In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 6 ( 2001-03-13), p. 3381-3386
Abstract:
Telomerase inhibition has been touted as a novel cancer-selective
therapeutic goal based on the observation of high telomerase levels in most cancers and the importance of telomere maintenance in long-term
cellular growth and survival. Here, the impact of telomere dysfunction on chemotherapeutic responses was assessed in normal and neoplastic
cells derived from telomerase RNA null (mTERC −/− ) mice.
Telomere dysfunction, rather than telomerase per se , was
found to be the principal determinant governing chemosensitivity specifically to agents that induced double-stranded DNA breaks (DSB).
Enhanced chemosensitivity in telomere dysfunctional cells was linked to therapy-induced fragmentation and multichromosomal fusions, whereas
telomerase reconstitution restored genomic integrity and chemoresistance. Loss of p53 function muted the cytotoxic effects of
DSB-inducing agents in cells with telomere dysfunction. Together, these results point to the combined use of DSB-inducing agents and telomere
maintenance inhibition as an effective anticancer therapeutic approach particularly in cells with intact p53-dependent checkpoint responses.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.051629198
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2001
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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