Chemistry Reference
In-Depth Information
treatment by cisplatin of haematopoietic cancer cells when used at concentrations
resulting in cytostatic growth inhibition
159
in human ovarian adenocarcinoma cell
lines,
160
neuroblastoma, Hela and acute lymphoblastic T cells
138
and of nasopharyn-
geal cancer cells.
161
No signifi cant downexpression of hTERT has been observed in
MCF-7 cells treated with cisplatin.
162
Since telomerase plays a role in cellular resistance to apoptosis, which is the
primary mode of cell death induced by several drugs, combining telomerase inhibi-
tion with chemotherapeutic treatment may prove more effi cient than each approach
on its own. Many studies have been done in order to investigate the relationship
between telomerase, telomere dysfunction and vulnerability to drug-induced apop-
tosis, particularly by cisplatin. Inhibition of telomerase activity or expression
increased the susceptibility of glioblastoma cells,
163
and of drug - resistant and drug -
sensitive promyelocytic leukemia and breast cancer cells
164
to cisplatin - induced
apoptosis. Results were controversial for melanoma cells, since neither an increase
in sensibility for cisplatin was detected when telomerase was inhibited
30
nor a
precise relationship was found between telomerase activity and cellular sensitivity
to cisplatin.
137,165
Moreover, telomerase activity of cisplatin-treated cells has also
been shown to depend on the period of treatment of prostate cell lines.
166
Other
studies revealed that the high level of hTERT expression and/or telomerase activity
are related to chemosensitivity to cisplatin in ovarian carcinoma,
167
and in oesopha-
geal cancer cell lines,
168
suggesting that telomerase could be a marker of prognosis
for cisplatin treatment. A study of cisplatin treatment of telomere dysfunctional and
telomere functional mice cells suggested that telomere dysfunction does not govern
chemosensitivity to cisplatin.
169
Based on all available data one may conclude that
telomerase may play a role in tumour cell proliferation by modulating the cellular
response to chemotherapy, particularly for drugs that affect DNA integrity.
7.9 Conclusion
In vitro
experiments have shown that telomerase and telomeres are good targets
for cisplatin and some of its derivatives. The various results from cellular studies
have been explained by differential suppression of hTERT expression and/or inhibi-
tion of telomerase activity that could lead to telomere shortening. However, this
inhibition seems to depend on the cell lines, the doses and the experimental condi-
tions. An unambiguous conclusion on the effects of cisplatin treatments may be
obtained by comparing different cell lines under strict identical experimental condi-
tions. Final conclusions must therefore await further studies.
There is one way that has not yet been investigated extensively, but that appears
to be of importance due to the increasing role of telomeres in cell viability; it con-
cerns the possible platination of telomeric DNA. This event could lead to the well-
known cellular responses to cisplatin treatment leading to apoptosis or senescence.
119
This hypothesis is supported by the fact that telomeric DNA is more accessible than
genomic DNA
94
and that telomere dysfunction induced by noncovalent quadruplex
DNA binders is favoured in cancer cells over normal cells.
33
Platination of telomeric
