Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas.
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.
Rodríguez-Antona
Cristina
C
Hereditary Endocrine Cancer Group, Spanish National Cancer Centre, C/Melchor Fernández Almagro no. 3, 28029 Madrid, Spain.
Leskelä
Susanna
S
Zajac
Magdalena
M
Cuadros
Marta
M
Alvés
Javier
J
Moneo
Maria Victoria
MV
Martín
Carmen
C
Cigudosa
Juan Cruz
JC
Carnero
Amancio
A
Robledo
Mercedes
M
Benitez
Javier
J
Martínez-Delgado
Beatriz
B
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002897:Chromosomes, Human, Pair 7; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004317:Doxorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000627:therapeutic use; D020440:Gene Duplication; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019169:Jurkat Cells; D016411:Lymphoma, T-Cell, Peripheral / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005047:Etoposide; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human