Submitted February 20, 2007
Accepted July 5, 2007
Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas
Cristina Rodriguez-Antona, Susanna Leskela, Magdalena Zajac, Marta Cuadros, Javier Alves, Maria Victoria Moneo, Carmen Martin, Juan Cruz Cigudosa, Amancio Carnero, Mercedes Robledo, Javier Benitez, and Beatriz Martinez-Delgado*
Hereditary Endocrine Cancer Group, Spanish National Cancer Center (CNIO), Madrid
Human Genetics Group, Spanish National Cancer Center (CNIO), Madrid
Department of Pathology, Hospital La Paz, Madrid
Assay Development Group, Spanish National Cancer Center (CNIO), Madrid
Molecular Cytogenetics Group, Spanish National Cancer Center (CNIO), Madrid
* Corresponding author; email: bmartinez{at}cnio.es.
Peripheral T-cell lymphomas (PTCL) are aggressive tumors in which the current therapy based on multiagent chemotherapy is not successful. Since cytocrome 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 PCR-Analysis and 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 which 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.
