INTERACTION OF 11 CISPLATIN ANALOGS WITH DNA - CHARACTERISTIC PATTERNOF DAMAGE WITH MONOFUNCTIONAL ANALOGS

In this paper the sequence specificity of DNA damage has been determin ed for 11 cisplatin analogues. A number of the analogues used in this study have been included in clinical trials. A Taq DNA polymerase line ar amplification technique was utilised to ascertain the sequence sele ctivity of cisplatin analogues damage to DNA. The analogues differed i n their ability to damage DNA with cisplatin being the most effective DNA damaging agent followed by (in decreasing order): tetraplatin (tet rachloro(1,2-diaminocyclohexane)platinum(IV) (RR isomer)), cis-dichlor obis(isopropylamine)platinum(II), dichloro(1,2-diaminocyclohexane)plat inum(II) (SS isomer), dichloro(1,2-diaminocyclohexane)platinum(II) (RR isomer), cis-bis(cyclohexylamine)dichloroplatinum(II), carboplatin, c is-dichlorobis(isopentylamine)platinum(II), and CHIP o-trans-dihydroxy bis(isopropylamine)platinum(IV)). However, the sequence specificity of these analogues was similar in position and relative intensity of dam age. We also provide evidence that platinum(IV) complexes can damage D NA without being reduced to platinum(II). It was found that a 10-fold higher concentration of cisplatin was required to damage DNA in Tris-H Cl compared to Hepes buffers. In this paper we have detected a charact eristic 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)p latinum(II) and cis-diamminechloro(1-octylamine)platinum(II) as well a s transplatin. (C) 1997 Elsevier Science B.V.