PMID- 22111840
OWN - NLM
STAT- MEDLINE
DCOM- 20130208
LR  - 20220316
IS  - 1476-4598 (Electronic)
IS  - 1476-4598 (Linking)
VI  - 10
DP  - 2011 Nov 23
TI  - Metabolism of the EGFR tyrosin kinase inhibitor gefitinib by cytochrome P450 1A1 
      enzyme in EGFR-wild type non small cell lung cancer cell lines.
PG  - 143
LID - 10.1186/1476-4598-10-143 [doi]
AB  - BACKGROUND: Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal 
      growth factor receptor (EGFR) especially effective in tumors with activating EGFR 
      gene mutations while EGFR wild-type non small cell lung cancer (NSCLC) patients 
      at present do not benefit from this treatment.The primary site of gefitinib 
      metabolism is the liver, nevertheless tumor cell metabolism can significantly 
      affect treatment effectiveness. RESULTS: In this study, we investigated the 
      intracellular metabolism of gefitinib in a panel of EGFR wild-type 
      gefitinib-sensitive and -resistant NSCLC cell lines, assessing the role of 
      cytochrome P450 1A1 (CYP1A1) inhibition on gefitinib efficacy. Our results 
      indicate that there is a significant difference in drug metabolism between 
      gefitinib-sensitive and -resistant cell lines. Unexpectedly, only sensitive cells 
      metabolized gefitinib, producing metabolites which were detected both inside and 
      outside the cells. As a consequence of gefitinib metabolism, the intracellular 
      level of gefitinib was markedly reduced after 12-24 h of treatment. Consistent 
      with this observation, RT-PCR analysis and EROD assay showed that mRNA and 
      activity of CYP1A1 were present at significant levels and were induced by 
      gefitinib only in sensitive cells. Gefitinib metabolism was elevated in crowded 
      cells, stimulated by exposure to cigarette smoke extract and prevented by hypoxic 
      condition. It is worth noting that the metabolism of gefitinib in the sensitive 
      cells is a consequence and not the cause of drug responsiveness, indeed treatment 
      with a CYP1A1 inhibitor increased the efficacy of the drug because it prevented 
      the fall in intracellular gefitinib level and significantly enhanced the 
      inhibition of EGFR autophosphorylation, MAPK and PI3K/AKT/mTOR signalling 
      pathways and cell proliferation. CONCLUSION: Our findings suggest that gefitinib 
      metabolism in lung cancer cells, elicited by CYP1A1 activity, might represent an 
      early assessment of gefitinib responsiveness in NSCLC cells lacking activating 
      mutations. On the other hand, in metabolizing cells, the inhibition of CYP1A1 
      might lead to increased local exposure to the active drug and thus increase 
      gefitinib potency.
FAU - Alfieri, Roberta R
AU  - Alfieri RR
AD  - Department of Experimental Medicine, Unit of Experimental Oncology, University of 
      Parma, Parma, Italy. roberta.alfieri@unipr.it
FAU - Galetti, Maricla
AU  - Galetti M
FAU - Tramonti, Stefano
AU  - Tramonti S
FAU - Andreoli, Roberta
AU  - Andreoli R
FAU - Mozzoni, Paola
AU  - Mozzoni P
FAU - Cavazzoni, Andrea
AU  - Cavazzoni A
FAU - Bonelli, Mara
AU  - Bonelli M
FAU - Fumarola, Claudia
AU  - Fumarola C
FAU - La Monica, Silvia
AU  - La Monica S
FAU - Galvani, Elena
AU  - Galvani E
FAU - De Palma, Giuseppe
AU  - De Palma G
FAU - Mutti, Antonio
AU  - Mutti A
FAU - Mor, Marco
AU  - Mor M
FAU - Tiseo, Marcello
AU  - Tiseo M
FAU - Mari, Ettore
AU  - Mari E
FAU - Ardizzoni, Andrea
AU  - Ardizzoni A
FAU - Petronini, Pier Giorgio
AU  - Petronini PG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111123
PL  - England
TA  - Mol Cancer
JT  - Molecular cancer
JID - 101147698
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP1A1/*metabolism
MH  - Drug Resistance, Neoplasm
MH  - ErbB Receptors/*antagonists & inhibitors/genetics/metabolism
MH  - Gefitinib
MH  - Humans
MH  - Lung Neoplasms
MH  - Mutation
MH  - Phosphorylation
MH  - Quinazolines/*pharmacology
PMC - PMC3281800
EDAT- 2011/11/25 06:00
MHDA- 2013/02/09 06:00
PMCR- 2011/11/23
CRDT- 2011/11/25 06:00
PHST- 2011/09/01 00:00 [received]
PHST- 2011/11/23 00:00 [accepted]
PHST- 2011/11/25 06:00 [entrez]
PHST- 2011/11/25 06:00 [pubmed]
PHST- 2013/02/09 06:00 [medline]
PHST- 2011/11/23 00:00 [pmc-release]
AID - 1476-4598-10-143 [pii]
AID - 10.1186/1476-4598-10-143 [doi]
PST - epublish
SO  - Mol Cancer. 2011 Nov 23;10:143. doi: 10.1186/1476-4598-10-143.