Abstract |
Peripheral T-cell lymphomas (PTCLs) are aggressive tumors in which the current therapy based on multiagent chemotherapy is not successful. Since cytochrome P450 3A subfamily ( CYP3A) enzymes are involved in the inactivation of chemotherapy drugs, we hypothesized that CYP3A and P-glycoprotein (MDR1) expression in these lymphomas could result in a poor clinical response. We measured tumoral CYP3A and MDR1 mRNA content in 44 T-cell lymphomas, finding a large variation in CYP3A expression. Multiplex polymerase chain reaction (PCR) analysis and fluorescence in situ hybridization (FISH) analysis showed genomic gains affecting CYP3A and MDR1 genes in T-cell lines and primary tumors, suggesting that this could be the mechanism underlying the tumoral expression variation. To test whether the tumoral expression of CYP3A and/or MDR1 could influence PTCL treatment outcome, their expression levels were compared with the clinical response and survival of the patients, finding that a high tumoral expression of CYP3A4 was significantly associated with a lower complete remission rate. This was further investigated with cell lines stably expressing CYP3A4 that exhibited an increased resistance to doxorubicin and etoposide. In conclusion, a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy; in these cases alternative chemotherapy combinations or doses should be explored.
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Authors | Cristina Rodríguez-Antona, Susanna Leskelä, Magdalena Zajac, Marta Cuadros, Javier Alvés, Maria Victoria Moneo, Carmen Martín, Juan Cruz Cigudosa, Amancio Carnero, Mercedes Robledo, Javier Benitez, Beatriz Martínez-Delgado |
Journal | Blood
(Blood)
Vol. 110
Issue 9
Pg. 3345-51
(Nov 01 2007)
ISSN: 0006-4971 [Print] United States |
PMID | 17634410
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- ABCB1 protein, human
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents
- Etoposide
- Doxorubicin
- Cytochrome P-450 Enzyme System
- Cytochrome P-450 CYP3A
- CYP3A4 protein, human
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Topics |
- ATP Binding Cassette Transporter, Subfamily B
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(genetics)
- Antineoplastic Agents
(therapeutic use)
- Chromosomes, Human, Pair 7
- Cytochrome P-450 CYP3A
- Cytochrome P-450 Enzyme System
(genetics)
- Doxorubicin
(therapeutic use)
- Drug Resistance, Neoplasm
(genetics)
- Etoposide
(therapeutic use)
- Gene Duplication
- Gene Expression
- Gene Expression Regulation, Neoplastic
- Humans
- Jurkat Cells
- Lymphoma, T-Cell, Peripheral
(diagnosis, drug therapy, genetics, mortality)
- Prognosis
- Survival Analysis
- Treatment Outcome
- Tumor Cells, Cultured
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