Mismatch repair status and the response of human cells to cisplatin.

Mismatch repair status and the response of human cells to cisplatin. Research Abstract Details 

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Mismatch repair status and the response of human cells to cisplatin. Abstract Text:

Elisabetta Pani,Lovorka Stojic,Mahmoud El-Shemerly,Josef Jiricny,Stefano Ferrari,

The emergence of resistance to cisplatin is a serious drawback of cancer therapy. To help elucidate the molecular basis of this resistance, we examined matched ovarian cancer cell lines that differ in their DNA mismatch repair (MMR) status and the response to cisplatin. Checkpoint activation by cisplatin was identical in both lines. However, sensitive cells delayed S-phase transition, arrested at G(2)/M and died by apoptosis. The G(2)/M block was characterized by selective disappearance of homologous recombination (HR) proteins, which likely resulted in incomplete repair of the cisplatin adducts. In contrast, resistant cells transiently arrested at G(2)/M, maintained constant levels of HR proteins and ultimately resumed cell cycle progression. The net contribution of MMR to the cisplatin response was examined using matched semi-isogenic (HCT116+/-chr3) or strictly isogenic (293T-Lalpha(-/+)) cell lines. Delayed transition through S-phase in response to cisplatin was also observed in the MMR-proficient HCT116+chr3 cells. Unlike in the ovarian cell lines, however, both HCT116+chr3 and HCT116 permanently arrested at G(2)/M with an intact complement of HR proteins and died by apoptosis. A similar G(2)/M arrest was observed in the strictly isogenic 293T-Lalpha(-/+) cells. This confirmed that although MMR undoubtedly contributes towards the cytotoxicity of cisplatin, it is only one of several pathways that modulate the cellular response to this drug. However, our data highlighted the importance of HR to cisplatin cytotoxicity and suggested that HR status might represent a novel prognostic marker and possibly also a therapeutic target, the inhibition of which would substantially sensitize cells to cisplatin chemotherapy.

Mismatch repair status and the response of human cells to cisplatin. Publishing Authors By Initials

E Pani,L Stojic,M El-Shemerly,J Jiricny,S Ferrari,

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Mismatch repair status and the response of human cells to cisplatin. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cell cycle (Georgetown, Tex.)

VOLUME: 6

Page Numbers: 1796-802

Journal Abbreviation: Cell Cycle

ISSN: 1551-4005

DAY: 22

MONTH: 05

YEAR: 2007

Mismatch repair status and the response of human cells to cisplatin. Information

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LANGUAGE: eng

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AFFILIATION: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.

Country: United States

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MEDLINETA: Cell Cycle

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