Expression and activity of taxane-metabolizing enzymes in ovarian tumors.
OBJECTIVE
Current firstline chemotherapy for ovarian cancer consists of carboplatin combined with either paclitaxel or docetaxel. Disposition of carboplatin is determined by renal clearance, while the taxanes are metabolized by cytochrome P450 (CYP450) enzymes. Although the majority of taxane metabolism occurs in the liver, recent data have shown that some solid tumors express CYP450 enzymes in the tumors themselves. The objective of this study was to determine whether ovarian tumors express genes regulating cellular efflux and subsequent metabolism, and whether any clinico-pathologic features correlated with expression.


METHODS
Gene expression of CYP2C8, CYP3A4/A5 and the ABC transporter ABCB1 was determined in 56 primary epithelial ovarian tumors. Cells were grown from seven different tumors and exposed ex vivo to paclitaxel (PAC) and docetaxel (DOC) for up to 24 h. PAC and DOC concentrations were measured in the media by an LC-MS assay.


RESULTS
Results from this analysis demonstrate that ovarian cancer cells do express functional taxane-metabolizing enzymes. Such expression appeared to enhance the ability of cancer cells to metabolize DOC. Specifically, the PK of DOC was correlated with the ratio of CYP4A5 to ABCB1 gene expression, thus representing a novel mechanism of chemotherapy resistance. There was no relationship between PAC PK parameters and gene expression.


CONCLUSIONS
Knowledge of inter-individual variation in CYP450 enzyme and ABC transporter tumor expression and activity may influence the individualization of chemotherapy, by avoiding agents that are rapidly metabolized and selecting agents that are not.
DeLoia
Julie A
JA
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA. jad99@georgetown.edu
Zamboni
William C
WC
Jones
Jacqueline M
JM
Strychor
Sandra
S
Kelley
Joseph L
JL
Gallion
Holly H
HH
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077143:Docetaxel; D005260:Female; D015870:Gene Expression; D006801:Humans; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D017239:Paclitaxel / Q000493:pharmacokinetics*; D043823:Taxoids / Q000493:pharmacokinetics*; 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; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel