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Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.

We have previously shown that loss of p53 function in A2780 human ovarian adenocarcinoma cells confers increased clonogenic resistance to several DNA-damaging agents, but not to taxol or camptothecin. We have now extended these studies, comparing wild-type p53-expressing A2780 cells with isogenic de...

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Autores principales: McDonald, A. C., Brown, R.
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group|1 1998
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2062955/
https://www.ncbi.nlm.nih.gov/pubmed/9743293
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author McDonald, A. C.
Brown, R.
author_facet McDonald, A. C.
Brown, R.
author_sort McDonald, A. C.
collection PubMed
description We have previously shown that loss of p53 function in A2780 human ovarian adenocarcinoma cells confers increased clonogenic resistance to several DNA-damaging agents, but not to taxol or camptothecin. We have now extended these studies, comparing wild-type p53-expressing A2780 cells with isogenic derivatives transfected with a dominant negative mutant (143; val to ala) p53. We show that, as well as retaining equivalent clonogenic sensitivity to camptothecin, mutant p53 transfectants of A2780 cells do not acquire significantly increased resistance to the camptothecin analogues topotecan and SN-38, the active metabolite of CPT-11. Compared with vector-alone transfectants they are, however, relatively (2.2-fold) resistant to GI 147211, a further camptothecin analogue undergoing clinical trial. Treatment of A2780 with camptothecin and each analogue produces an increase, maximal at 24-48 h after drug exposure, of cells in the G2/M phase of the cell cycle and a decrease in both G1 and S-phase cells. The G2 arrest is independent of p53 function for camptothecin and the three analogues. All four compounds can induce apoptosis in A2780, which is reduced in mutant p53 transfectants, as measured using the terminal DNA transferase-mediated b-d UTP nick end labelling (TUNEL) assay. Thus, although p53-dependent apoptosis is induced by camptothecin, topotecan and SN-38 in this human ovarian carcinoma cell line, these drugs induce p53-independent death, as measured by clonogenic assay. IMAGES:
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spelling pubmed-20629552009-09-10 Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors. McDonald, A. C. Brown, R. Br J Cancer Research Article We have previously shown that loss of p53 function in A2780 human ovarian adenocarcinoma cells confers increased clonogenic resistance to several DNA-damaging agents, but not to taxol or camptothecin. We have now extended these studies, comparing wild-type p53-expressing A2780 cells with isogenic derivatives transfected with a dominant negative mutant (143; val to ala) p53. We show that, as well as retaining equivalent clonogenic sensitivity to camptothecin, mutant p53 transfectants of A2780 cells do not acquire significantly increased resistance to the camptothecin analogues topotecan and SN-38, the active metabolite of CPT-11. Compared with vector-alone transfectants they are, however, relatively (2.2-fold) resistant to GI 147211, a further camptothecin analogue undergoing clinical trial. Treatment of A2780 with camptothecin and each analogue produces an increase, maximal at 24-48 h after drug exposure, of cells in the G2/M phase of the cell cycle and a decrease in both G1 and S-phase cells. The G2 arrest is independent of p53 function for camptothecin and the three analogues. All four compounds can induce apoptosis in A2780, which is reduced in mutant p53 transfectants, as measured using the terminal DNA transferase-mediated b-d UTP nick end labelling (TUNEL) assay. Thus, although p53-dependent apoptosis is induced by camptothecin, topotecan and SN-38 in this human ovarian carcinoma cell line, these drugs induce p53-independent death, as measured by clonogenic assay. IMAGES: Nature Publishing Group|1 1998-09 /pmc/articles/PMC2062955/ /pubmed/9743293 Text en https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
McDonald, A. C.
Brown, R.
Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
title Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
title_full Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
title_fullStr Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
title_full_unstemmed Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
title_short Induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
title_sort induction of p53-dependent and p53-independent cellular responses by topoisomerase 1 inhibitors.
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2062955/
https://www.ncbi.nlm.nih.gov/pubmed/9743293
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