Abstract
Lack of p53 or mismatch repair (MR) function and scarce cell proliferation are commonly associated with tumor cell resistance to antineoplastic agents. Recently, inhibition of poly(ADP-ribose) polymerase (PARP) has been considered as a tool to overcome resistance of MR-deficient tumors to methylating agents. In the present study we demonstrated that infection with p53 expressing adenovirus (Ad-p53), enhances chemosensitivity of MR-deficient tumor cell lines to the methylating agent temozolomide (TZM), either used as single agent or, more efficiently, when combined with PARP inhibitor. Moreover, the association of Ad-p53 with drug treatment induced a more pronounced growth inhibitory effect than that provoked by Ad-p53 infection only. Cells, growth arrested by p53 transduction, and then subsequently exposed to the drugs, were still highly susceptible to cytotoxicity induced by TZM and PARP inhibitor. The results suggested that this drug combination might be effective even in non-proliferating tumor cells. It is conceivable to envisage future possible strategies to enhance cytostatic or cytotoxic effects induced by Ad-p53, based on the use of TZM, alone or combined with PARP inhibitor for the therapy of resistant tumors. Cell Death and Differentiation (2001) 8, 457–469
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Abbreviations
- MR:
-
mismatch repair
- BER:
-
base excision repair
- TZM:
-
temozolomide
- PARP:
-
poly(ADP-ribose) polymerase
- Ad:
-
adenovirus
- MOI:
-
multiplicity of infection
- beta-Gal:
-
beta-galactosidase
- 3-AB:
-
3-aminobenzamide
- 5-BrdU:
-
5-bromodeoxyuridine
- TS:
-
thymidylate synthase
- 5-FU:
-
5-fluorouracil
- raltitrexed:
-
N-[5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl]-L-glutamic acid
- O.D.:
-
optical densities
- PI:
-
propidium iodide
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Acknowledgements
This study was supported by a grant from the Italian Association for Cancer Research (AIRC) and by MURST (Molecular bases for the pharmacological control of neoplastic diseases). The authors would like to thank Dr. A Bergamini (University of Rome ‘Tor Vergata’) for suggestions on Ad infection and C Mastrilli and G Bonelli for their excellent technical assistance.
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Tentori, L., Portarena, I., Bonmassar, E. et al. Combined effects of adenovirus-mediated wild-type p53 transduction, temozolomide and poly (ADP-ribose) polymerase inhibitor in mismatch repair deficient and non-proliferating tumor cells. Cell Death Differ 8, 457–469 (2001). https://doi.org/10.1038/sj.cdd.4400832
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DOI: https://doi.org/10.1038/sj.cdd.4400832
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