues damage to DNA. The analogues differed in their ability to damage DNA with cisplatin being the most effective DNA damaging agent followed by (in decreasing order): tetraplatin (tetrachloro(1,2-diaminocyclohexane)platinum(IV) (RR isomer)), cis-dichlorobis(isopropylamine)platinum(II), dichloro(1,2-diaminocyclohexane)platinum(II) (SS isomer), dichloro(1,2-diaminocyclohexane)platinum(II) (RR isomer), cis-bis(cyclohexylamine)dichloroplatinum(II), carboplatin, cis-dichlorobis(isopentylamine)platinum(II), and CHIP ( cis-dichloro- trans-dihydroxybis(isopropylamine)platinum(IV)). However, the sequence specificity of these analogues was similar in position and relative intensity of damage. We also provide evidence that platinum(IV) complexes can damage DNA without being reduced to platinum(II). It was found that a 10-fold higher concentration of cisplatin was required to damage DNA in Tris–HCl compared to Hepes buffers. In this paper we have detected a characteristic pattern of damage with monofunctional analogues that could be used to determine the mode of binding of a cisplatin analogue with DNA. The monofunctional analogues tested were chloro(diethylenetriamine)platinum(II) and cis-diamminechloro(1-octylamine)platinum(II) as well as transplatin.