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1.
Oncogene ; 23(19): 3328-37, 2004 Apr 22.
Article in English | MEDLINE | ID: mdl-15077186

ABSTRACT

A single-nucleotide polymorphism (SNP) in exon 4 results in expression of either arginine (72R) or proline (72P) at codon 72 of p53. We demonstrate that the in vitro response of cells exposed to anticancer agents is strongly influenced by this SNP in wild-type p53. In inducible systems and in cells expressing the endogenous protein, expression of 72P wild-type p53 results in a predominant G1 arrest, with only a minor apoptosis, at drug concentrations causing extensive apoptosis in cells expressing the 72R wild-type variant. The superior apoptosis-inducing activity of the 72R form correlates with more efficient induction of specific apoptosis-associated genes, and is maximal in the presence of serine 46 (S46). In vivo, the outcome of chemo-radiotherapy of squamous carcinomas is more favourable in cancers retaining a wild-type 72R allele, such cases having higher response rates and longer survival than those with wild-type 72P. Together, these results reveal that this SNP is an important determinant of response to anticancer agents in cells expressing wild-type p53. Analysis of complete p53 genotype (mutation and SNP) merits detailed investigation as a simple means for prediction of treatment response and survival in clinical oncology.


Subject(s)
Antineoplastic Agents/pharmacology , Genes, p53 , Neoplasms/drug therapy , Polymorphism, Single Nucleotide , Apoptosis/drug effects , Cell Line, Tumor , Humans , Neoplasms/genetics , Neoplasms/pathology
2.
Cancer Cell ; 3(4): 387-402, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12726864

ABSTRACT

Intact p73 function is shown to be an important determinant of cellular sensitivity to anticancer agents. Inhibition of p73 function by dominant-negative proteins or by mutant p53 abrogates apoptosis and cytotoxicity induced by these agents. A polymorphism encoding either arginine (72R) or proline (72P) at codon 72 of p53 influences inhibition of p73 by a range of p53 mutants identified in squamous cancers. Clinical response following cisplatin-based chemo-radiotherapy for advanced head and neck cancer is influenced by this polymorphism, cancers expressing 72R mutants having lower response rates than those expressing 72P mutants. Polymorphism in p53 may influence individual responsiveness to cancer therapy.


Subject(s)
Apoptosis/genetics , Carcinoma, Squamous Cell/genetics , DNA-Binding Proteins/physiology , Drug Resistance, Neoplasm/genetics , Genes, p53/physiology , Nuclear Proteins/physiology , Adult , Aged , Drug Therapy , Female , Genes, Tumor Suppressor , Head and Neck Neoplasms/genetics , Humans , Immunoblotting , Immunohistochemistry , Male , Middle Aged , Mutation , Plasmids , Polymorphism, Single Nucleotide , Prognosis , RNA, Small Interfering/metabolism , Tumor Cells, Cultured , Tumor Protein p73 , Tumor Suppressor Proteins
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