Chemistry Reference
In-Depth Information
assay using mammalian or rodent cell-free extracts.
117
Consistent with the different
affi nity of the intrastrand crosslinks of both enantiomers to HMG-domain proteins,
addition of HMG-domain protein only blocked NER of the crosslinks of [Pt(
R,R
-
DAB)]
2+
, whereas NER of the crosslinks formed by [Pt(
S,S
- DAB)]
2+
in the TGGT
sequence remained unaffected.
Thus, these results suggest that very fi ne structural modifi cations, such as those
promoted by enantiomeric ligands in bifunctional platinum(II) compounds, can
modulate the 'downstream effects', such as specifi c protein recognition by DNA
processing enzymes and other cellular components. More specifi cally, as a conse-
quence of enantiomorphism of carrier amine ligands of cisplatin analogues, their
major DNA crosslinks not only exhibit different conformational features, but are
also processed differently by cellular components, including NER. It may be also
suggested that these differences are associated with different antitumour and other
biological activities of the two enantiomers.
The original empirical structure-activity relationships considered the
trans
isomer of cisplatin and other transplatin analogues to be inactive.
119
However,
several new analogues of transplatin, which exhibit a different spectrum of cytostatic
activity including activity in tumour cells resistant to cisplatin have been identifi ed.
Examples are analogues containing heterocyclic amine ligands, aliphatic ligands or
iminoether groups.
3,120,121
The molecular mechanism of antitumour activity of trans-
platinum compounds has been extensively investigated. Unlike cisplatin or transpla-
tin, modifi cation of DNA by antitumour
trans
compounds leads to monofunctional
and bifunctional intra- and interstrand crosslinks in different proportions. In addi-
tion, structure of intrastrand and interstrand crosslinks of antitumour
trans
com-
plexes and conformational distortions induced by these adducts in DNA are mostly
fundamentally different from that of the crosslinks of cisplatin and parent transpla-
tin. Thus, it is not surprising that cellular processing of DNA adducts of antitumour
transplatin analogues, including NER, is also different. The interstrand crosslinks of
these
trans
-platinum compounds are not removed from DNA in the same way as
the corresponding adducts of cisplatin. In contrast to cisplatin, intrastrand crosslinks
of antitumour
trans
-platinum analogues are removed from DNA by NER with
markedly lower effi ciency than the major adducts of cisplatin.
122,123
Hence, a general
property of DNA adducts of these new antitumour
trans
- platinum compounds is
that they can persist for a considerably long time in cells, which is a prerequisite for
the toxicity of these lesions in tumors sensitive to these transplatin analogs, without
being protected from the recognition and attack of the NER components.
An intriguing example of how NER modulates the antitumour effects of
trans
-
platinum compounds is the case of
trans
- [PtCl
2
(
E
- iminoether)
2
]. The replacement
of both NH
3
groups in transplatin by an iminoether ligand results in a marked
enhancement of its cytotoxicity. It is more cytotoxic than its
cis
congener and exhib-
its signifi cant antitumour activity, including activity in cisplatin-resistant tumour
cells.
124
The new
trans
compound (
trans
- [PtCl
2
(
E
- iminoether)
2
]) forms mainly stable
monofunctional adducts at guanine residues when reacted with DNA.
125
These
adducts locally distort DNA, are not recognized by HMG-domain proteins and are
readily removed from DNA by the NER system. The monofunctional adducts of
trans
- [PtCl
2
(
E
- iminoether)
2
] readily crosslink proteins, which markedly enhances
