Document Detail


Paclitaxel sensitivity correlates with p53 status and DNA fragmentation, but not G2/M accumulation.
MedLine Citation:
PMID:  10421546     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: The antitumor agent paclitaxel (Taxol) has been shown to arrest cells in mitosis through microtubule stabilization and to induce apoptosis. The tumor suppressor gene p53 is implicated in the regulation of cell cycle checkpoints and can mediate apoptotic cell death. Although initial studies demonstrated that various DNA-damaging agents can induce p53, more recent studies have also shown p53 induction following nonDNA-damaging agents, including paclitaxel. We investigated the influence of p53 abrogation on paclitaxel-induced cell kill and correlated the extent of mitotic arrest and DNA fragmentation by paclitaxel with the drug's cytotoxic effect. MATERIALS AND METHODS: The parental human colorectal carcinoma cell line (RKO) with wild-type p53 alleles, and two transfected RKO cell lines with inactivated p53 (RKO.p53.13 with transfected mutant p53 and RC 10.3 with HPV-16-derived E6 gene) were exposed to graded doses of paclitaxel (1-100 nM) for 24-h intervals. The functional status of p53 in cells was assessed by thymidine and BrdU incorporation following exposure to ionizing radiation (4 Gy). Reproductive integrity following paclitaxel treatment was assessed by clonogenic assay. Immunolabeling and microscopic evaluation were used to assess mitotic accumulation and micronucleation. Apoptosis was assayed using DNA fragmentation analyses. RESULTS: A 4-fold increase in paclitaxel sensitivity was observed among RKO cells deficient in p53 function compared with wild-type RKO cells (IC 50: 4 nM, 1 nM, 1nM for RKO, RKO.p53.13, RC 10.3, respectively). The increased cytotoxic effect in RKO cells with inactive p53 correlated with an increased propensity towards micronucleation and DNA fragmentation following paclitaxel treatment. However, no significant difference in peak mitotic accumulation was observed among RKO cells with functional or abrogated p53. CONCLUSIONS: RKO cells lacking functional p53 demonstrate significantly enhanced sensitivity to paclitaxel compared with that of wild-type RKO cells. This response corresponded with increased micronucleation and DNA fragmentation in cells deficient in p53 function. Although previous published reports of enhanced paclitaxel sensitivity in p53-deficient cells correlated this finding with increased G2/M arrest, we did not observe any significant correlation between paclitaxel-induced cell kill and the degree of mitotic arrest. Our data suggest that apoptosis is the predominant mechanism of paclitaxel cytotoxicity in RKO cells and is likely mediated by a p53-independent process.
Authors:
E Rakovitch; W Mellado; E J Hall; T K Pandita; S Sawant; C R Geard
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  International journal of radiation oncology, biology, physics     Volume:  44     ISSN:  0360-3016     ISO Abbreviation:  Int. J. Radiat. Oncol. Biol. Phys.     Publication Date:  1999 Jul 
Date Detail:
Created Date:  1999-07-29     Completed Date:  1999-07-29     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7603616     Medline TA:  Int J Radiat Oncol Biol Phys     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1119-24     Citation Subset:  IM    
Affiliation:
Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / pharmacology*
DNA Fragmentation
DNA, Neoplasm / drug effects
Dose-Response Relationship, Drug
Drug Resistance
Genes, p53 / physiology*
Humans
Micronuclei, Chromosome-Defective
Paclitaxel / pharmacology*
Tumor Cells, Cultured / drug effects
Tumor Stem Cell Assay
Grant Support
ID/Acronym/Agency:
CA73061/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/DNA, Neoplasm; 33069-62-4/Paclitaxel

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