Identification of adenovirus E1A gene regions involved in chemosensitisation of prostate cancer cells
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Replication-selective adenoviruses are promising anti-cancer therapies
(virotherapy). Viruses can be engineered to selectively target cancer cells by
deleting viral genes involved in cell cycle regulation. These deletions impair
replication in normal cells, as the virus cannot overcome cellular checkpoints and
pro-apoptotic pathways triggered by the infection. In cancer cells, however, these
pathways are often deregulated hence viral propagation is not affected by these
deletions. Despite the efforts to maximise potency and selectivity of adenoviruses
as therapeutic agents, efficacy was poor when evaluated alone in clinical trials.
Enhancement of efficacy was demonstrated in combination with chemotherapy
and radiotherapy. A requirement for virus-mediated sensitisation to chemotherapy
and enhancement of efficacy is the expression of the early viral gene E1A.
However, the exact E1A regions required for increased cell death have not yet
been identified. The E1A proteins bind to a variety of cellular factors, including
the transcriptional and cell cycle regulators p300/CBP and pRb. This thesis
describes the use of replication-selective and replication-defective adenoviruses
expressing different mutation of the E1A gene in order to identify regions
involved in chemosensitisation of prostate cancer cell lines to two cytotoxic
drugs, mitoxantrone and docetaxel. Synergistic interactions were observed with
all replication-selective adenoviruses and mitoxantrone in a cell dependent
manner. The results obtained indicate that mutations in the p300/CBP binding
site, but not pRb, impaired the sensitising activity of E1A to the cytotoxic drugs.
Expression of E1A enhanced the arrest in the G2/M phase induced by
mitoxantrone and increased the percentage of apoptotic cells in a process
dependent on E1A binding to p300/CBP. Deletion of this binding site also
attenuated the potency of replicating adenoviruses, indicating that binding to
p300/CBP plays a central role in sensitisation to chemotherapy and control of
viral cycle in prostate cancer cells.
Authors
Rota, Enrique MirandaCollections
- Theses [3834]