Evaluation of the Combined Effect of p53 Codon 72 Polymorphism and Hotspot Mutations in Response to Anticancer Drugs
| Autor: | Mobin M. Siddique, Kanaga Sabapathy, Faina Vikhanskaya, Massimo Broggini, Ming Kei Lee |
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| Rok vydání: | 2005 |
| Předmět: |
Cancer Research
Paclitaxel Cell Survival Blotting Western Mutant Mutation Missense Antineoplastic Agents Biology Transfection Vinblastine medicine.disease_cause Deoxycytidine Cell Line Tumor Genotype medicine Humans Missense mutation Genes Tumor Suppressor Codon Etoposide Genetics Cisplatin Polymorphism Genetic Base Sequence Tumor Suppressor Proteins Nuclear Proteins Drug Synergism Tumor Protein p73 Gemcitabine DNA-Binding Proteins Oncology Drug Resistance Neoplasm Cancer research Tumor Suppressor Protein p53 Carcinogenesis Plasmids medicine.drug |
| Zdroj: | Clinical Cancer Research. 11:4348-4356 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-04-1547 |
| Popis: | Mutations in p53 are common events during carcinogenesis and have been suggested to affect sensitivity to chemotherapy. Recently, the common polymorphism at codon 72, resulting in either an arginine (72R) or proline (72P) residue, was shown to differentially affect the response to anticancer drugs. Here, we have generated isogenic lung cancer cell lines to evaluate the effect of six p53 hotspot mutations (R175H, G245S, R248W, R249S, R273H, and R282W) in conjunction with the codon 72 polymorphism, for their response to a variety of anticancer drugs, either alone or in combination. The data indicate that 72R mutations do not confer general resistance to cisplatin, etoposide, gemcitabine, vinblastine, and taxol. For doxorubicin, cells expressing 249-72R were more resistant than the 249-72P cells. Combined treatment with cisplatin + etoposide resulted in an additive effect in cells expressing most 72R and 72P mutations, except for the 175-72R cells which were refractory to combined treatment. However, combined treatment with cisplatin + gemcitabine resulted in the absence of an additive effect in cells expressing the 273-72R and 282-72R mutants, unlike their 72P counterparts. Nonetheless, all p53 mutants (72R or 72P) equally inhibited p73-mediated transcriptional activity in lung cancer cells, suggesting that the selective resistance conferred by some 72R mutants to certain drugs is probably due to other p73-independent effects of these mutants. Together, the data show that the status of codon 72 polymorphism and p53 mutations can be used as a means for prediction of treatment response, although variables for each cancer type requires detailed evaluation. |
| Databáze: | OpenAIRE |
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