Chemistry Reference
In-Depth Information
insuffi cient to allow total hydrolysis of the platinum complexes;
151
indeed, the half
life of hydrolysis of cisplatin and carboplatin is about 2 and 286 h, respectively.
Therefore, the
in vitro
assay of telomerase activity is not fully informative, since a
part of the platinum complexes remains inactive.
Many workers have also investigated the cellular effects of cisplatin on tel-
omere lengths, and telomerase residual activity and expression. However, the three
parameters have never been taken into account at the same time. Until now, the
effect of cisplatin on telomeres has not been well clarifi ed.
Concerning the effect of cisplatin on telomere length, the fi rst study showed
that telomere loss in Hela-treated cells (20 kbp in telomere length) was dependent
on cisplatin dose. Low concentration of cisplatin (0.5 mM) induces telomere shorten-
ing after 24 h of treatment, whereas higher concentrations that blocked DNA repli-
cation in the S phase did not have any effect on telomere length.
152
Cisplatin was
also shown to induce the shortening of telomeres in hepatoma cells after 24 to 72 h
treatment (0.8 to 50 m M).
153
Since the rapid loss in telomere length was observed
after only one to three rounds of replications, it probably did not result from tel-
omerase inhibition, which induces a progressive shortening of telomeres.
83
It can
thus be proposed that platination of telomeres may inhibit telomere replication
and/or could uncap the telomere, as already suggested for rapid loss of telomeres
from quadruplex - binder - treated cells.
93
A gradual shortening of telomeres was
observed when yeast NER (nucleotide excision repair) mutant cells were treated
by doses of cisplatin that did not affect cell viability.
154
This suggests that the NER
pathway, which is involved in repair of cisplatin adducts,
119,155,156
may play a critical
role in the repair and maintenance of telomeres. However, in another recent study
it was found that cisplatin treatment (0.5-500 mM) induced no loss of telomeres after
2 to 72 h in three cell lines, independent of their initial telomere length (4-80 kbp)
(neuroblastoma, Hela, acute lymphoblastic T cell).
138
The results from these different studies were not conclusive and gave only an
indication of the possibility that cisplatin could interfere with telomeres. It could
depend on the susceptibility of the various cell lines used in the studies toward cis-
platin. Moreover, the high cytotoxic activity of cisplatin makes it diffi cult to discrimi-
nate between overall cellular effects and the specifi c effect on telomerase and/or
telomeres.
Telomerase activity of cisplatin-treated cells has also been investigated. Telom-
erase expression (hTERT, mRNA or hTR quantifi cation) has been controlled in
parallel, in some cases, in order to fi nd out if the decrease in telomerase activity was
due to its downregulation or to its inactivation. Since the evaluation of this activity
has been performed with TRAP assay
150
after cell extraction, telomerase inhibition
can refl ect only irreversible inactivation of telomerase. This inactivation, which
occurs upon cell treatment, could be attributed to covalent binding of cisplatin to
telomerase (hTR or hTERT), but there is no proof of this event at this time. The
results are still the subject of controversy. Upon cisplatin treatment, a decrease in
telomerase activity has been found in human testicular cancer cells,
157
associated
with a downregulation of hTR. A decrease in telomerase activity has also been
observed in hepatoma cells,
153
breast cancer cells in culture and in xenograph
tumours.
158
In contrast, no decrease of telomerase activity has been detected after
