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Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells

Defects in DNA mismatch repair (MMR) are associated with a predisposition to tumorigenesis and with drug resistance owing to high mutation rates and failure to engage DNA-damage-induced apoptosis. DNA minor groove binders (MGBs) are a class of anticancer agents highly effective in a variety of human...

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Autores principales: Fedier, A, Fowst, C, Tursi, J, Geroni, C, Haller, U, Marchini, S, Fink, D
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394335/
https://www.ncbi.nlm.nih.gov/pubmed/14562032
http://dx.doi.org/10.1038/sj.bjc.6601316
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author Fedier, A
Fowst, C
Tursi, J
Geroni, C
Haller, U
Marchini, S
Fink, D
author_facet Fedier, A
Fowst, C
Tursi, J
Geroni, C
Haller, U
Marchini, S
Fink, D
author_sort Fedier, A
collection PubMed
description Defects in DNA mismatch repair (MMR) are associated with a predisposition to tumorigenesis and with drug resistance owing to high mutation rates and failure to engage DNA-damage-induced apoptosis. DNA minor groove binders (MGBs) are a class of anticancer agents highly effective in a variety of human cancers. Owing to their mode of action, DNA MGB-induced DNA damage may be a substrate for DNA MMR. This study was aimed at investigating the effect of loss of MMR on the sensitivity to brostallicin (PNU-166196), a novel synthetic α-bromoacrylic, second-generation DNA MGB currently in Phase II clinical trials and structurally related to distamycin A. Brostallicin activity was compared to a benzoyl mustard derivative of distamycin A (tallimustine). We report that the sensitivities of MLH1-deficient and -proficient HCT116 human colon carcinoma cells were comparable after treatment with brostallicin, while tallimustine resulted in a three times lower cytotoxicity in MLH1-deficient than in -proficient cells. MSH2-deficient HEC59 parental endometrial adenocarcinoma cells were as sensitive as the proficient HEC59+ch2 cells after brostallicin treatment, but were 1.8-fold resistant after tallimustine treatment as compared to the MSH2-proficient HEC59+ch2 counterpart. In addition, p53-deficient mouse fibroblasts lacking PMS2 were as sensitive to brostallicin as PMS2-proficient cells, but were 1.6-fold resistant to tallimustine. Loss of neither ATM nor DNA-PK affected sensitivity to brostallicin in p53-deficient mouse embryonic fibroblasts, indicating that brostallicin-induced cytotoxicity in a p53-deficient genetic background does not seem to require these kinases. These data show that, unlike other DNA MGBs, MMR-deficient cells retain their sensitivity to this new α-bromoacrylic derivative, indicating that brostallicin-induced cytotoxicity does not depend on functional DNA MMR. Since DNA MMR deficiency is common in numerous types of tumours, brostallicin potentially offers the advantage of being effective against MMR-defective tumours that are refractory to several anticancer agents.
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spelling pubmed-23943352009-09-10 Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells Fedier, A Fowst, C Tursi, J Geroni, C Haller, U Marchini, S Fink, D Br J Cancer Experimental Therapeutics Defects in DNA mismatch repair (MMR) are associated with a predisposition to tumorigenesis and with drug resistance owing to high mutation rates and failure to engage DNA-damage-induced apoptosis. DNA minor groove binders (MGBs) are a class of anticancer agents highly effective in a variety of human cancers. Owing to their mode of action, DNA MGB-induced DNA damage may be a substrate for DNA MMR. This study was aimed at investigating the effect of loss of MMR on the sensitivity to brostallicin (PNU-166196), a novel synthetic α-bromoacrylic, second-generation DNA MGB currently in Phase II clinical trials and structurally related to distamycin A. Brostallicin activity was compared to a benzoyl mustard derivative of distamycin A (tallimustine). We report that the sensitivities of MLH1-deficient and -proficient HCT116 human colon carcinoma cells were comparable after treatment with brostallicin, while tallimustine resulted in a three times lower cytotoxicity in MLH1-deficient than in -proficient cells. MSH2-deficient HEC59 parental endometrial adenocarcinoma cells were as sensitive as the proficient HEC59+ch2 cells after brostallicin treatment, but were 1.8-fold resistant after tallimustine treatment as compared to the MSH2-proficient HEC59+ch2 counterpart. In addition, p53-deficient mouse fibroblasts lacking PMS2 were as sensitive to brostallicin as PMS2-proficient cells, but were 1.6-fold resistant to tallimustine. Loss of neither ATM nor DNA-PK affected sensitivity to brostallicin in p53-deficient mouse embryonic fibroblasts, indicating that brostallicin-induced cytotoxicity in a p53-deficient genetic background does not seem to require these kinases. These data show that, unlike other DNA MGBs, MMR-deficient cells retain their sensitivity to this new α-bromoacrylic derivative, indicating that brostallicin-induced cytotoxicity does not depend on functional DNA MMR. Since DNA MMR deficiency is common in numerous types of tumours, brostallicin potentially offers the advantage of being effective against MMR-defective tumours that are refractory to several anticancer agents. Nature Publishing Group 2003-10-20 2003-10-14 /pmc/articles/PMC2394335/ /pubmed/14562032 http://dx.doi.org/10.1038/sj.bjc.6601316 Text en Copyright © 2003 Cancer Research UK 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 Experimental Therapeutics
Fedier, A
Fowst, C
Tursi, J
Geroni, C
Haller, U
Marchini, S
Fink, D
Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells
title Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells
title_full Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells
title_fullStr Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells
title_full_unstemmed Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells
title_short Brostallicin (PNU-166196) – a new DNA minor groove binder that retains sensitivity in DNA mismatch repair-deficient tumour cells
title_sort brostallicin (pnu-166196) – a new dna minor groove binder that retains sensitivity in dna mismatch repair-deficient tumour cells
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2394335/
https://www.ncbi.nlm.nih.gov/pubmed/14562032
http://dx.doi.org/10.1038/sj.bjc.6601316
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