Chemistry Reference
In-Depth Information
while histone H1 sits on the base of the nucleosome at the junction between nucleo-
some DNA and linker DNA, extending along the DNA into the linker region.
111
Nucleosomes modulate many cellular processes so that it is of interest to know how
NER of DNA adducts of platinum compounds is affected when these adducts are
present in nucleosomes.
Nucleosomes were prepared containing either a site-specifi c 1,2 - GG or 1,3
GTG intrastrand crosslink of cisplatin.
112
It was found that the nucleosome signifi -
cantly inhibited NER, the inhibition being more pronounced in the case of the 1,3-
intrastrand crosslink. Interestingly, excision from native nucleosomal DNA was
higher than the level observed with recombinant material. This result reveals that
posttranslational modifi cation of histones can modulate NER from damaged
chromatin.
Despite its success, cisplatin has several disadvantages: it is active against a
limited range of human tumours, can cause severe side effects and its administration
may result in acquired resistance. The drawbacks, coupled with the toxicity of cispla-
tin and its analogues, have been the impetus for the development of platinum drugs
with improved pharmacological properties and a broader range of antitumour
activity.
Antitumour activity of platinum drugs is multifactorial in nature and also
includes contributions from differential DNA repair mechanisms. Therefore it is of
interest to know whether NER and other repair pathways discriminate between
cisplatin and novel platinum drugs that exhibit altered biological effects.
A study of this kind was focused on NER of DNA adducts formed by a third
generation antitumour platinum drugs oxaliplatin [(
1R,2R
- diamminocyclohexane)
oxalato - platinum(II)] and satraplatin [bis - acetatoamminedichlorocyclohexylamine
platinum(IV), JM216].
113
Interestingly, the types of DNA lesions generated by the
three platinum drugs, cisplatin, oxaliplatin and satraplatin, are repaired
in vitro
with
similar kinetics by the mammalian NER pathway. This result is consistent with
reports that major DNA adducts of cisplatin, oxaliplatin and satraplatin cause
similar distortions in DNA.
114,115
Besides oxaliplatin ([Pt(
R,R
- DACH)]
2+
, DACH = 1,2 - diaminocyclohexane),
another enantiomeric form of this complex exists, [Pt(
S,S
- DACH)]
2+
. Whereas con-
formational alterations induced in DNA by the major adduct of [Pt(
R,R
- DACH)]
2+
are not markedly different from those induced by the adduct of cisplatin, confor-
mational alterations induced by the major adduct formed by [Pt(
S,S
- DACH)]
2+
in
the TGGT sequence are different.
115
The major differences resulting from the modi-
fi cation by the two enantiomers consist in sequence-dependent thermodynamic
destabilization and conformational distortions.
Interestingly, the 1,2-GG intrastrand crosslinks of [Pt(
R,R
- DACH)]
2+
bind to
HMG-domain proteins with a similar affi nity as the same crosslink of cisplatin.
115
In contrast, the crosslink formed by [Pt(
S,S
- DACH)]
2+
in the TGGT sequence binds
to the HMG-domain protein with a noticeably lower affi nity. Similar results have
also been obtained with DNA modifi ed by [Pt(DAB)]
2+
(DAB = 2,3 - diaminobu-
tane) enantiomers (which are closely related to [Pt(DACH)]
2+
enantiomers).
116 - 118
Intrastrand crosslinks between neighbouring guanine residues of both enanti-
omers of [Pt(DAB)]
2+
were effi ciently removed from DNA by NER in an
in vitro
