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Differential killing of mismatch repair-deficient and -proficient cells: towards the therapy of tumors with microsatellite instability


Cejka, P; Marra, G; Hemmerle, C; Cannavó, E; Storchova, Z; Jiricny, J (2003). Differential killing of mismatch repair-deficient and -proficient cells: towards the therapy of tumors with microsatellite instability. Cancer Research, 63(23):8113-8117.

Abstract

DNA mismatch repair (MMR) defects bring about a strong mutator phenotype and microsatellite instability (MSI). In an attempt to exploit MSI in cancer therapy, we constructed expression vectors carrying a thymidine kinase/blasticidin deaminase fusion gene downstream from a (C)(12) or an (A)(26) microsatellite and stably transfected these constructs into human cells in which the MMR status could be regulated by doxycycline. We now show that ganciclovir-resistant clones arising through frameshifts in the (C)(12) microsatellite were 20 times more frequent in cells in which MMR was inactivated. This difference may be exploited in gene therapy of tumors with MSI, which represent a substantial proportion of cancers of many different tissues.

Abstract

DNA mismatch repair (MMR) defects bring about a strong mutator phenotype and microsatellite instability (MSI). In an attempt to exploit MSI in cancer therapy, we constructed expression vectors carrying a thymidine kinase/blasticidin deaminase fusion gene downstream from a (C)(12) or an (A)(26) microsatellite and stably transfected these constructs into human cells in which the MMR status could be regulated by doxycycline. We now show that ganciclovir-resistant clones arising through frameshifts in the (C)(12) microsatellite were 20 times more frequent in cells in which MMR was inactivated. This difference may be exploited in gene therapy of tumors with MSI, which represent a substantial proportion of cancers of many different tissues.

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8 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2003
Deposited On:09 Jul 2010 07:10
Last Modified:07 Dec 2017 01:03
Publisher:American Association for Cancer Research
ISSN:0008-5472
Official URL:http://cancerres.aacrjournals.org/content/63/23/8113
PubMed ID:14678962

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