Document Detail


Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer.
MedLine Citation:
PMID:  20395368     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis-leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells.
Authors:
Trudy G Oliver; Kim L Mercer; Leanne C Sayles; James R Burke; Diana Mendus; Katherine S Lovejoy; Mei-Hsin Cheng; Aravind Subramanian; David Mu; Scott Powers; Denise Crowley; Roderick T Bronson; Charles A Whittaker; Arjun Bhutkar; Stephen J Lippard; Todd Golub; Juergen Thomale; Tyler Jacks; E Alejandro Sweet-Cordero
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Genes & development     Volume:  24     ISSN:  1549-5477     ISO Abbreviation:  Genes Dev.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-16     Completed Date:  2010-04-19     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  837-52     Citation Subset:  IM    
Affiliation:
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*,  therapeutic use*
Carcinoma, Non-Small-Cell Lung / drug therapy*,  pathology
Carrier Proteins / metabolism
Cell Line, Tumor
Cisplatin / pharmacology*,  therapeutic use*
DNA Repair / drug effects*
Death Domain Receptor Signaling Adaptor Proteins
Disease Models, Animal
Drug Resistance, Neoplasm / physiology
Gene Expression Profiling
Humans
Lung Neoplasms / drug therapy*,  pathology
Mice
Oligonucleotide Array Sequence Analysis
Grant Support
ID/Acronym/Agency:
5-UO1-CA84306/CA/NCI NIH HHS; CA034992/CA/NCI NIH HHS; P30-CA14051/CA/NCI NIH HHS; R01 CA127547/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Carrier Proteins; 0/Death Domain Receptor Signaling Adaptor Proteins; 0/Lrdd protein, mouse; 15663-27-1/Cisplatin
Comments/Corrections

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