Chemistry Reference
In-Depth Information
the effi ciency of this adduct to terminate DNA polymerization
in vitro
and to inhibit
removal of this adduct from DNA by the NER system.
126
Hence, DNA - protein
ternary crosslinks produced by
trans
- [PtCl
2
(
E
- iminoether)
2
] persist considerably
longer than the noncrosslinked monofunctional adducts, which potentiates toxicity
toward tumour cells. Thus,
trans
- [PtCl
2
(
E
- iminoether)
2
] belongs to a class of plati-
num antitumour drugs in which activation of the
trans
geometry is associated with
an increased effi ciency to form DNA-protein ternary crosslinks.
Polynuclear platinum compounds comprise a unique class of anticancer plati-
num agents with distinct chemical and biological properties different from mono-
nuclear platinum drugs.
127
The lead compound is BBR3464, a trinuclear, bifunctional
DNA binding agent.
Quite surprisingly, in comparison with cisplatin, enhanced cellular uptake of
the charged polynuclear platinum compounds has been demonstrated,
128,129
but the
enhanced uptake is not suffi cient to explain the increased toxicity of BBR3464 in
tumour cells.
130
The interactions of antitumour polynuclear platinum compounds
with target DNA (for review see, for instance, ref. 127) are distinct from the mono-
nuclear-based cisplatin family and, indeed, unlike those of any DNA-damaging
agent in clinical use. The ability of BBR3464 to induce long-range delocalized intra-
and interstrand crosslinks,
131
which are not produced by conventional mononuclear
platinum compounds, suggests that BBR3464 may escape, at least in part, the clas-
sical mechanism of cisplatin resistance related to DNA damage recognition and
repair. The crosslinks of BBR3464 distort the DNA conformation. In contrast to
distortions induced by the major crosslinks of cisplatin, the crosslinks of BBR3464
do not extensively unwind and rigidly bend DNA. Hence they are not substrates
for damaged-DNA binding proteins, such as HMG-domain proteins.
62,63
On the
other hand, while intrastrand adducts of BBR3464 are readily removed from DNA
by the NER systems, the interstrand crosslinks are not. It has been suggested
62,63
that interstrand, and not intrastrand, crosslinks of BBR3464 could persist for a suf-
fi ciently long time in cells to potentiate toxicity of this drug.
6.4.3 Mismatch Repair
Recent observations support the view that another cellular repair mechanism, such
as MMR, can affect the antitumour effi ciency of cisplatin,
132,133
and that dysfunction
of this type of DNA repair may result in the resistance of tumour cells to cisplatin,
or in drug tolerance.
134
The function of the MMR is to scan newly synthesized DNA
and remove mismatches that result from nucleotide incorporation errors made by
the DNA polymerases.
To explain cisplatin tolerance, it is assumed that replication bypass of DNA
adducts of cisplatin leads to mutations. During MMR, the strand to be corrected is
nicked, a short fragment containing the mismatch is excised, and a new DNA frag-
ment is synthesized. The MMR system always replaces the incorrect sequence in
the daughter strand, which would leave the cisplatin adduct unrepaired. This activity
initiates a futile cycle. During DNA synthesis to replace the excised short fragment,
the DNA polymerases would again incorporate mutations followed by attempts to
remove them. The repeated nicks in DNA formed at each ineffective cycle of repair
