[Study of CYP3A5 in drug resistance mechanisms in acute leukemia].
OBJECTIVE
To investigate if CYP3A5 is involved in drug resistances mechanisms of acute leukemia.


METHODS
By using RT-PCR, immunohistochemistry and MTT assay, CYP3A5 mRNA and protein were detected in leukemia cell lines and acute leukemia patients, meanwhile transcriptional regulation of CYP3A5 induced by daunorubicin was observed. A pcDNA3-CYP3A5 reconstituted plasmid and its stably transfected cell line HL-60/CYP3A5 were both established.


RESULTS
CYP3A5 mRNA was detected in K562 and U937 cells, whose IC(50) values of daunorubicin were 2.1-fold higher than those of NB4 and HL-60 cells. Bone marrow CYP3A5 positive blast cell percentage at the time of diagnosis in primary drug resistance group (17.2%) was significantly higher than that of continuous complete remission (CCR) group (0.4%) and secondary drug resistance group (5.4%). In their first complete remission of the early relapsed group, the positive rate had been 23.9% as compared with that of CCR group (1.3%). Daunorubicin increased CYP3A5 mRNA level in K562/A02 and activated its transcription in HL-60/ADR. HL-60/CYP3A5 cell was significantly resistant to daunorubicin and vincristine than HL-60 cells did (3.0 and 4.0 times, respectively).


CONCLUSIONS
CYP3A5 expressed in leukemia cells may cause in situ metabolization of many kinds of anticancer drugs, thus led to drug resistance.
Wang
Ting
T
Hematology Department, Renji Hospital of Shanghai Second Medical University, Shanghai Institute of Hematology, Shanghai 200001, China.
Chen
Fang-yuan
FY
Han
Jie-ying
JY
Shao
Nian-xian
NX
Ou-Yuang
Ren-rong
RR
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology*; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D003630:Daunorubicin